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Lipoprotein (a), homocysteine, and hypercoagulable states in young men with premature peripheral atherosclerosis: A prospective, controlled analysis

Valentine R.J.; Kaplan H.S.; Green R.; Jacobsen D.W.; Myers S.I.; Clagett G.P.; Taylor Jr. L.M.; Deiparine M.K.; Brantigan C.O. Department of Surgery, Univerity of Texas SW Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235 USA Journal of Vascular Surgery (USA) , 1996, 23/1 (53-63)

Purpose: Elevated lipoprotein (a) (Lp(a)) lipoprotein, total homocysteine, and hypercoagulable states (HCS) have all been implicated as risk factors for premature-onset atherosclerosis. This study was performed to determine the prevalence of these abnormalities in young men with chronic lower extremity ischemia (peripheral vascular disease (PVD)) and to determine their relative strengths as risk factors for premature peripheral atherosclerosis. Methods: We analyzed 50 young white men (age 45 years or younger at onset of symptoms) and compared them with 45 age-matched white male control subjects. Results: Atherosclerotic risk factors were similar in both groups. The mean (plus or minus SEM) Lp(a) lipoprotein level was 36 plus or minus 6 mg/dl among the study patients, compared with 14 plus or minus 2 mg/dl among control subjects (p = 0.02, Mann-Whitney). Twenty (40%) study patients and seven (16%) control subjects had Lp(a) lipoprotein levels of 30 mg/dl or greater (atherosclerotic risk threshold) (p = 0.01, odds ratio = 3.62, confidence interval (CI) 1.4 to 9.5). Positive HCS panels (antiphospholipid antibodies or deficiencies in antithrombin III, protein C, or protein S) were nearly twice as prevalent in study patients (n = 15, 30%) as in controls (n = 8, 18%), but this difference did not achieve statistical significance. The mean total plasma homocysteine level among the study patients was 15.9 plus or minus 0.9 micromol/L, which was not significantly different from the mean control value of 14.7 plus or minus 0.7 micromol/L. Lp(a) lipoprotein was related to risk of premature PVD through a linear logistic relationship (p = 0.003, odds ratio per each 1 mg/dl Lp(a) change was 1.03, CI 1.0 to 1.1). Multivariate analysis with stepwise logistic regression selected two variables: Lp(a) lipoprotein greater than or equal to30 mg/dl (p = 0.01, odds ratio = 3.6, CI 1.3 to 9.9) and family history (p = 0.07, odds ratio = 2.2, CI 0.9 to 5.3). Tests of interaction demonstrated no effect between Lp(a) lipoprotein, HCS, and homocysteine. Conclusions: Lp(a) lipoprotein of 30 mg/dl or greater is an independent risk factor for premature peripheral atherosclerosis in men. None of the other examined variables exhibited a significant association with premature PVD.



Plasma homocysteine and severity of atherosclerosis in young patients with lower-limb atherosclerotic disease

Van den Berg M.; Stehouwer C.D.A.; Bierdrager E.; Rauwerda J.A. Department of Vascular Surgery, Inst. for Cardiovascular Research, Free University Hospital, PO Box 7057, 1007 MB Amsterdam Netherlands Arteriosclerosis, Thrombosis, and Vascular Biology (USA) , 1996, 16/1 (165-171)

Elevated plasma homocysteine levels are recognized as an independent risk factor for atherosclerotic disease. It is not known (1) whether the severity of atherosclerotic disease is related to hyperhomocyst(e)inemia or (2) whether any such relation differs between fasting and post-methionine loading plasma homocysteine levels. Therefore, in 171 consecutive patients, under 55 years of age with first symptoms of lower-limb disease, we examined the relation between severity of atherosclerosis and plasma homocysteine concentration. Severity of atherosclerotic disease was estimated from the prevalence of coronary artery disease and cerebrovascular disease and from the angiographic extent of lower-limb disease. Plasma homocysteine was measured after a period of fasting and in response to methionine loading (0.1 g/kg). In multivariate analysis, the prevalence of coronary artery disease plus cerebrovascular disease was related to both fasting and post methionine homocysteine levels (odds ratio (OR) for the upper quartile versus the lower three quartiles, 2.8, 95% confidence interval (CI), 1.1 to 7.5; and OR 3.0, 95% CI, 1.1 to 7.8, respectively). The extent of lower-limb disease was weakly related to the fasting homocysteine level (partial correlation coefficient, .12; P=.17) and more strongly related to the postmethionine homocysteine level (partial correlation coefficient, .25; P=.003). These relations tended to be more pronounced in women than in men. They were independent of age, total serum cholesterol, blood pressure, and smoking habit. We concluded that the severity of atherosclerotic disease in young patients with lower-limb atherosclerotic disease is associated with high postmethionine and fasting homocysteine concentrations.



High dose B-vitamin treatment of hyperhomocysteinemia in dialysis patients

Bostom A.G.; Shemin D.; Lapane K.L.; Hume A.L.; Yoburn D.; Nadeau M.R.; Bendich A.; Selhub J.; Rosenberg I.H. Vitamin Bioavailability Laboratory, USDA Hum. Nutrition Res. Cter. Aging, New England Medical Center, 711 Washington Street, Boston, MA 02111 USA Kidney International (USA) , 1996, 49/1 (147-152)

Hyperhomocysteinemia, an arteriosclerotic risk factor, persists in 75% of dialysis patients despite routine low dose supplementation with the B-vitamin co-factors/substrates for homocysteine (Hcy) metabolism, and normal or supernormal plasma status of these vitamins (Atherosclerosis 114:93, 1995). We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid (15 mg/day), B-6 (100 mg/day), and B-12 (1 mg/day) to the usual daily dosing of 1 mg folic acid, 10 mg B-6, and 12 microg B-12, in 27 hyperhomocysteinemic dialysis patients. Total plasma homocysteine was measured at baseline, and after four and eight weeks. Blinded analyses revealed no evidence of toxicity in the group randomized to supraphysiologic dose B-vitamin supplementation. Plasma homocysteine was significantly reduced after both four weeks (-29.8% vs. -2.0%; P = 0.0024) and eight weeks (-25.8% vs. +0.6%; P = 0.0009) of active versus placebo treatment. Also, 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hey reduced to within the normative range (< 15 micromol/liter). Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients.



