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Biomedical subjects

M R Malinow

Publications and source records attributed to M R Malinow.

At least 19 recordsLinked to original sources
PubMed1996

Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.

Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.O +/- O.2 microM when monkeys were fed normal diet to 10.6 +/- 2.6 microM when they were fed modified diet (mean +/- SE; P = 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 +/- 9% in monkeys fed modified diet, compared with 14 +/- 11% in monkeys fed normal diet (P = 0.008), Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function.

Animals↗
PubMed1996

A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians.

OBJECTIVE: To assess prospectively the risk of myocardial infarction (MI) associated with decreased plasma levels of folate and pyridoxal phosphate (PLP, a form of vitamin B6) in relation to elevated levels of total homocysteine (tHcy). DESIGN: Nested case-control study using prospectively collected blood samples. SETTING: Participants in the Physicians' Health Study. SUBJECTS: 14,916 male physicians, aged 40-84 years, with no prior MI or stroke provided plasma samples at baseline and were followed for 7.5 years. Samples from 333 men who subsequently developed MI, and their paired controls matched by age and smoking, were analyzed for folate and PLP levels. MEASURES OF OUTCOME: Acute MI or death due to coronary disease. RESULTS: In a model controlling for diabetes, angina, hypertension, Quetelet's index, and total/high-density lipoprotein cholesterol, men with the lowest 20% of folate levels (< 2.0 ng/mL) had a relative risk of 1.4 (95% confidence interval 0.9-2.3) compared with those in the top 80%. For the lowest 20% of vitamin B6 values, the relative risk was 1.5 (95% CI: 1.0-2.2). When we included both folate and B6 in a model with cardiovascular risk factors, the relative risk of MI for low as compared to high levels of folate was 1.3 (95% CI: 0.8-2.1) and for PLP, 1.3 (95% CI: 0.9-2.1). Adding tHcy to this model did not add significant predictive value (chi sq = 2.0, p > 0.05), except in the first half of the follow-up interval when men with the top 5% of tHcy values had an almost three-fold increase in risk of MI. CONCLUSIONS: Although not statistically significant, these prospective data are compatible with the hypothesis that low dietary intake of folate and/or vitamin B6 contribute to risk of MI.

Adult↗
PubMed1996

Plasma homocyst(e)ine: a risk factor for arterial occlusive diseases.

Results of basal plasma homocyst(e)ine concentrations in patients reported in the literature are reviewed, with emphasis on the series of subjects analyzed by the author. Findings support the hypothesis that plasma homocyst(e)ine is a risk factor for coronary, cerebral and peripheral arterial occlusive diseases, as well as for carotid thickening. Results of four studies show that heritability influences plasma homocyst(e)ine. Moreover, data suggest that a graded risk for atherothrombotic disease is distributed across the entire distribution of plasma homocyst(e)ine levels. Elevated levels of homocyst(e)ine can be decreased effectively by supplementary folate, occasionally requiring the addition of vitamin B-12, vitamin B-6, choline or betaine. Consequently, it is important that placebo-controlled clinical trials be conducted to determine whether the clinical evolution of arterial occlusive diseases is influenced by those supplements.

Arterial Occlusive Diseases↗
PubMed1996

Relationship among homocyst(e)ine, vitamin B-12 and cardiac disease in the elderly: association between vitamin B-12 deficiency and decreased left ventricular ejection fraction.

