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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.
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PMID:Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases. 1525 38

About 1,000 children develop end-stage renal disease (ESRD) each year in the United States and about 5,000 children are currently receiving dialysis. Children who develop ESRD are eligible to receive renal replacement therapy, including renal transplantation. There are inherent risks associated with transplantation, including renal insufficiency, infections, post-transplant lymphoproliferative disorder, and cardiovascular disease (CVD). Potential risk factors for CVD in pediatric renal transplant recipients include renal insufficiency, hyperlipidemia, hyperhomocysteinemia, inflammation, malnutrition, anemia, and hyperglycemia/insulin resistance. Despite evidence that many children may possess various risk factors for CVD post-renal transplantation, there are very few studies that have attempted to assess the link between these risk factors and CVD in pediatric renal transplant recipients.
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PMID:Risk factors for cardiovascular disease in pediatric renal transplant recipients. 1526 67

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetically transmitted cerebrovascular disease. Typically, the first clinical manifestation is migraine and the full clinical spectrum of the disease with recurrent strokes of the subcortical type, cognitive, and mood disorders is seen during the fourth and fifth decades of life. Vascular risk factors are usually absent in CADASIL patients and the diagnosis of the disease is particularly suspected in young adults with cerebrovascular events of unknown cause, diffuse leukoencephalopathy on computed tomography or magnetic resonance imaging, and a history of cerebrovascular diseases or dementia in many family members. We describe three Italian CADASIL patients who presented to medical attention for cerebrovascular events occurred after the age of 55 and had, in addition to hypertension and hyperlipidemia, thrombophilic risk factors such as hyperhomocysteinemia, elevated levels of lipoprotein(a), and antiphospholipid antibodies. Symptoms possibly related to cortical involvement, such as dysphasia and visual field deficits, were reported by two of these patients. We conclude that a diagnosis of CADASIL should not be disregarded in patients with vascular risk factors and presenting with symptoms not immediately referable to subcortical damage at ages more advanced than commonly reported.
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PMID:Thrombophilic risk factors and unusual clinical features in three Italian CADASIL patients. 1552 1

Significant progress in the field of VaD resulted from publication of the NINIDS-AIREN Diagnostic Criteria for VaD (G.C. Roman, T.K. Tatemichi, T. Erkinjuntti, et al., Vascular dementia (VaD): diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43 (1993) 250-260). Epidemiological studies confirmed the importance of VaD as the second most common cause of dementia in the elderly, representing 15-20% of all cases of dementia. In Europe and North America, Alzheimer's disease (AD) predominates over VaD in a 2:1 ratio; in contrast, in Japan and China VaD accounts for almost 50% of all dementias. Case-control studies have identified risk factors for VaD including ageing, hypertension, diabetes mellitus, hyperlipidemia, recurrent stroke, cardiac disease, smoking, sleep apnea, and more recently, hyperhomocysteinemia, among others. Hypertension treatment may prevent VaD and AD. This finding has enormous importance from the Public Health viewpoint to decrease the future number of patients with dementia in the elderly. Along with advances in the field of VaD came a number of controversies and damaging misconceptions and myths. Myth no. 1--Vascular dementia is a non-entity: The false idea that VaD does not exist is particularly destructive because it creates the perspective that VaD is unworthy of study or research. A condition that either does not exist or represents only a minute proportion of all cases of dementia in the elderly, lacks public health relevance and becomes a low priority for research by funding agencies and industry. In fact, vascular brain lesions are the commonest and most important component of dementia in the elderly. Myth no. 2--Vascular dementia is so difficult to diagnose that only experts can recognize and identify it accurately: VaD does exist and the diagnosis of post-stroke VaD, in particular is straightforward. Most cases fulfill NINDS-AIREN criteria for probable VaD; i.e., (1) there is acute onset of dementia demonstrated by impairment of memory and two other cognitive domains, such as orientation, praxis or executive dysfunction; (2) relevant cerebrovascular lesions are demonstrated by neuroimaging; and (3) a temporal relation between stroke and cognitive loss is evident. In the donepezil trials on VaD, post-stroke dementia represented about 75% of the >1,200 patients enrolled. Myth no. 3--Improvement in clinical trials of cholinergics in VaD is due to underlying AD, not to the vascular lesions. Experimental, clinical and pathological evidence has demonstrated cholinesterase deficits in VaD (independently of any concomitant AD pathology), including low acetylcholine in cerebrospinal fluid, and reduced choline acetyltransferase (ChAT) in the brain.
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PMID:Facts, myths, and controversies in vascular dementia. 1553 19