The influence of methionine and its metabolites on the progression of atherosclerosis in rabbits

Koyama J. Second Dept. of Internal Medicine, Nippon Medical School First Hospital, 3-5-5 Iidabashi, Chiyoda-ku, Tokyo 102 Japan Journal of Nippon Medical School (Japan) , 1995, 62/6 (596-604)

The effects of a high level of methionine on the changes of lipid and amino acid metabolism were investigated. Eighteen New Zealand White rabbits were divided into three groups; a methionine group, which was fed a diet supplemented with 3% D,L-methionine, a Cholesterol + Methionine group, which was fed a 3% D,L-methionine and a 0.2% cholesterol diet, and a Cholesterol group which was fed a 0.2% cholesterol diet for 22 weeks. The plasma triglyceride, cholesterol, homocysteine, cysteine and serum SO42- levels were measured and compared. On the first and the final day of the experiment, lipid peroxide levels in blood samples were also measured. We found that the Methionine group and the Cholesterol + Methionine group showed elevated levels of plasma triglyceride, cholesterol, homocysteine, cysteine, serum SO42- and lipid peroxide compared with the Cholesterol group. More prominent fat deposits in the aorta were observed in the Methionine group and the Cholesterol + Methionine group than in the Cholesterol group. Our results indicated that the interaction of cholesterol with methionine or its derivative plays a role in the progression of atherosclerosis.



Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure

Chauveau P.; Chadefaux B.; Coude M.; Aupetit J.; Kamoun P.; Jungers P. Departement de Nephrologie, Hopital Necker, 161, rue de Sevres, F-75743 Paris Cedex 15 France Mineral and Electrolyte Metabolism (Switzerland) , 1996, 22/1-3 (106-109)

Moderate hyperhomocysteinemia, a risk factor for premature atherosclerosis, is present in chronic uremic patients. We prospectively evaluated the effects of sequential supplementation with pyridoxine (70 mg/day) and folic acid (10 mg/day) for two 3-month periods in 37 nondialyzed patients (29 males) with creatinine clearance (C(Cr)) ranging from 10 to 80 ml/min, whose plasma vitamin B12 and folate level was in the normal range. Mean (plus or minus SD) baseline plasma total homocysteine (Hcy) was 14.9 plus or minus 5.2, 16.5 plus or minus 5.1 and 26.1 plus or minus 12.1 micromol/l (upper limit in 45 healthy controls 14.1 micromol/l) in patients with C(Cr) 40-80, 20-40 and < 20 ml/min, respectively. Following pyridoxine Hcy did not significantly decrease whereas following folic acid Hcy decreased significantly to 9.9 plus or minus 2.9 (-33% vs. baseline), 10.3 plus or minus 3.4 (-37%) and 15.4 plus or minus 5.5 (-40%), respectively (Student's paired t test, p < 0.001) in the 3 groups. We conclude that folate (but not pyridoxine) pharmacologic supplementation is effective in lowering elevated plasma Hcy in chronic renal failure patients, thus suggesting that enhancing the Hcy remethylation pathway may overcome hyperhomocysteinemia in such patients. In view of the potential atherogenic effects of hyperhomocysteinemia, long-term folate supplementation should be considered in uremic patients.



Lipoproteins and homocyst(e)ine as risk factors for atherosclerosis: Assessment and treatment

Frohlich J.J. St Paul's Hospital, Lipid Clinic, 1081 Burrard Street, Vancouver, BC V6Z 1Y6 Canada Canadian Journal of Cardiology (Canada) , 1995, 11/SUPPL. C (18C-23C)

Two new important independent risk factors for coronary artery disease (CAD) have been identified: lipoprotein (a) (Lp(a)) and homocyst(e)ine. Both are associated with increased frequency of cardiovascular events, both coronary and peripheral. Measurement of these two factors should he considered in patients with symptomatic CAD, stroke, a strong family history (but low other conventional risk factors); in first degree relatives of those with very high Lp(a) or homocyst(e)ine levels; and in other individuals in whom the need for an aggressive treatment of metabolic risk factors is indicated. While treatment of high serum Lp(a) with drugs is difficult it appears from the epidemological or clinical evidence that the additional risk due to Lp(a) can be drastically lowered by decreasing the patient's low density lipoprotein (LDL) cholesterol levels to below 3 mmol/L. The treatment of increased homocyst(e)ine can be easily accomplished by vitamin B6 or folic acid administration. Various analyses describing the value of positive tests for diagnosis of atherosclerosis indicate that overall risk evaluated by computer models from Framingham data, use of total: high density lipoprotein (HDL) cholesterol ratio and/or the National Cholesterol Education Program (NCEP) II guidelines are the best predictors of future cardiovascular events. The stategic aim for treatment regimens should be threefold: lower serum LDL cholesterol levels; decrease serum triglycerides (and triglyceride-rich lipoproteins); and increase HDL cholesterol. Niacin and statin drugs are the most cost effective means to achieve the former and niacin and fibrates to achieve the latter goal. Where target LDL cholesterol levels can be achieved with less expensive statin preparations their use may be economically advantageous.



New aspects in lipidology and atherosclerosis

Superko H.R. Lipid Institute, Sequoia Hospital, 170 Alameda de las Pulgas, Redwood City, CA 94062-2799 USA Canadian Journal of Cardiology (Canada) , 1995, 11/SUPPL. C (4C-8C)

Recent-advances in lipidology and metabolic aspects of atherosclerosis allow detailed coronary artery disease (CAD) risk assessment that is of clinical relevance. Genetic dyslipidemias can be identified in over 75% of CAD patients and include the atherosclerosis susceptibility trait (low density lipoprotein (LDL) pattern B), hyperapobetalipoproteinemia, lipoprotein (a), apo E isoforms, and lipoprotein susceptibility to oxidative damage. The inherited amino acid disorder homocysteinemia is present in approximately 20% of CAD patients and is easily treated. Recent studies have highlighted significant differences in response to diet and drug therapy that can be predicted based on the presence or absence of these traits.