We evaluated the association of moderate hyperhomocyst(e)inemia and vitamin B-12 status with coronary artery disease (CAD) and left ventricular ejection fraction in 367 elderly patients undergoing coronary angiography. The extent of CAD was scored, left ventricular ejection fraction was assessed and vitamins B-12 and folate and the metabolites homocyst(e)ine, methylmalonic acid and 2-methylcitric acid were measured. There was no significant trend in change in homocyst(e)ine as the extent of CAD increased. There was an association between vitamin B-12 deficiency, i.e., vitamin B-12 < 221 pmol/l and homocyst(e)ine > 16 nmol/ml and low left ventricular ejection fraction (P = 0.014). Of 105 samples, selected for vitamin B-12 < 221 pmol/l or high normal vitamin B-12 and folate levels, metabolites including methylmalonic acid revealed a specific diagnosis of vitamin B-12 deficiency in 18 patients. The trend among these vitamin B-12-deficient patients and low left ventricular ejection fraction was significant (P = 0.028). In vitro studies on rat heart revealed that nitrous oxide in the presence of 200 microM/l methionine reduced contractility of the heart. In conclusion, vitamin B-12-deficient patients had significantly lower left ventricular ejection fractions than nonvitamin B-12-deficient patients. Whether low left ventricular ejection fraction results in malabsorption of vitamin B-12 and vitamin B-12 deficiency, or conversely, whether vitamin B-12 and its marker, elevated homocyst(e)ine, depress left ventricular function warrants further evaluation.

Aged↗
PubMed1995

Role of blood pressure, uric acid, and hemorheological parameters on plasma homocyst(e)ine concentration.

Elevated concentration of plasma homocyst(e)ine is an independent risk factor for clinical atherosclerosis. In this study, the concentration of plasma homocyst(e)ine in men who lacked a history of atherosclerotic disease was correlated with hemodynamic, rheological and biochemical parameters. Hypertensive subjects had higher concentrations of plasma homocyst(e)ine than normotensive subjects. Positive correlations were found between concentrations of plasma homocyst(e)ine and several risk factors, but some of these correlations disappeared when they were adjusted for other variables. However, multivariate analyses demonstrated that systolic blood pressure, plasma uric acid, and hematocrit were predictors of concentrations of plasma homocyst(e)ine, after adjusting for certain risk factors. The possible significance of these interrelationships in atherogenesis require further study.

Blood Flow Velocity↗
PubMed1995

Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia.

Studies by various investigators have indicated that elevated levels of plasma homocyst(e)ine are strongly associated with the occurrence of occlusive vascular diseases. With the eventual aim of determining whether or not elevated plasma homocyst(e)ine concentrations are directly causative of cardiovascular diseases, we have generated mice that are moderately and severely homocyst(e)inemic. Homologous recombination in mouse embryonic stem cells was used to inactivate the cystathionine beta-synthase [L-serine hydrolyase (adding homocysteine), EC 4.2.1.22] gene. Homozygous mutants completely lacking cystathionine beta-synthase were born at the expected frequency from matings of heterozygotes, but they suffered from severe growth retardation and a majority of them died within 5 weeks after birth. Histological examination showed that the hepatocytes of homozygotes were enlarged, multinucleated, and filled with microvesicular lipid droplets. Plasma homocyst(e)ine levels of the homozygotes were approximately 40 times normal. These mice, therefore, represent a model for severe homocyst(e)inemia resulting from the complete lack of cystathionine beta-synthase. Heterozygous mutants have approximately 50% reduction in cystathionine beta-synthase mRNA and enzyme activity in the liver and have twice normal plasma homocyst(e)ine levels. Thus, the heterozygous mutants are promising for studying the in vivo role of elevated levels of homocyst(e)ine in the etiology of cardiovascular diseases.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

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

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.

Arterial Occlusive Diseases↗
PubMed1994

Influence of serum lipoprotein(a) and homocyst(e)ine levels on graft patency after coronary artery bypass grafting.

High serum levels of lipoprotein(a) and homocyst(e)ine are considered independent risk factors for atherothrombotic disease. In a prospective study in patients undergoing coronary artery bypass grafting, the preoperatively determined lipoprotein(a) and homocyst(e)ine levels were related to the frequency of 1-year graft occlusion. A cohort of 610 patients who underwent coronary artery bypass surgery was followed through the first postoperative year. Shunt angiography was performed in 581 patients (95%) at a mean of 12.1 +/- 1.5 months after the operation. The serum levels of lipoprotein(a) (n = 570) and homocyst(e)ine (n = 565) in patients with occluded internal mammary artery (IMA) grafts were not significantly different from the levels in those with open IMA grafts. Also, the serum lipoprotein(a) and homocyst(e)ine levels in patients with > or = 1 occluded vein graft were not significantly different from those in patients with all vein grafts patent. This study also determined the incidence of graft occlusion in quartiles of the lipoprotein(a) and homocyst(e)ine levels, respectively, and tested for linear trends. No significant trends in the incidence of graft occlusion were found, but the number of patients with vein graft occlusions was higher in the lowest quartile of lipoprotein(a) than that in the upper 3 quartiles (odds ratio, 1.82, 95% confidence interval, 1.21 to 2.74, p = 0.0025). Controlling for background variables in multivariate models only slightly modified the results. Thus, apart from an unexplained excess of vein graft occlusions in the lowest quartile of lipoprotein(a) levels, no association between the preoperative serum lipoprotein(a) or homocyst(e)ine levels and the frequency of 1-year graft occlusion could be demonstrated.

