Bo Israelsson

Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease Effects of pyridoxine and folic acid treatment☆

Severe homocysteinemia due to genetic defects either of pyridoxal 5-phosphate (PLP)-dependent cystathionine beta-synthase (CBS) or of enzymes in vitamin B12 and folate metabolism is associated with very early-onset vascular disease. Therefore, we studied homocysteine metabolism in 72 patients presenting before the age of 55 years with occlusive arterial disease of cerebral, carotid, or aorto-iliac vessels. Twenty patients (28%) had basal homocysteinemia; and 26 patients (36%) had abnormal increases of plasma homocysteine after peroral methionine loading, which exceeded the highest value for 46 comparable controls and was within the range for 20 obligate heterozygotes for homocystinuria due to CBS deficiency. Basal plasma homocysteine content was strongly and negatively correlated to vitamin B12 and folate concentrations. Plasma PLP was depressed in most patients but there was no correlation between PLP and homocysteine values. In 20 patients, treatment with pyridoxine hydrochloride (240 mg/day) and folic acid (10 mg/day) reduced fasting homocysteine after 4 weeks by a mean of 53%, and methionine response by a mean of 39%. These data show that a substantial proportion of patients with early-onset vascular disease have impaired homocysteine metabolism, which may contribute to vascular disease, and that the impaired metabolism can be improved easily and without side effects.

Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects.

Abstract. Objectives. Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. We explored possible determinants of plasma homocysteine and cysteine concentrations amongst middle‐aged and elderly subjects.

Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors.

Abstract. Moderate hyperhomocysteinaemia is a frequent finding in atherothrombotic cerebrovascular disease. This study confirms and extends this observation. Hyperhomocysteinaemia was present in 57 of 142 survivors with stroke (40%) and in four of 66 controls (6%). Plasma homocysteine concentrations were increased not only in carotid artery disease or lacunar stroke but also in haemorrhagic or embolic strokes. Homocysteine values were unrelated to the presence of hypertension, smoking, or hypercholester‐olaemia, or to the concentrations of blood glucose, glycosylated haemoglobin, and plasma fibrinogen. Multiple regression analysis of the patient data showed that about 40% of the variation in plasma homocysteine concentrations could be predicted by the values for the homocysteine metabolism cofactors, blood folate and plasma pyridoxal 5‐phosphate and by renal function as reflected in the values for serum creatinine. In patients, urine excretion of homocysteine per unit creatinine was significantly increased and strongly correlated both to the plasma homocysteine concentration and to the values for blood folate, plasma pyridoxal 5‐phosphate, and serum vitamin B12. We conclude that moderate hyperhomocysteinaemia is frequently present in cases of stroke, is independent of other stroke risk factors or the type of stroke, and is partly related to renal function and the concentrations of homocysteine metabolism cofactors.

Ultrasound-determined intima-media thickness and atherosclerosis. Direct and indirect validation.

To evaluate ultrasonographically determined intima-media thickness as a measure of early atherosclerosis, three studies were performed. Ultrasound measurements of intima-media thickness in the carotid artery were directly validated by comparing the same thickness measured by light microscopy. The values were closely correlated (r = .82, P < .001). Intima-media thickness determined by light microscopy was consistently smaller than that determined by ultrasound, probably due to shrinkage during histological preparation. As an indirect validation, mean intima-media thickness was calculated in three large groups of patients with no plaque (n = 224), one plaque (n = 105), and one circumferential or two or more plaques (n = 54) in the carotid bifurcation. Intima-media thickness increased significantly with increasing plaque score, indicating that diffuse intima-media thickening is more pronounced with more severe atherosclerosis. The intima-media thickness also increased with increasing multifactorial cardiovascular risk, reflecting a positive relation between signs of early atherosclerosis and the burden of known risk factors for the disease. Our studies support earlier findings that have found that ultrasonographically determined intima-media thickness is a valid way to study early atherosclerosis.

Non-compliance and knowledge of prescribed medication in elderly patients with heart failure.

To determine the extent of non‐compliance to prescribed medication in elderly patients with heart failure and to determine to what extent patients recall information given regarding their medication.

Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine β-synthase deficiency☆

Homocysteine is an amino acid considered to cause vascular injury, arteriosclerosis, and thromboembolism. Total plasma homocysteine (free and protein-bound) was found to be twice as high in asymptomatic vitamin B12-deficient subjects (23.8 +/- 3.8 mumol/L, means +/- SEM, n = 20) as in controls (11.5 +/- 0.9 mumol/L, P less than .0001, n = 21), and higher than in heterozygotes for homocystinuria due to cystathionine beta-synthase deficiency (13.8 +/- 1.6 mumol/L, P less than .01, n = 14), who were recently shown to be much more common among patients with premature vascular disease than expected. Eight (40%) vitamin B12-deficient and two (14%) heterozygote subjects had significant homocysteinemia (greater than mean +2 SD for controls). After administration of hydroxycobalamin to vitamin B12-deficient subjects, homocysteine levels decreased to normal (-49%, 12.2 +/- 1.5 mumol/L, P less than .0001, n = 20). Thus, if homocysteine does cause vascular injury, theoretically vitamin B12-deficiency might be associated with an increased frequency of vascular disease.

Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid

Abstract. Objectives. Moderate hyperhomocysteinaemia is an independent risk factor for cardiovascular disease which may be causal. We investigated whether the concentration of plasma homocysteine changes between the acute phase of myocardial infarction and follow‐up, and whether treatment with oral folic acid was effective in lowering homocysteine levels in patients with myocardial infarction.

Homocysteine and myocardial infarction.

Five (24%) subjects out of a group of 21 men, 48-58 years old (mean 54), who had suffered their first myocardial infarction (MI) before the age of 55 and with a low risk profile vis-à-vis conventional risk factors in a health screening preceding the MI, had abnormally high total plasma homocysteine values in the fasting state when investigated within 1-7 years (mean 3) after their MI. The patient group was exactly matched with 36 control subjects for sex, age, diastolic blood pressure, smoking, and serum concentrations of cholesterol and triglycerides. Total plasma homocysteine was negatively correlated to both erythrocyte folate and serum vitamin B12, and vitamin concentrations below the median of the normal distribution were found in the five with high plasma homocysteine content, indicating a possible involvement of reduced remethylation of plasma homocysteine to methionine. After methionine loading, in 3 of the patient group (14%) homocysteine levels exceeded mean +2 SD for controls, which may indicate heterozygosity for homocystinuria. Results are consistent with the hypothesis that a high plasma homocysteine content may be a risk factor for MI.

Cardiovascular risk groups and mortality in an urban Swedish male population: the Malmö Preventive Project

Objectives. To describe the size, overlap and mortality of four cardiovascular risk groups, in order to give a scientific background for the prevention of cardiovascular disease in a representative urban population.

Hyperhomocysteinaemia : a common finding in a psychogeriatric population

Abstract. Plasma homocysteine concentration is a sensitive marker for cobalamin and folate deficiency. The previously reported high incidence of increased plasma homocysteine in psychogeriatric patients and the association between reduced concentrations of cobalamin, folate and neuropsychiatric symptoms led to the present study on 741 consecutive psychogeriatric patients. The concentrations of plasma homocysteine correlated significantly with blood folate, serum cobalamin and serum creatinine both in demented (n= 295) and in non‐demented patients with other psychiatric disorders (n= 215). Plasma homocysteine concentrations were significantly increased in both the demented and the non‐demented patients, whereas only the demented patients had lower blood folate and serum creatinine concentrations than 163 control subjects. Almost all of the different diagnostic groups of demented and non‐demented patients exhibited significantly increased plasma homocysteine concentrations compared with control subjects. Significantly decreased blood folate concentrations were mainly found in the different diagnosis groups of demented patients. Plasma homocysteine concentrations in both demented and non‐demented patients with serum cobalamin and blood folate above the lower 20th percentile of these vitamins in the control subjects were also studied. Despite these vitamin concentrations, both groups of patients still exhibited significantly higher plasma homocysteine concentrations than the control subjects, which may indicate an increased frequency of impaired genetic capacity to metabolize homocysteine in these patients. Patients with either dementia of vascular cause or a history of other occlusive arterial disease had a significantly higher plasma homocysteine concentration than those without a history of vascular disease.