Metabolism of homocysteine, its relation to the other cellular thiols and its mechanism of cell damage in a cell culture line (human histiocytic cell line U-937)

Hultberg B.; Andersson A.; Isaksson A. Department of Clinical Chemistry, University Hospital, Lund S-221 85 Sweden Biochimica et Biophysica Acta - Molecular Cell Research (Netherlands) , 1995, 1269/1 (6-12)

This study shows that the intracellular concentration of homocysteine in cultured cells is kept low due to an accumulation in the medium. The intracellular level of homocysteine was decreased when its precursor, methionine, was omitted from the culture medium. Intracellular glutathione and cysteine were lowered in cystine-deficient medium. Intracellular glutathione was also lowered when copper ions were added to the culture medium. It is evident from this study that the intracellular concentration of homocysteine was not influenced by the lowered level of glutathione and/or cysteine. High amounts of homocysteine added to the medium give rise to an increase of intracellular reduced homocysteine, which participates in the transsulfuration pathway and can replace cysteine in the synthesis of gluthathione. The addition of relatively high amounts of reduced homocysteine (500 micromol/l) in the presence of copper ions (100 micromol/l) to the culture medium can be directly toxic to the cells, possibly due to oxygen radicals formed by thiol auto-oxidation. Whilst the level of homocysteine in this study using short-time cell culture experiment is much higher than the mild hyperhomocysteinemia thought to be atherogenic in humans, it is conceivable that over a longer time course these levels of homocysteine could be sufficient to induce endothelial dysfunction, eventually leading to atherosclerosis.



Prevention of myocardial infarction by vitamin B6

Ellis J.M.; McCully K.S. Titus County Memorial Hospital, Mt. Pleasant, TX 75455 USA Research Communications in Molecular Pathology and Pharmacology (USA) , 1995, 89/2 (208-220)

Vitamin B6 is effective in the treatment of carpal tunnel syndrome and related disorders in patients with vitamin B6 deficiency. Hyperhomocysteinemia, a risk factor for atherosclerosis, is associated with deficiencies of vitamin B6, folate, and cobalamin. Patients who were given vitamin B for carpal tunnel syndrome and other degenerative diseases were found to have 27% of the risk of developing acute cardiac chest pain or myocardial infarction, compared with patients who had not taken vitamin B6. Among elderly patients of the author (JE) expiring at home, the average age at death from myocardial infarction was 8 years later in those who had taken vitamin B6, compared with those who had not taken vitamin B6. The preventive effect of vitamin B6 on progression of coronary heart disease may be related to increased formation of pyridoxal phosphate, the coenzyme that is required for catabolism of the atherogenic amino acid, homocysteine.



Vitamin B6: The overlooked key to preventing heart attacks

Hattersley J.G. 7031 Glen Terra Court, S.E., Olympia, WA 98503-7119 USA Journal of Applied Nutrition (USA) , 1995, 47/1-2 (24-31)

Vitamin B6 (pyridoxine) opens the door to eliminating the 20th century's epidemic of heart attacks, cardiac arrests and strokes. Although shunned by the researchers who receive the bulk of heart disease research funding, it is creating excitement among a growing number of investigators. In this article relevant bits of B6's history are presented to show how it can prevent heart attacks with almost no side effects from moderate amounts. This article will also integrate the effects of vitamin B6 deficiency with Mathias Rath and Linus Pauling's theory (blaming heart attacks on deficient vitamin C and excess Lp(a) and Bruce Lipton's histamine theory into a general theory of atherogenesis.



New approaches to the prevention of atherosclerosis

Naito M.; Hayashi T.; Iguchi A. Department of Geriatrics, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466 Japan Drugs (New Zealand) , 1995, 50/3 (440-453)

In recent years, remarkable progress has been made in the prevention and treatment of atherosclerosis. However, much of the research has been devoted to the investigation of lipid metabolism and lipid-lowering drugs. This review highlights some recent topics in both experimental and clinical investigations, with emphasis on studies other than those on lipid-lowering drugs. These topics include oxidative modification of lipoproteins, hyperfibrinogenaemia, hyperhomocysteinaemia, female sex hormones and endothelium-derived relaxing factor (or nitric oxide). Some of these approaches have already been applied in the clinic.



Role of folate in the modulation of lipids, lipoproteins and eicosanoids in hypertension and diabetes

Katki K.A.; Viswanathan G.; Noronha J.M. Radiation Biol./Biochemistry Div., Bhabha Atomic Research Center, Bombay 400 085 India Pteridines (Germany) , 1995, 6/2 (63-68)

Besides elevated levels of lipids and lipoproteins, levels of the physiological amino acid homocysteine as well as whole blood folates are now known to play a role in atherogenesis. The role of folates in atherosclerosis is rather peculiar in that it helps to catalyse the remethylation of homocysteine (a proatherogenic agent) to methionine thus preventing the accumulation of homocysteine in plasma and hence its antiatherogenic role. We estimated whole blood folate levels of 69 normotensive, 34 diabetic and 94 hypertensive individuals and have attempted to correlate these values with lipid and non-lipid parameters. Whole blood levels of simple, conjugated and total folates were significantly higher among the diabetics as well as the hypertensives when compared to the normotensives. In all the study groups, levels of conjugated folates correlated significantly to those of total folates even after adjustments for age and body mass index were introduced. Among the normotensive individuals the significance of the inverse correlation between simple folates and total cholesterol/high density lipoprotein cholesterol ratio was lost after adjusting for age and body mass index. Levels of total and conjugated folates were positively correlated to plasma levels of thromboxane B2 among the diabetics. In the same group the positive correlation between total folates and thromboxane B2 and that between total folates and the eicosanoid ratio remained significant even after adjustments for age and body mass index were introduced. None of the other metabolic variables correlated with whole blood levels of simple folates in any of the study groups.



