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Biomedical subjects

I H Rosenberg

Publications and source records attributed to I H Rosenberg.

At least 19 recordsLinked to original sources
PubMed2002

Plasma homocysteine and parental myocardial infarction in young adults in Jerusalem.

BACKGROUND: A causal role for mildly elevated plasma homocysteine (tHcy) in cardiovascular disease remains undetermined. To address the unresolved issue of the antecedent-consequent directionality of the relationship, we assessed the familial association of tHcy with parental myocardial infarction (MI) in young Israeli men and women. We also compared tHcy concentrations in Jerusalem, where rates of coronary heart disease (CHD) are high, with the United States Third National Health and Examination Survey (NHANES III). METHODS AND RESULTS: A total of 8646 17-year-olds and 6952 parents were examined from 1976 to 1979 in Jerusalem. At ages 28 to 32 years, offspring of parents who experienced a documented MI during a 10-year follow-up (n=133 men, 62 women; 72% response) and offspring of CHD-free parents (n=389 men, 208 women; 71% response) were reexamined. tHcy levels were determined by the same laboratory for the NHANES non-Hispanic white population aged 25 to 34 years (n=379) and the Jerusalem population sample (n=858). Men from Jerusalem, but not women, had clearly higher tHcy levels than the sample from the United States (90th percentile, 23 versus 14 micromol/L). This difference was largely attributable to lower plasma vitamin B12 levels in the Israeli population. Male case offspring had higher adjusted tHcy than did controls (1.9 micromol/L, P=0.002). Logistic modeling revealed a graded increase in risk of parental MI across quintiles of offspring tHcy, with an adjusted odds ratio of 2.7 in the 5th quintile (P=0.0026 for trend). CONCLUSIONS: The higher tHcy in young male offspring of parents with CHD suggests that elevated tHcy precedes manifestation of CHD. The elevated population tHcy in men may contribute to the high incidence of CHD in Israel.

Adolescent↗
PubMed2001

Power Shortage: clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour.

Large randomized, controlled trials of total homocysteine-lowering therapy for the potential reduction of cardiovascular disease outcomes are ongoing in the United States and Canada. These trials are the Vitamin Intervention for Stroke Prevention (VISP) trial, the Women's Antioxidant Cardiovascular Disease Study (WACS), and the Heart Outcomes Prevention Evaluation (HOPE-2). However, the dramatic effect of policies mandating fortification of cereal grain flour products with folic acid may reduce the statistical power of these trials. All three trials assume that the active treatment groups will achieve the same mean effects of total homocysteine-lowering therapy as those reported in the absence of folic acid-fortified cereal grain flour. This paper examines this assumption using data from studies of total homocysteine-lowering therapy in U.S. and Canadian patients with cardiovascular disease who were exposed to products made with folic acid-fortified cereal grain flour. These data showed that the VISP trial, HOPE-2, and WACS will probably achieve only approximately 20% to 25% of the projected treatment effects of mean total homocysteine-lowering therapy (1.0 to 1.5 micromol/L vs. 4.0 to 6.0 micromol/L). As a result, all three trials will be substantially underpowered to test the specific hypotheses of total homocysteine-lowering therapy identified a priori. In contrast, renal transplant recipients have a persistent excess prevalence of hyperhomocysteinemia in the era of fortification but remain very responsive to supraphysiologic doses of folic acid-based supplementation (mean reduction in total homocysteine level, 5.0 to 6.0 micromol/L). Therefore, unlike other populations with normal renal function that are at high risk for cardiovascular disease but are profoundly affected by fortification efforts, renal transplant recipients continue to merit serious consideration for a controlled trial of the "homocysteine hypothesis."

Arteriosclerosis↗
PubMed2001

Low circulating vitamin B(6) is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels.