Aged↗
PubMed1994

Homocyst(e)ine and arterial occlusive diseases.

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.

Arterial Occlusive Diseases↗
PubMed1994

Effects of age, lipoproteins, and hemostatic parameters on the role of homocyst(e)inemia as a cardiovascular risk factor in men.

Previous studies have identified moderately elevated plasma concentrations of homocyst(e)ine as an independent risk factor for coronary heart disease (CHD). The atherogenicity of homocyst(e)ine has mostly been attributed to its effects on endothelial cells, platelets, and the hemostatic system. In this case-control study of 199 male CHD patients and 156 age-matched control subjects, we analyzed the role of homocyst(e)ine as a cardiovascular risk marker in the context of traditional risk factors as well as of plasma fibrinogen, plasminogen, and viscosity. Both univariate and multivariate regression analyses revealed that homocyst(e)ine levels were significantly correlated with age, fibrinogen, and plasma viscosity in both study groups. Geometric mean homocyst(e)ine levels by univariate analysis were significantly higher in patients than in control subjects (8.9 versus 7.8 mumol/L, P < .001). This difference remained significant on multiple logistic function analysis after being adjusted for body mass index, systolic blood pressure, serum cholesterol, and high-density lipoprotein cholesterol but not after additional adjustment for fibrinogen. By contrast, geometric mean fibrinogen levels after adjustment for homocyst(e)ine levels were significantly different between patients and control subjects (296.4 versus 230.8 mg/dL, P < .001). Within the group of CHD patients, both fibrinogen and homocyst(e)ine significantly increased in parallel with the number of stenosed coronary vessels. We conclude that hyperhomocyst(e)inemia is an independent coronary risk factor and that its interrelation with fibrinogen levels merits further study.

Adult↗
PubMed1994

A prospective study of plasma homocyst(e)ine and risk of ischemic stroke.

BACKGROUND AND PURPOSE: Several studies have reported elevated circulating homocyst(e)ine levels in subjects with cerebral atherosclerosis. We assessed prospectively whether high plasma levels of homocyst(e)ine affect risk of ischemic stroke and evaluated whether high blood pressure modifies any such effect. METHODS: The study sample was drawn from the Physicians' Health Study, a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in 22,071 US male physicians. A total of 14,916 subjects 40 to 84 years old with no prior history of stroke, transient ischemic attack, or myocardial infarction provided blood samples at baseline and were followed for 5 years, with 99.7% morbidity and 100% mortality follow-up. Using a nested case-control design, we assayed homocyst(e)ine in samples from 109 subjects who subsequently developed ischemic stroke and 427 control subjects. RESULTS: The mean plasma concentration of homocyst(e)ine was slightly higher in subjects with stroke (11.1 +/- 4.0 [+/- SD] nmol/mL) than in control subjects (10.6 +/- 3.4 nmol/mL), but the difference was not statistically significant (P = .12). The crude odds ratio of ischemic stroke for subjects in the upper 20% (> 12.7 nmol/mL) compared with those in the bottom 80% of homocyst(e)ine levels was 1.4 (95% confidence interval, 0.8 to 2.2). The odds ratio was 1.2 (95% confidence interval, 0.7 to 2.0) after controlling for several risk factors and other potential confounders. In subgroup analyses, elevated homocyst(e)ine levels appeared to be more strongly predictive of ischemic stroke in normotensive subjects and in men 60 years or younger. Although not statistically significant, in these subgroups increases in risks of 100% and 70%, respectively, were observed for men in the upper 20% of homocyst(e)ine values. CONCLUSIONS: In this study, the data were compatible with a small but nonsignificant association between elevated plasma homocyst(e)ine and risk of ischemic stroke. However, since the sample size is small and the confidence intervals are wide, either no association or a moderate increase in risk cannot be excluded, particularly in subgroups otherwise at low risk, eg, younger men and those with normal blood pressure.