Hyperhomocysteinemia: An independent risk factor for atherosclerotic vascular disease

Kardaras F.; Kardara D.F. 1st Department of Cardiology, Evangelismos Hospital, Athens Greece Hellenic Journal of Cardiology (Greece) , 1995, 36/3 (275-279)

Homocysteine (HCY) is a thiol-containing amino acid, toxic to the vascular endothelium, that results from the demethylation of methionine. Elevated levels of HCY are associated with an increased risk of atherosclerosis and thrombosis. High plasma HCY levels are found in homocystinuria. This genetic condition is due to metabolic defects involved in the enzymatic control of HCY metabolism. Moderate hyperhomocysteinemia is also found in 20-30% of patients with coronary and peripheral vascular disease. There are probably multiple mechanisms involved in the pathogenesis of hyperhomocysteinemia in these patients, including heterozygosity for metabolic defects involved in the enzymatic control of HCY, as well as dietary factors. Subjects to be looked into are as follows: What is the exact relationship between hyperhomocysteinemia and vascular disease? Is this relation independent of other risk factors? Can the treatment of hyperhomocysteinemia slow down the process of atherosclerosis?



Hyperhomocysteinemia and the risk for vascular disease in hemodialysis patients

Bachmann J.; Tepel M.; Raidt H.; Riezler R.; Graefe U.; Langer K.; Zidek W. Medizinische Poliklinik, Albert Schweitzer Strasse 33, 48129 Munster Germany Journal of the American Society of Nephrology (USA) , 1995, 6/1 (121-125)

The objective of this study was to examine if hyperhomocysteinemia is associated with occlusive vascular disease in hemodialysis patients. The study design included risk factor analysis and determination of serum homocysteine in hemodialysis patients. Fifty chronic uremic patients on regular hemodialysis treatment were studied. Twenty-four patients had coronary, cerebral, or peripheral signs of occlusive vascular disease. Cerebral vascular disease was diagnosed by computed tomography, arterial angiography, or Doppler sonography of the carotid and vertebral arteries. Coronary vascular disease was diagnosed by documented history of myocardial infarction or by coronary angiography. The diagnosis of peripheral vascular disease was established by angiography of the lower limb arteries. In all control patients, Doppler sonography of the carotid, vertebral, and lower limb arteries and thallium-201 exercise imaging were without pathologic results. Measurements included blood pressure, body mass Index, smoking behavior, serum homocysteine (measured by gas chromatography/mass spectrometry), serum total, low-density lipoprotein, and high-density lipoprotein cholesterol, lipoprotein (a), triglycerides, and plasma fibrinogen. In a stepwise multiple logistic regression analysis, high serum homocysteine was significantly associated with occlusive arterial disease (R = 0.23; P = 0.031). Furthermore, hypertension (R = 0.18; P = 0.058), but not serum total, low-density lipoprotein, and high-density lipoprotein cholesterol, lipoprotein (a), triglycerides, diabetes mellitus, body mass index, plasma fibrinogen, and smoking behavior, was significantly associated with atherosclerosis. Our results support the hypothesis that hyperhomocysteinemia is an independent risk factor for vascular disease in hemodialysis patients.



New aspects of risk factors for the development of atherosclerosis, including small low-density lipoprotein, homocyst(e)ine, and lipoprotein(a)

Superko H.R. Sequoia Hospital, Lipid Institute, 170 Alameda de las Pulgas, Redwood City, CA 94062 USA Current Opinion in Cardiology (United Kingdom) , 1995, 10/4 (347-354)

The risk factors for coronary artery disease have been expanded in recent years to include several clinically significant metabolic disorders. The-small, dense low-density lipoprotein trait is one of the most common inherited coronary artery disease risk factors and recent reports describe the clinical use of low-density lipoprotein phenotyping for coronary artery disease risk determination, and for treatment in patients with established disease. Apolipoprotein E isoforms play a role in diet responsiveness and may explain approximately 12% of cases of myocardial infarction. Hypoalphalipoproteinemia appears to be a spectrum of overlapping disorders and is difficult to treat. Low-density lipoprotein oxidation may be affected by dietary sources of oxidized fat, and a recent antioxidation trial reported negative results. In the past year, homocyst(e)inemia was reported to play a significant role in coronary artery disease risk prediction and lipoprotein(a) phenotypes appear to clarify the risk of lipoprotein(a).



Homocysteine and vascular disease

Berwanger C.S.; Jeremy J.Y.; Stansby G. Academic Surgical Unit, QEQM, St Mary's Hospital Medical School, Praed Street, London W2 1NY United Kingdom British Journal of Surgery (United Kingdom) , 1995, 82/6 (726-731)

There is increasing evidence that a raised blood level of homocysteine (HC) is a risk factor for premature atherosclerosis. With a gene frequency between one in 70 and one in 200 this condition may be more common than previously thought. It should be suspected especially in young patients in whom other risk factors are absent. The diagnosis may be made by demonstrating raised plasma HC levels, either basally or after methionine loading. Studies have shown significantly increased levels of HC inpatients with premature coronary artery, peripheral vascular and cerebrovascular disease. The mechanisms by which HC produces vascular damage are, as yet, not completely understood but endothelial injury is probably a central factor. The principle of treatment is to lower HC levels in the blood by administration of vitamin B6, vitamin B12, folate or betaine. How effective this strategy will be in preventing complications is not yet known.



Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: Initial results from the NHLBI family heart study

Bostom A.G.; Jacques P.F.; Nadeau M.R.; Williams R.R.; Ellison R.C.; Selhub J. The NHLBI Family Heart Study, 5 Thurber Street, Framingham, MA 01701 USA Atherosclerosis (Ireland) , 1995, 116/1 (147-151)

Hyperhomocysteinemia, either fasting or after oral methionine loading, appears to be an independent risk factor for coronary heart disease (CHD). It remains unclear whether fasting total homocysteine determination alone adequately detects the full spectrum of hyperhomocysteinemic individuals. We measured fasting and 4-h post methionine loading (0.1 g L-methionine/kg body weight) total plasma homocysteine in 274 participants in The NHLBI Family Heart Study, a population-based investigation of genetic and non-genetic determinants of CHD. Of the total number (n = 47) of hyperhomocysteinemic persons, 43% (20/47) were identified only by methionine loading, while 32% (15/47) of the total number, and 75% of those with post-methionine loading hyperhomocysteinemia only (15/20), had fasting total homocysteine concentrations below the 75th percentile (10.7 micromol/l). We conclude that fasting total plasma homocysteine determination alone fails to identify a sizable percentage (> 40%) of persons who may have clinically relevant hyperhomocysteinemia post methionine loading.