BACKGROUND: Lower vitamin B(6) concentrations are reported to confer an increased and independent risk for cardiovascular disease (CVD). The mechanism underlying this relationship, however, remains to be defined. Other diseases, such as rheumatoid arthritis, are associated with reduced vitamin B(6) levels. Despite a clear distinction in pathophysiology, inflammatory reaction may be the major link between these diseases. We hypothesized a relationship between pyridoxal 5'-phosphate (PLP), the active form of vitamin B(6), and the marker of inflammation C-reactive protein (CRP). We also evaluated whether total plasma homocysteine (tHcy), a well-defined risk factor for CVD and a major determinant of plasma PLP levels, had a possible role as a mediator of this hypothesized relationship. METHODS AND RESULTS: Data from 891 participants from the population-based Framingham Heart Study cohort were analyzed. Subjects were divided into 2 groups according to normal or elevated CRP values: group 1, CRP <6 mg/L; group 2, CRP >/=6 mg/L. Plasma PLP levels were substantially lower in group 2 than in group 1 (mean values in group 2, 36.5 nmol/L versus 55.8 nmol/L in group 1, P<0.001). In a multiple logistic regression model adjusted for tHcy, the association of PLP with CRP remained highly significant (P=0.003). CONCLUSIONS: Low plasma PLP is associated with higher CRP levels independently of tHcy. This observation may reflect a vitamin B(6) utilization in the presence of an underlying inflammatory process and represent a possible mechanism to explain the decreased vitamin B(6) levels in CVD.

Aged↗
PubMed2001

Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey.

Hypothyroid (thyroid stimulating hormone (TSH)> or =20 mIU/l; N=32) participants in the third National Health and Nutrition Examination Survey, Phase 2 (1991-1994) were compared with non-hypothyroid subjects (0.5 mIU/l 12 micromol/l) and hypercholesterolemia (serum total cholesterol>6.2 mmol/l). After controlling for age, gender, and race ethnicity, the odds ratios (95% confidence interval (CI)) relating hypothyroidism to hyperhomocysteinemia and high total cholesterol were 4.9 (1.8-14.0) and 8.0 (2.9-21.9), respectively. Based on 26 hypothyroid and 5811 non-hypothyroid subjects with triglyceride concentration < or =2.82 mmol/l, the odds ratio for the relationship between hypothyroidism and high low-density lipoprotein (LDL)-cholesterol (>4.6 mmol/l by the Friedewald equation) was 5.3 (95% CI, 1.3-20.9). Adding additional terms to the multivariate logistic regression model had little effect on the odds ratios relating hypothyroidism to high total or LDL-cholesterol, but adding terms for serum creatinine concentration >123.8 micromol/l and for red blood cell folate and serum vitamin B-12 concentrations resulted in an attenuated, but still significant (P<0.05), odds ratio relating hypothyroidism to hyperhomocysteinemia (2.5; 95% CI, 1.0-6.1). Controlling for cigarette smoking, heart attack/stroke history, body mass index, and serum albumin concentration did not affect the odds ratios. Hyperhomocysteinemia and hypercholesterolemia could help to explain the increased risk for arteriosclerotic coronary artery disease in hypothyroidism.

Adult↗
PubMed2001

Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort.

BACKGROUND: Established determinants of fasting total homocysteine (tHcy) concentration include folate and vitamin B-12 status, serum creatinine concentration, and renal function. OBJECTIVE: Our objective was to examine the relation between known and suspected determinants of fasting plasma tHcy in a population-based cohort. DESIGN: We examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in 1960 men and women, aged 28-82 y, from the fifth examination cycle of the Framingham Offspring Study between 1991 and 1994, before the implementation of folic acid fortification. RESULTS: Geometric mean tHcy was 11% higher in men than in women and 23% higher in persons aged > or = 65 y than in persons aged < 45 y (P < 0.001). tHcy was associated with plasma folate, vitamin B-12, and pyridoxal phosphate (P for trend < 0.001). Dietary folate, vitamin B-6, and riboflavin were associated with tHcy among non-supplement users (P for trend < 0.01). The tHcy concentrations of persons who used vitamin B supplements were 18% lower than those of persons who did not (P < 0.001). tHcy was positively associated with alcohol intake (P for trend = 0.004), caffeine intake (P for trend < 0.001), serum creatinine (P for trend < 0.001), number of cigarettes smoked (P for trend < 0.001), and antihypertensive medication use (P < 0.001). CONCLUSIONS: Our study confirmed, in a population-based setting, the importance of the known determinants of fasting tHcy and suggested that other dietary and lifestyle factors, including vitamin B-6, riboflavin, alcohol, and caffeine intakes as well as smoking and hypertension, influence circulating tHcy concentrations.