Adult↗
PubMed1994

Synthesis and transsulfuration of homocysteine in blood.

Interest in total plasma homocysteine (homocyst[e]ine) as a risk factor for atherosclerosis is expanding. However, the origin of plasma homocyst(e)ine has not been defined. Our studies examined the metabolism of homocyst(e)ine by blood cells as a potential contributor to the homeostasis of homocyst(e)inemia. Incubation of blood for 24 hours at 37 degrees C produced a threefold increase in the level of plasma homocyst(e)ine. In samples of fractionated blood cells incubated in vitro, increases in total plasma homocysteine were limited to incubated erythrocyte fractions and were influenced by addition of methionine. Anticoagulants had no significant effect. Incubation of blood in the presence of methionine tagged with sulfur 35 demonstrated incorporation of label into homocysteine and transsulfuration products. Similar incubations of blood cell fractions suggested that synthesis of homocysteine occurred in erythrocytes, whereas leukocytes both synthesized and transsulfurated homocysteine. These findings demonstrated a possible interaction of different blood cells in the metabolism of methionine, as well as their potential role as a source of total plasma homocysteine in plasma.

Adult↗
PubMed1993

Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study.

BACKGROUND: Plasma levels of homocyst(e)ine are elevated in certain patients with occlusive arterial diseases. We extended these findings to asymptomatic adults. METHODS AND RESULTS: We determined plasma homocyst(e)ine levels in 287 pairs of asymptomatic adults. Cases and controls were defined on the basis of intimal-medial thickness of the carotid wall as measured by B-mode ultrasound. Study subjects had no history of atherosclerotic disease and were selected from a probability sample of 15,800 men and women between 45 and 64 years old. Subjects with thickened intimal-medial carotid walls (cases) had higher plasma homocyst(e)ine levels than controls (p < 0.001). The odds ratio for having a thickened carotid artery wall was 3.15 (p < 0.001) for subjects in the top quintile of plasma homocyst(e)ine levels (> 10.5 mumol/L) compared with those in the bottom quintile (< 5.88 mumol/L). CONCLUSIONS: The present study as well as observations on the common occurrence of elevated plasma homocyst(e)ine levels in patients with occlusive arterial diseases suggest that clinical trials should be conducted to determine whether normalization of hyperhomocyst(e)inemia may prevent progression of atherosclerosis.

Arteriosclerosis↗
PubMed1993

Total homocysteine in plasma or serum: methods and clinical applications.

Total homocysteine is defined as the sum of all homocysteine species in plasma/serum, including free and protein-bound forms. In the present review, we compare and evaluate several techniques for the determination of total homocysteine. Because these assays include the conversion of all forms into a single species by reduction, the redistribution between free and protein-bound homocysteine through disulfide interchange does not affect the results, and total homocysteine can be measured in stored samples. Total homocysteine in whole blood increases at room temperature because of a continuous production and release of homocysteine from blood cells, but artificial increase is low if the blood sample is centrifuged within 1 h of collection or placed on ice. Different methods correlate well, and values between 5 and 15 mumol/L in fasting subjects are considered normal. Total homocysteine in serum/plasma is increased markedly in patients with cobalamin or folate deficiency, and decreases only when they are treated with the deficient vitamin. Total homocysteine is therefore of value for the diagnosis and follow-up of these deficiency states and may compensate for weaknesses of the traditional laboratory tests. In addition, total homocysteine is an independent risk factor for premature cardiovascular diseases. These disorders justify introduction of the total homocysteine assay in the routine clinical chemistry laboratory.

Blood Chemical Analysis↗