Net uptake of plasma homocysteine by the rat kidney in vivo

Bostom A.; Brosnan J.T.; Hall B.; Nadeau M.R.; Selhub J. The Framingham Heart Study, 5 Thurber Street, Framingham, MA 01701 USA Atherosclerosis (Ireland) , 1995, 116/1 (59-62)

Hyperhomocysteinemia is a common finding in dialysis-dependent end-stage renal disease (ESRD) patients, but its etiology and refractoriness to standard homocysteine-lowering B-vitamin therapy are poorly understood. In the absence of actual in vivo data, it has been hypothesized that loss of normal renal parenchymal Uptake and metabolism of homocysteine is an important determinant of hyperhomocysteinemia in ESRD, given that urinary homacysteine excretion by healthy kidneys is trivial. We assessed net renal uptake and metabolism of homocysteine using an established rat model for measuring arteriovenous amino acid differences across the rat kidney, along with simultaneous determination of renal plasma flow, urine flow, and urinary homocysteine concentration. Substantial homocysteine uptake and metabolism by normal rat kidneys was demonstrated, and we also confirmed that urinary homocysteine excretion is minimal. These data suggest that loss of the sizable homocysteine metabolizing capacity of the intact kidneys may be an important determinant of the refractory, potentially atherothrombotic hyperhomocysteinemia frequently observed in ESRD.



Homocysteine and coronary artery disease in French Canadian subjects: Relation with vitamins B12, B6, pyridoxal phosphate, and folate

Dalery K.; Lussier-Cacan S.; Selhub J.; Davignon J.; Latour Y.; Genest J. Jr. Cardiovascular Genetics Laboratory, Clinical Research Inst. of Montreal, 110 Pine Avenue West, Montreal, Que. H2W 1R7 Canada American Journal of Cardiology (USA) , 1995, 75/16 (1107-1111)

We determined plasma levels of homocysteine in 584 healthy subjects (380 men and 204 women) from a major utility company in the province of Quebec, Canada, and in 150 subjects (123 men and 27 woman) with angiographically documented coronary artery disease (CAD) (age &lt60 years). Plasma levels of vitamins B12, B6, pyridoxal phosphate (a vitamin B6 derivative), and folate were also determined. Mean homocysteine levels were higher (p &lt0.05) in the bottom quartiles for folate, vitamin B12, and pyridoxal phosphate. A significant correlation was noted between homocysteine levels and folate and vitamin B12 levels. No significant correlation was found between plasma homocysteine levels and age, lipids and lipoprotein cholesterol, glucose, and the presence of hypertension or cigarette smoking in healthy subjects or in paints with CAD. Control men had higher homocysteine levels than control women (p &lt0.005). Men and women with CAD had higher levels of homocysteine than controls (11.7 plus or minus 5.8 vs 9.7 plus or minus 4.9 nmol/ml (p &lt0.001) and 12.0 plus or minus 6.3 vs 7.6 plus or minus 4.1 nmol/ml, p &lt0.01, respectively). Women and men with CAD had similar homocysteine levels. The proportion of patients with CAD having homocysteine levels >90th percentile of controls was 18.1% for men and 44.4% for women (both p &lt0.01). Significantly lower pyridoxal phosphate levels were seen in subjects with CAD, men and women combined (27.7 plus or minus 29.5 vs 42.1 plus or minus 38.4 ng/ml, p &lt0.005). No significant differences were observed for B12, folate, or total B6. Multivariate analysis reveals that an elevated homocysteine level is a risk factor for CAD in French Canadian men and woman and that reduced levels of pyridoxal phosphate, folate, and vitamin B12 may contribute to elevated plasma homocysteine levels. We conclude that in our subjects of French Canadian descent, plasma levels of homocysteine are influenced by levels of folate, vitamin B12, and pyridoxal phosphate. In healthy men, mean homocysteine levels are higher than in healthy women. Men and women with CAD had significantly higher homocysteine levels than controls and this elevation is independent of traditional risk factors. Prospective studies are needed to determine the role of homocysteine in CAD. The influence of treatment of elevated homocysteine levels on cardiovascular morbidity and mortality must he assessed.



Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits

Toborek M.; Kopieczna-Grzebieniak E.; Drozdz M.; Wieczorek M. Department of Nutrition/Food Science, University of Kentucky, 219 Funkhouser Building, Lexington, KY 40506-0054 USA Atherosclerosis (Ireland) , 1995, 115/2 (217-224)
Methionine is converted by the transmethylation/transsulfuration pathway to homocysteine which may exert atherogenic effects by several mechanisms, including lipid peroxidation. Therefore, the excessive dietary methionine may induce the development of atherosclerosis. To test this hypothesis, plasma and aortic thiobarbituric acid reactive substances (TBARS), as well as activities of aortic and erythrocyte superoxide dismutase (SOD), catalase and selenium-dependent glutathione peroxidase (GPX) were measured in rabbits fed a diet enriched with 0.3% methionine for 6 or 9 months. Histological examinations of aortas also were performed. Feeding rabbits a methionine-enriched diet for 6 or 9 months resulted in significant increases in plasma and aortic TEARS levels and aortic antioxidant enzyme activities. However, a decrease in plasma antioxidant activity (AOA) was observed. In erythrocytes, SOD activity increased, catalase remained normal and GPX decreased in the treated animals. Histological examination of aortas showed typical atherosclerotic changes, such as intimal thickening, deposition of cholesterol, and calcification in methionine-fed rabbits. These results confirm that high-methionine diet may induce atherosclerosis in rabbits and indicate disturbances in lipid peroxidation and antioxidant processes as possible mechanisms of its atherogenic influence.