Adult↗
PubMed2001

Hyperhomocysteinemia associated with poor recall in the third National Health and Nutrition Examination Survey.

BACKGROUND: High circulating total homocysteine (tHcy) concentrations are associated with stroke, which is a major cause of cognitive dysfunction. Blood homocysteine concentrations are inversely correlated with performance on some cognitive-function tests and a relation was recently shown between hyperhomocysteinemia and Alzheimer disease. OBJECTIVE: The objective was to evaluate the relation between serum tHcy concentrations and performance on short delayed-recall tests of elderly men and women participating in the third National Health and Nutrition Examination Survey, phase 2 (1991--1994). DESIGN: Subjects were aged > or =60 y. Subjects reported no previous stroke, completed > or =8 y of education, and took a test of delayed recall of story ideas (n = 1200) or words (n = 1270). RESULTS: After adjustment for sex, age, race-ethnicity, income, years of education, and serum creatinine concentration, subjects in the upper half of the folate distribution recalled, on average, >4 of 6 story ideas; subjects with lower folate status recalled significantly fewer ideas (P < 0.001). Of the subjects with low folate status, story recall was significantly poorer in those with serum tHcy concentrations above the 80th percentile of the distribution (13.7 micromol/L) than in those with lower tHcy concentrations (P < 0.03). The odds ratio relating hyperhomocysteinemia to recall of > or =1 of 3 previously learned words was 0.3 (95% CI: 0.2, 0.7) after adjustment for the 5 demographic factors alone and was 0.4 (0.2, 0.9) after further adjustment for serum folate concentration. CONCLUSION: Hyperhomocysteinemia is related to poor recall and this association was partially independent of folate status.

Age Factors↗
PubMed2001

Folic acid fortification increases red blood cell folate concentrations in the Framingham study.

In 1996 the Food and Drug Administration (FDA) issued a regulation to take effect in January 1998 that all enriched cereal grain products include 140 microg of folic acid/100 g. The present cross-sectional study was undertaken to assess the effect of this fortification on RBC folate concentrations in the Framingham Offspring Cohort. Among those who did not take B-vitamin supplements, we compared RBC folate in 561 individuals who were examined before implementation of the FDA mandatory folic acid fortification (not exposed) vs. 354 individuals who were examined after implementation of fortification (exposed). We calculated the prevalence of deficient (<160 microg/L, 362.6 nmol/L) and acceptable (>200 microg/L, 453.2 nmol/L) RBC folate concentrations in both groups. Those exposed to folic acid fortification had a mean RBC folate of 450.0 microg/L (1019.7 nmol/L), a value 38% higher than the mean RBC folate of 325.3 microg/L (737.1 nmol/L) in those who were not exposed to fortification (P < 0.001). The prevalence of individuals with deficient RBC folate was 4.9% in the group not exposed to fortification compared with 1.9% in the group exposed to fortification (P < 0.02), and the prevalence of individuals with acceptable RBC folate was 87.0% in the group not exposed to fortification compared with 96.1% in the group exposed to fortification (P < 0.001). Similar results were seen in individuals who used supplements containing B-vitamins. The results of this study showed that in this cohort, the introduction of folic acid fortification significantly improved folate nutritional status measured as RBC folate.