Cardiovascular disease is the leading cause of morbidity and mortality following renal transplantation. Because many renal transplant recipients die with functioning grafts, deaths resulting from cardiovascular disease have became an increasingly important cause of graft loss, particularly after the first post-transplantation year. Moreover, a contribution of some cardiovascular risk factors to renal allograft dysfunction has been demonstrated. A number of observational studies suggest that cardiovascular disease is more common in renal transplant patients than in the general population. The excessive risk for cardiovascular disease is related to a high prevalence and accumulation of atherogenic risk factors before and after transplantation. Hypertension, post-transplantation diabetes and hyperlipidemia are well-recognized risk factors for the development of cardiovascular events after renal transplantation and are strongly associated with immunosuppressive therapy. Progressive renal dysfunction may also influence the risk of cardiovascular complications after renal transplantation. The elevated risk may also be caused by non- traditional risk factors such as anaemia, adhesion molecules, hyperhomocysteinemia, microinflammatory state, abnormal coagulation and oxidative stress. To prevent post-transplantation cardiovascular disease it is crucial to define the etiological risk factors. Some risk factors can be modified, and for some of these, there is strong evidence from studies in the general population that intervention improves survival. Given the significant morbidity and mortality of cardiovascular disease in renal transplant recipients, aggressive treatment intervention for potentially modifiable factors are strongly advocated after transplantation. In addition to treatment intervention, risk management should also involve tailoring the immunosuppressive regimen to minimize both direct and indirect cardiovascular risks. In this article we attempted to review and quantify the post-transplant risk factors for cardiovascular disease as well as offer suggestions on optimizing the therapy or treatment strategies to minimize the risk of cardiovascular complications in renal transplant patients. Reduction of cardiovascular morbidity and mortality can improve not only the life expectancy and quality of life of the transplant recipients but also their graft function and survival.
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PMID:[Cardiovascular disease after renal transplantation]. 1573 47

Atherosclerosis, and its most common manifestation, coronary artery disease (CAD), are rather common causes of morbidity and mortality worldwide. Recognition of its various risk factors is important to planning effective preventive measures. After the homocysteine theory was presented in 1969, attention has been directed toward the serum homocysteine level as a coronary artery disease risk factor. The authors aimed to assess the relationship between hyperhomocysteinemia and CAD in an Iranian population. In a case control study, 197 individuals (male: 123 [62.4%]) who were scheduled for coronary angiography were selected. Venous samples were taken from the patients in fasting state before angiography. Data about age, sex, risk factors (eg, hypertension, diabetes, smoking, hyperlipidemia, obesity) were obtained from prepared questionnaires. Homocysteine levels in patients were measured by ELISA method. A homocysteine level above 15 mumol/liter was considered high. Angiography reports and homocysteine levels were analyzed by independent sample t test, one-way ANOVA, multiple linear regression, and stratified analysis. In comparison with the patients with normal angiography reports (32.5%), patients with abnormal angiography reports (67.5%) had increased levels of homocysteine (p = 0.001). About 28.1% of patients with normal angiography reports had hyperhomocysteinemia. After further evaluation, linear correlations were detected between the numbers of involved vessels and homocysteine level (p = 0.000). Multiple linear regression analysis of data detected that in individuals without any risk factors, the relationship was stronger and more meaningful (p = 0.000). These data show that hyperhomocysteinemia is related to CAD as an independent risk factor. In individuals without any risk factors a linear correlation between homocysteine level and numbers of coronary artery involvement was present. If this equation is confirmed prospectively in other studies, the level of plasma homocysteine may he used as a noninvasive way of predicting the number of diseased coronary arteries.
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PMID:Homocysteine level and coronary artery disease. 1644 51