Hyperhomocysteinaemia: A role in the accelerated atherogenesis of chronic renal failure?

Janssen M.J.F.M.; Van den Berg M.; Stehouwer C.D.A.; Boers G.H.J. Department of Internal Medicine, University Hospital, Free University, De Boelelaan 1117, 1081 HV Amsterdam Netherlands Netherlands Journal of Medicine (Netherlands) , 1995, 46/5 (244-251)

Moderate hyperhomocysteinaemia has recently been established as an independent risk factor for atherothrombotic disease. It might be caused by heterozygosity for cystathionine beta-synthase deficiency, an enzyme involved in the conversion of methionine to cysteine through the transsulphuration pathway or by inherited thermolability of the enzyme which remethylates homocysteine into methionine. In chronic renal failure (CRF) homocysteine levels are significantly elevated at a relatively early stage. The normal kidney possibly plays an important role in homocysteine catabolism, which cannot be performed in CRF. Alternatively, decreased extrarenal catabolism can contribute to the hyperhomocysteinaemia in this disease state. Treatment with folic acid, 5 mg daily, significantly lowers homocysteine levels in chronic renal patients.



Plasma homocysteine in the acute and convalescent phases after stroke

Lindgren A.; Brattstrom L.; Norrving B.; Hultberg B.; Andersson A.; Johansson B.B. Department of Neurology, University Hospital, S-221 85 Lund Sweden Stroke (USA) , 1995, 26/5 (795-800)

Background and Purpose: Stroke patients frequently manifest moderate hyperhomocysteinemia. In most published studies, plasma homocysteine was measured at least 1 month after stroke (or the interval was not reported). To determine whether plasma homocysteine concentrations change in the acute phase, we compared acute-phase values with both convalescent-phase and control values.

Methods: Plasma homocysteine concentrations were measured in the acute phase (mean, 2 days after stroke onset) in 162 first-ever stroke patients aged 50 years or more (median, 75 years) and again at a median interval of 583 days (range, 460 to 645 days) after stroke onset in a subgroup of 17 patients, with values for 60 age-matched subjects serving as controls. Twenty of the control subjects were reexamined 2 to 3 years after their initial examination.

Results:The median plasma homocysteine concentration was 13.4 micromol/L in the patient group compared with 13.8 micromol/L for control subjects (NS, Mann-Whitney U test) and increased from 11.4 micromol/L in the acute phase to 14.5 micromol/L in the convalescent phase in the subgroup of patients examined twice (P&lt.01, Wilcoxon signed rank test). In the 20 reexamined control subjects, no significant change over time in plasma homocysteine concentration was found.

Conclusions: The post-acute- phase increase in plasma homocysteine may explain why higher values were obtained for stroke patients than for control subjects in previous studies. Possible reasons for the variation in plasma homocysteine concentrations over time are (1) an acute-phase reduction secondary to a decrease in plasma albumin and (2) an increase in plasma homocysteine during the convalescent phase due to modified vitamin intake and/or lifestyle. The timing of plasma homocysteine measurements relative to stroke onset is a factor to be considered in the interpretation of results.



Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease

Van den Berg M.; Boers G.H.J.; Franken D.G.; Blom H.J.; Van Kamp G.J.; Jakobs C.; Rauwerda J.A.; Kluft C.; Stehouwer C.D.A. Department of Internal Medicine, Institute Cardiovascular Research, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam Netherlands European Journal of Clinical Investigation (United Kingdom) , 1995, 25/3 (176-181)

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (less than or equal to 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomo cysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.



Lipid peroxidation and susceptibility of low-density lipoprotein to in vitro oxidation in hyperhomocysteinaemia

Blom H.J.; Kleinveld H.A.; Boers G.H.J.; Demacker P.N.M.; Hak-Lemmers H.L.M.; Te Poele-Pothoff M.T.W.B.; Trijbels J.M.F. Department of Pediatrics, University Hospital nijmegen, PO Box 9101, 6500 HB Nijmegen Netherlands European Journal of Clinical Investigation (United Kingdom) , 1995, 25/3 (149-154)

The pathobiochemical mechanism of arteriosclerosis in hyperhomocysteinaemia has not yet been elucidated. In vitro studies have shown that the cytotoxic properties of homocysteine can be ascribed to its generation of reactive oxygen species. We studied lipid peroxidation, both in vivo and in vitro, in 10 homozygous cystathionine synthase-deficient (CSD) patients and in a control group of 10 healthy subjects of comparable age and sex. The susceptibility of low-density lipoprotein (LDL) from hyperhomocysteinaemic patients to oxidation was determined in vitro by continuously measuring the conjugated diene production induced by incubation with copper ions. Oxidation resistance (expressed as lag time), maximal oxidation rate, and extent of oxidation (expressed as total diene production) of LDL from CSD patients were not significantly different from those of LDL from controls. Furthermore, the time needed to reach maximal diene production, i.e. t(max), was similar for LDL from patients and controls. In addition, the vitamin E concentrations in LDL of CSD patients and controls were similar. The mean concentration (plus or minusSD) of plasma thiobarbituric acid reactive substances (TEARS), an indicator of in vivo lipid peroxidation, was 2.2 plus or minus 0.7 micromol L-1 in CSD patients, a lower value than that measured in the matched controls (5.0 plus or minus 2.0 micromol L-1). Investigation of in vivo and in vitro parameters of lipid peroxidation shows that the increased risk of arteriosclerosis in hyperhomocysteinaemia is unlikely to be due to increased lipid peroxidation.