Adult↗
PubMed2001

Renal insufficiency, vitamin B(12) status, and population attributable risk for mild hyperhomocysteinemia among coronary artery disease patients in the era of folic acid-fortified cereal grain flour.

Fortification of enriched cereal grain flour products with folic acid has drastically reduced the prevalence of deficient plasma folate status, a major determinant of plasma total homocysteine (tHcy) levels. We hypothesized that even more liberally defined "suboptimal" plasma folate status might no longer contribute importantly to the population attributable risk (PAR) for mild hyperhomocysteinemia, a putative atherothrombotic risk factor. We determined fasting plasma tHcy, folate, vitamin B(12), and pyridoxal 5'-phosphate levels, along with serum creatinine and albumin levels, in 267 consecutive patients (aged 61+/-9 [mean+/-SD] years, 76.4% men and 26.6% women) with stable coronary artery disease (CAD) who were nonusers of vitamin supplements or had abstained from supplement use for at least 6 weeks before examination. Subjects were evaluated a minimum of 3 months after the implementation of flour fortification was largely completed. Relative risk estimates for the calculation of PAR were derived from a multivariable-adjusted logistic regression model with >/=12 micromol/L tHcy as the dependent variable and with age, sex, pyridoxal 5'-phosphate (continuous), albumin (continuous), <5 ng/mL folate, <250 pg/mL vitamin B(12), and >/=1.3 mg/dL creatinine as the independent variables. The prevalence of >/=12 micromol/L plasma tHcy was 11.2% (30 of 267 patients). PAR estimates (percentage) for >/=12 micromol/L tHcy were as follows: <5 ng/mL folate (<1%), <250 pg/mL vitamin B(12) (24.5%), and >/=1.3 mg/dL creatinine (37.5%). In the era of folic acid-fortified cereal grain flour, renal insufficiency and suboptimal vitamin B(12) status (but not folate status) contribute importantly to the PAR for mild hyperhomocysteinemia among patients with stable CAD.

Adult↗
PubMed2000

Total homocysteine and estrogen status indicators in the Third National Health and Nutrition Examination Survey.

The possibility that estrogen status modulates total homocysteine concentration, a risk factor for vascular occlusion, was examined in a representative sample of the US population, the Third National Health and Nutrition Examination Survey (phase 2), 1991-1994. The geometric mean serum total homocysteine concentration was compared among population subgroups differing on inferred estrogen status, after adjusting for potential confounding by age, race-ethnicity, smoking, and the serum concentration of creatinine, folate, and vitamin B-12. Premenopausal women aged 17-54 years had a lower mean serum total homocysteine concentration (8.1 micromol/liter, 95% confidence interval (CI): 7.9, 8.2) than men in the same age range (8.9 micromol/liter, 95% CI: 8.6, 9.3). In the age range 17-44 years, pregnant women (6.0 micromol/liter, 95% CI: 5.4, 6.8), but not oral contraceptive users (7.9 micromol/liter, 95% CI: 7.6, 8.2), had a lower mean serum total homocysteine concentration than nonpregnant, non-oral-contraceptive-using women (8.1 micromol/liter, 95% CI: 7.9, 8.2). The mean serum total homocysteine concentration of estrogen-using women aged > or = 55 years (9.5 micromol/liter, 95% CI: 8.9, 10.1) was significantly decreased relative to nonestrogen users (10.7 micromol/liter, 95% CI: 10.3, 11.1) and men (10.4 micromol/liter, 95% CI: 9.8, 11.0) in the same age range. These findings suggest that higher estrogen status is associated with a decreased mean serum total homocysteine concentration, independent of nutritional status and muscle mass, and that estrogen may explain the previously reported male-female difference in total homocysteine concentration.

Adolescent↗
PubMed2000

Plasma total homocysteine levels in subjects with hyperinsulinemia.