Nephropathy is one of the frequent sequelae of hypertension. Arterial hypertension causes both arterial and capillary changes in the kidneys as well as development of interstitial fibrosis. Systemic or intraglomerular pressure increase leads to albuminuria and proteinuria, which in turn contributes to further damage of the kidneys. Impairment of the kidneys due to hypertension can ultimately result in terminal renal insufficiency necessitating dialysis. Metabolic factors such as hyperlipidemia, hyperuricemia, hyperhomocysteinemia, and insulin resistance can aggravate renal lesions. Effective lowering of blood pressure in conjunction with management of the metabolic risk factors is decisive for prevention of chronic kidney disease, which in turn must be considered a factor involved in exacerbation of the hypertension.
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PMID:[Sequelae of hypertenson: kidney disease]. 1647 Mar 57

Asymmetric dimethylarginine (ADMA) is synthesized during the methylation of protein arginine residues by protein arginine methyltransferases (PRMT) and is released during proteolysis. ADMA is a competitive inhibitor of nitric oxide synthase and may decrease NO availability. ADMA is eliminated by renal excretion or is metabolized by dimethylarginine dimethylaminohydrolase (DDAH) to citruline and dimethylamine. Two other endogenous methylarginines are also synthesized by PRMT: N-monomethyl-L-arginine (L-NMMA) and symmetric dimethylarginine (SDMA). L-NMMA inhibits NO synthase but its concentrations in circulation are much lower than ADMA whereas SDMA is inactive. Plasma concentration of ADMA is markedly increased in patients with chronic renal failure and moderately increased in patients with many other diseases including hyperlipidemia, diabetes mellitus, arterial hypertension, hyperhomocysteinemia and heart failure. The increased concentration of ADMA is positively correlated with markers of atherosclerosis, such as carotid artery intima-media thickness and has a predictive value for acute cardiovascular events in prospective studies. Angiotensin-converting enzyme inhibitors, angiotensin AT1 receptor antagonists, vitamin E and, according to some studies, estrogens used in hormonal replacement therapy reduce plasma ADMA concentration, which may contribute to their beneficial effect on NO synthesis and endothelial function. However, in some states associated with excess of NO, such as septic shock or excitotoxic neuronal injury ADMA may be protective by limiting toxic effect of high concentrations of NO. This article reviews the effect of pharmacotherapy on ADMA metabolism and its possible clinical implications.
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PMID:Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy. 1670 18

Prevalence of hyperhomocysteinemia (HHC) in a sample of male population (n=84, age 50-64 year) of Novosibirsk assessed in the framework of the international project "Determinants of cardio-vascular diseases in the Eastern Europe: multicentral cohort research" during winter-spring period of vitamin deficiency was 50%. In 90.5% of cases HHC was moderate (15-30 micromol/l) and in 9.5% of cases -- medium (30-100 micromol/l). No correlations or independent associations were found between homocysteine blood level and CHD, as well as main risk factors (hyperlipidemia, hypertension, smoking and excessive body weight). No cases of CHD were registered among men with medium HHC. Homocysteinemia correlated positively with age, history of stroke, and negatively -- with alpha-tocopherol concentration in LDL. Men with medium HHC compared with those with normohomocysteinemia had higher systolic and diastolic blood pressure and 29% lower alpha-tocopherol concentration in LDL.
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PMID:[Hyperhomocysteinemia in men of Novosibirsk]. 1671 Jan 98

The authors studied prevalence of atherosclerosis, serum levels of lipids and homocysteine in coal miners suffering from pulmonary dust diseases. More marked hyperlipidemia and hyperhomocysteinemia are associated with combination of atherosclerosis and pulmonary dust diseases. Respiratory failure as a complication of pulmonary dust diseases promotes hyperlipidemia.
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PMID:[Serum biochemistry data in association of atherosclerosis with pulmonary dust diseases]. 1689 44


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