Hyperhomocysteiaemia and traditional cardiovascular disease risk factors in end-stage renal disease patients-on dialysis: A case-control study

Bostom A.G.; Shemin D.; Lapane K.L.; Miller J.W.; Sutherland P.; Nadeau M.; Seyoum E.; Hartman W.; Prior R.; Wilson P.W.F.; Selhub J. The Framingham Heart Study, Epidemiology and Biometry Program, 5 Thurber Street, Framingham, MA 01701 USA Atherosclerosis (Ireland) , 1995, 114/1 (93-103)

Hyperhomocysteinemia occurs frequently in end-stage renal disease (ESRD), but its prevalence in comparison with traditional cardiovascular disease (CVD) risk factors is unknown. Fasting total plasma homocysteine, potential determinants of plasma homocysteine (i.e., plasma B-vitamins and serine), total and HDL cholesterol, glucose, and creatinine, were determined in 24 ESRD patients on dialysis, and 24 age, gender, and race matched Framingham Offspring Study controls with normal renal function. Presence of clinical CVD and CVD risk factors was established by standardized methods. Mean plasma homocysteine was markedly higher in the ESRD patients versus controls (22.7 vs. 9.5 pmol/l). ESRD patients were 33 times more likely than controls to have hyperhomocysteinemia (> 15.8 micromol/l) (95% confidence interval, 5.7-189.6). Hyperhomocysteinemia persisted in the ESRD patients despite normal to supernormal B-vitamin status. Plasma serine levels below the tenth percentile of the control distribution were found in 75% of the ESRD patients. oral serine supplementation caused a 37% increase in mean plasma serine, but had no effect on plasma homocysteine in four; ESRD patients with supernormal plasma folate, low plasma serine, and hyperhomocysteinemia. Given its unusually high prevalence, improved management of hyperhomocysteinemia might reduce CVD sequelae in ESRD.



Hyperhomocysteinaemia in heart transplant recipients

Ambrosi P.; Barlatier A.; Habib G.; Garcon D.; Kreitman B.; Roland P.H.; Saingra S.; Metras D.; Luccioni R. Service de Cardiologie B, Hopital de la Timone, Boulevard Jean Moulin, 13005 Marseille France European Heart Journal (United Kingdom) , 1994, 15/9 (1191-1195)

The aim of this study was to determine the prevalence of hyperhomocysteinaemia in cardiac transplant recipients. Three groups of subjects were studied: 27 heart transplant recipients, 14 to 63 months (mean = 36.5) after transplantation; 10 patients with moderate chronic renal insufficiency without clinical evidence of vascular disease; 17 apparently healthy individuals. Twenty-five out of 27 transplanted patients had a coronaroangiography within 6 months of homocysteine measurement. Plasma homocysteine was measured both while the subject was fasting (t0) and 6 h after administration of 0.1 g.kg-1 of methionine (t6). Hyperhomocysteinaemia was present in 14/27 fasting in transplanted patients and after methionine loading. Mean plasma levels of homocysteine at t0 were higher (P = 0.03) in transplanted heart recipients (15.4 plus or minus 7 micromol.l-1) than in the venal patients (9.9 plus or minus 5 micromol.l-1) despite similar mean plasma creatinin. In eight transplanted patients with angiographic coronary abnormalities of the cardiac graft, homocysteinaemia was at t0 17.1 plus or minus 9 micromol.l-1 and at t6 47.8 plus or minus 25 micromol.l-1. In 17 transplanted patients with angiographically normal coronary arteries, plasma homocysteine levels were at t0, 13.2 plus or minus 4 micromol.l-1 and at t6, 46.8 plus or minus 25 micromol.l-1. We conclude that hyperhomocysteinaemia is common in transplanted heart recipients, and partly related to renal insufficiency. No correlation was found between hyperhomocysteinaemia and angiographic evidence of coronary atherosclerosis of the graft, but the population of the study was possibly too small to establish this correlation.



Homocyst(e)ine and arterial occlusive diseases

Malinow M.R. Oregon Regional Primate Res. Center, St Vincent Hospital/Medical Center, Oregon Health Sciences University, Beaverton Street, Portland, OR USA Journal of Internal Medicine (United Kingdom) , 1994, 236/6 (603-617)

Homocysteine is a thiol-containing amino acid resulting from demethylation of methionine. The free and protein-bound forms of the amino acid and derived disulfides are called homocyst(e)ine (H(e)). Multiple studies have shown elevated H(e) levels in patients with coronary, cerebrovascular, or peripheral arterial diseases; this association is frequent and independent of most other risk factors for atherosclerosis. In the 1993 Frontiers in Medicine Symposium* investigators discussed the genetic, physiological, nutritional, and pharmacological mechanisms involved in the regulation of plasma H(e), the association of H(e) with arterial occlusive diseases, and the relationships of H(e) with nitric oxide and haemostasis, High plasma H(e) levels usually can be reversed with vitamin supplements. Whether vitamin supplements will affect the evolution of arterial occlusive diseases needs to be established in prospective, placebo-controlled, randomized, clinical trials.



Hyperhomocysteinemia

Blom H.J.; Boers G.H.J.; Eskes T.K.A.B.; Trijbels J.M.F. Lab. Kindergeneeskunde/Neurologie, Academisch Ziekenhuis, Postbus 9101, 6500 HB Nijmegen Netherlands Nederlands Tijschrift voor de Klinische Chemie (Netherlands) , 1995, 20/1 (20-26)

Cystathionine beta-synthase deficiency and thermolability of 5,10-methylenetetrahydrofolate reductase (MTHFR) were examined as a possible cause of mild hyperhomocysteinemia in patients with premature vascular disease. Only one out of 20 patients with mild hyperhomocysteinemia and vascular disease had cystathionine beta-synthase activity in the range of obligate heterozygotes for cystathionine beta-synthase deficiency. Five out of 21 patients with mild hyperhomocysteinemia and vascular disease had thermolabile MTHFR. In conclusion, heterozygosity for cystathionine beta-synthase deficiency is probably not a major cause for mild hyperhomocysteinemia. In about 25% of the hyperhomocysteinemic patients with premature vascular disease, abnormal homocysteine metabolism can be attributed to thermolabile MTHFR.