OBJECTIVES: Hyperhomocysteinemia as well as insulin resistance are considered to be risk factors for the development of coronary artery disease. This study was aimed at determining whether any relationship between plasma insulin and glucose levels and total plasma homocysteine (tHcy) concentrations exists in a population based survey performed 10 years apart. DESIGN AND SETTING: A cross-sectional study was undertaken during the years 1986-87 to examine risk factors for diabetes and for coronary artery disease (CAD) in the Jewish population of Jerusalem. Ten years later two groups of individuals were invited for re-examination. SUBJECTS: Two groups of individuals were examined: the first one consisted of nondiabetic subjects (n = 86), who had hyperinsulinemia 10 years previously (at the first visit), the second group consisted of normoinsulinemic nondiabetic individuals (n = 265) who had initially normal glucose and insulin levels. MAIN OUTCOME MEASURES: Metabolic, biochemical and anthropomorphic features were determined. Fasting and post load glucose, as well as insulin concentrations on fasting and 2 h post glucose load were measured at the first and second visits. Plasma tHcy and folic acid were determined only at the second visit. RESULTS: The results demonstrated a significant negative correlation between plasma tHcy levels and insulin levels at the second visit. No difference was found in folic acid levels between these two groups. CONCLUSIONS: In general, hyperinsulinemia and hyperhomocysteinemia are both related to an increased incidence of CAD. In our population most of the subjects examined had tHcy levels within the normal range and only a few demonstrated very high levels. However, negative association between insulin levels and tHcy concentrations was found. Possible explanations for this finding are discussed.

Adult↗
PubMed2000

B vitamins, homocysteine, and neurocognitive function in the elderly.

Evidence of the importance of the B vitamins folic acid, vitamin B-12, and vitamin B-6 for the well-being and normal function of the brain derives from data showing neurologic and psychologic dysfunction in vitamin deficiency states and in cases of congenital defects of one-carbon metabolism. The status of these vitamins is frequently inadequate in the elderly and recent studies have shown associations between loss of cognitive function or Alzheimer disease and inadequate B vitamin status. The question that arises is whether these B vitamin inadequacies contribute to such brain malfunctions or result from aging and disease. From a theoretical standpoint, these inadequacies could give rise to impairment of methylation reactions that are crucial to the health of brain tissue. In addition or perhaps instead, these inadequacies could result in hyperhomocysteinemia, a recently identified risk factor for occlusive vascular disease, stroke, and thrombosis, any of which may result in brain ischemia. Advances in the understanding of this putative relation between inadequate vitamin status and loss of cognitive function in the elderly are likely to be slow and may depend on the outcomes of both prospective studies and longitudinal studies in which nutritional intervention is provided before cognitive decline occurs.

Aging↗
PubMed2000

Serum total homocysteine concentration is related to self-reported heart attack or stroke history among men and women in the NHANES III.

High circulating total homocysteine (tHcy) concentration, which is influenced by folate and vitamin B-12 status, is a suspected cause of cardiovascular events. This relation has been investigated in both case-control and prospective studies but has not been evaluated for different sex x age subgroups of the general U.S. population. We used data on adult (i.e., aged > or =40 y) male (n = 1097) and female (n = 1107) participants in the third National Health and Nutrition Examination Survey, excluding diabetics and those supplemented with estrogen, vitamins or minerals, to evaluate the association between serum tHcy concentration and self-report of heart attack or stroke. After adjustment for age, race-ethnicity, smoking, blood pressure, blood pressure medication, body mass index and serum concentrations of creatinine and cholesterol, past events were reported 2.4 (95% confidence interval 1.0-5.5) times as often by men with tHcy concentration of >12 micromol/L as by men with lower values. The odds ratio for women was 2.6 (95% confidence interval 1.1-6.6) after adjustment for the same factors plus menopausal status. A stronger relation in men aged < or =60 y compared with older men may help reconcile conflicting results of earlier studies.