Plasma levels of the atherogenic amino acid homocysteine in post-menopausal women with breast cancer treated with tamoxifen

Anker G.; Lonning P.E.; Ueland P.M.; Refsum H.; Lien E.A. Division of Pharmacology, Department of Clinical Biology, University Hospital, N-5021 Bergen Norway INT. J. CANCER (USA) , 1995, 60/3 (365-368)

Long-term treatment of breast-cancer patients with the anti-oestrogen tamoxifen has been found to be associated with reduced cardiovascular mortality. Plasma homocysteine is an independent risk factor for atherosclerotic disease, and its level is determined by folate and cobalamin status, and possibly also by oestrogen status. We measured the effect of tamoxifen on plasma homocysteine, serum cholesterol, serum cobalamin and serum and erythrocyte folate in 31 post-menopausal women with breast cancer. The plasma homocysteine level was decreased by a mean value of 29.8% after 9-12 months and by 24.5% after 13-18 months of treatment. Tamoxifen suppressed serum cholesterol by mean values varying between 7.2% and 17.6% after 3 to 19 months of treatment. There was no correlation between changes in plasma homocysteine and serum cholesterol. These findings suggest that the homocysteine-lowering effect of tamoxifen may contribute to the reduction of cardiovascular mortality observed in patients on adjuvant therapy with tamoxifen.



Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis

Selhub J.; Jacques P.F.; Bostom A.G.; D'Agostino R.B.; Wilson P.W.F.; Belanger A.J.; O'Leary D.H.; Wolf P.A.; Schaefer E.J.; Rosenberg I.H. USDA HNRCA, Tufts University, 711 Washington St., Boston, MA 02111 USA NEW ENGL. J. MED. (USA) , 1995, 332/5 (286-291)

Background. Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia. Methods. We performed a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study. We examined the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6. The subjects were classified into two categories according to the findings in the more diseased of the two carotid vessels: stenosis of 0 to 24 percent and stenosis of 25 to 100 percent. Results. The prevalence of carotid stenosis of greater than or equal to25 percent was 43 percent in the men and 34 percent in the women. The odds ratio for stenosis of greater than or equal to25 percent was 2.0 (95 percent confidence interval, 1.4 to 2.9) for subjects with the highest plasma homocysteine concentrations (greater than or equal to14.4 micromol per liter) as compared with those with the lowest concentrations (less than or equal to9.1 micromol per liter), after adjustment for sex, age, plasma high-density lipoprotein cholesterol concentration, systolic blood pressure, and smoking status (P&lt0.001 for trend). Plasma concentrations of folate and pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) and the level of folate intake were inversely associated with carotid-artery stenosis after adjustment for age, sex, and other risk factors. Conclusions. High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.



Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients

Glueck C.J.; Shaw P.; Lang J.E.; Tracy T.; Sieve-Smith L.; Wang Y. Cholesterol Center, Jewish Hospital, 3200 Burnet Avenue, Cincinnati, OH 45229 USA AM. J. CARDIOL. (USA) , 1995, 75/2 (132-136)

In 482 patients sequentially referred for diagnosis and therapy of hyperlipidemia, our specific aim was to determine the prevalence of homocysteinemia, to assess whether it was independently associated with atherosclerotic vascular disease, and to determine how effectively high homocysteine could be treated with folic acid and pyridoxine. Of the 482 patients, 18 (3.7%) had high homocysteine (greater than or equal to16.2 micromol/L, median = 19), 31 had high cystathionine (greater than or equal to342 nmol/L) with normal homocysteine (median = 12), and 433 had normal cystathionine and homocysteine (median = 9). Of the 18 patients with high homocysteine, 13 (72%) had atherosclerotic vascular disease, much higher than the 44% (192 of 433 patients) with normal homocysteine (chi-square = 5.4, p = 0.02). In the 18 kindreds with a homocysteinemic proband, 14 (78%) had greater than or equal to1 first-degree relatives with atherosclerotic vascular disease before age 65, compared with 50% (215 of 433) of the families where the proband had normal homocysteine (chi-square = 5.5, p = 0.02). In the 482 patients already at high risk for atherosclerotic vascular disease by virtue of hyperlipidemia, when assessed by logistic regression, homocysteine was an independent positive predictor of atherosclerotic vascular disease p = 0.007); relative risk for atherosclerotic events was 2.8 times higher (p = 0.0004) in patients with top (greater than or equal to11.4 micromol/L) than with bottom (&lt6.9 micromol/L) quintile homocysteine. After 15 weeks of folic acid (5 mg/day) and pyridoxine (100 mg/day) therapy in 10 patients with high homocysteine, median homocysteine normalized, decreasing from 18 to 11 micromol/L (p = 0.001). To best quantitate and ameliorate risk far atherosclerotic vascular disease, homocysteine should routinely be measured at least once in hyperlipidemic patients at high risk far atherosclerosis and, if high, should be treated.



Plasma homocyst(e)ine and arterial occlusive diseases: A mini-review

Malinow M.R. Oregon Regional Primate Res. Center, 505 NW 185th Ave., Beaverton, OR 97006 USA CLIN. CHEM. (USA) , 1995, 41/1 (173-176)

Homocysteine (HCY), which is derived from the intracellular metabolism of methionine, is exported into plasma, where it circulates mostly in oxidized forms (i.e., homocystine and cysteine-HCY disulfide) and mainly bound to proteins. Concentrations of total HCY, or homocyst(e)ine (H(e)), are increased in 15-40% of patients with coronary, cerebral, or peripheral arterial diseases. Such association of H(e) with arterial occlusive diseases has been documented in retrospective, cross-sectional, and prospective studies. Concentrations of H(e) are also increased in subjects having thickened carotid arteries, as determined by ultrasonography, and who are asymptomatic for atherosclerosis. Statistical analyses of data from several series of patients demonstrate that H(e) concentrations are associated with coronary artery disease, independently from most other risk factors for atherosclerosis. The increased concentrations of H(e) are readily corrected by folic acid, occasionally supplemented with pyridoxine, vitamin B12, choline, or betaine. Whether these supplements affect the evolution of atherosclerotic disease needs to be established by prospective, placebo- controlled clinical trials.

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