Adult↗
PubMed2000

Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolic acid (5-CH(3)-H(4) folic acid), the methyl donor for the formation of methionine from homocysteine. A common C677T transition in the MTHFR gene results in a variant with a lower specific activity and a greater sensitivity to heat than the normal enzyme, as measured in vitro. This study was undertaken to determine the capacity of homozygotes for the MTHFR C677T transition to convert 5-formyltetrahydrofolic acid (5-HCO-H(4) folic acid) to 5-CH(3)-H(4) folic acid, a process that requires the action of MTHFR. Six subjects homozygous for the C677T transition (T/T) and 6 subjects with wild-type MTHFR (C/C) were given a 5-mg oral dose of (6R:,S:)-5-HCO-H(4) folic acid. Plasma and urine were analyzed for 5-CH(3)-H(4) folic acid concentrations using affinity/HPLC coupled with fluorescence or UV detection. The mean areas under the curves created by the rise and fall of plasma 5-CH(3)-H(4) folic acid after the oral dose did not differ between the two genotypes, 424.5 +/- 140.3 (T/T) vs. 424.1+/- 202.4 h.nmol/L (C/C). There also was no significant difference in the mean cumulative 7-h urinary excretion of 5-CH(3)-H(4) folic acid between the T/T (2.5 +/- 1.4 micromol) and C/C (1.9 +/- 1.0 micromol) genotypes. Under the conditions employed, the conversion of oral 5-HCO-H(4) folic acid to 5-CH(3)-H(4) folic acid is not impaired in persons with the T/T MTHFR genotype. Possible reasons for these findings are discussed.

Administration, Oral↗
PubMed2000

Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification.

Recent studies have demonstrated associations between occlusive vascular disease and hyperhomocysteinemia of both genetic and nutritional origin. In the present study we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to vitamins that serve as coenzymes in homocysteine metabolism and to prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B12 and pyridoxal-5'-phosphate. We saw similar inverse associations between homocysteine and intakes of folate and vitamin B6, but not vitamin B12. Prevalence of high homocysteine (> 14 mumol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Prevalence of stenosis > or = 25% was 43% in men and 34% in women, with an odds ratio of 2.0 for individuals in the highest homocysteine quartile (> or = 14.4 mumol/L) compared with those in the lowest quartile (< or = 9.1 mumol/L), after adjustment for sex, age, HDL cholesterol, systolic blood pressure, and cigarette smoking (Ptrend < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and folate intake were inversely associated with extracranial carotid stenosis after adjustment for age, sex, and other risk factors. Studies using samples from the Framingham Study Offspring Cohort have shown that the US-mandated folic acid fortification of flour and cereal grain products resulted in an increase in the mean folate concentrations from 4.8 to 10.0 ng/mL (P < 0.001) and prevalence of low folate (< 3 ng/mL) decreased from 22.0 to 1.7% (P < 0.001) between the baseline and follow-up visits. Mean homocysteine concentration decreased from 10.1 to 9.4 microM (P < 0.001), and prevalence of high homocysteine (> 13 mumol/L) decreased from 18.7 to 9.8% (P < 0.001) between study visits. There were no statistically significant changes in the control group for folate or homocysteine between examinations. These data indicate a high prevalence of hyperhomocysteinemia in the Framingham Study population, the majority of which can be attributed to vitamin status and that this hyperhomocysteinemia is clinically relevant because of its association with increased risk of occlusive extracranial carotid stenosis. Insufficient levels of folate, and to a lesser extent vitamin B6, appear to predict part of this elevated risk through their role in homocysteine metabolism. These studies also indicate that the recently-implemented fortification of grain and cereal products with folic acid resulted in a substantial decline in plasma homocysteine. The impact of fortification on the US population is likely to be similar; however it awaits the next survey for further confirmation.

Aged↗