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Background: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. Methods: We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). Results: In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. Conclusions: In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.

Introduction: Diet quality may alter cardiometabolic risk by the modification of circulating lipid species. Ceramides are a class of sphingolipid implicated in cardiometabolic risk. We hypothesized that a higher diet quality may be associated with lower plasma concentrations of three ceramide species. Methods: Diet quality was reflective of adherence to the 2010 Dietary Guidelines for Americans and was determined using the 2010 dietary guideline adherence index (DGAI-2010) score. The DGAI-2010 score is composed of 14 energy specific components and 11 healthy choice components. A higher score represents higher adherence with a maximum score of 100. We determined the average cumulative DGAI-2010, reflective of usual diet quality over 14 years. Plasma ceramide concentrations were assayed using a validated LC-MS/MS protocol. Participants of Framingham Offspring cohort (N = 2174; mean age, 66 years; 55% women) according to quartile of DGAI-2010 score. Multivariable linear regression was used to relate diet quality to plasma ceramide concentrations (C16:0, C22:0, and C24:0), and to ceramide ratios (C22:0/C16:0 and C24:0/C16:0). An initial model was adjusted for age, sex, smoking status, use of lipid-lowering medication, total energy intake, and physical activity, and then additionally for body mass index (BMI). Results: The median (IQR) DGAI-2010 score within each quartile was Q1: 49 (7), Q2: 58 (4), Q3: 65 (3), and Q4: 73 (6). On average participants in the highest quartile (Q4) of DGAI-2010 score were older, more likely to be a woman, less likely to smoke, were slightly more physically active, and had a lower BMI (P trend trend Table 1 ). Conclusion: Inverse relations of dietary quality and select circulating ceramide species may help elucidate how diet may influence cardiometabolic risk.

Objective: Adherence to the Mediterranean- DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs) or brain atrophy. Methods: We aimed to evaluate, cross-sectionally and longitudinally, whether consumption of a diet consist with the MIND diet was associated with larger brain volumes, fewer SBIs and fewer atrophy in the community-based Framinham Heart Study. We included 1,904 participants (mean age 69 (SD, 9)) who completed a brain MRI and a validated food frequency questionnaire (FFQ). The MIND diet consists of 10 healthy and five unhealthy components (range: 0-15). A cumulative MIND diet score was calculated by averaging across three FFQs (exams 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001)). From the total study population, 86 % completed all three FFQs. Brain MRI was performed proximal to exam 7 and again after a mean of 7 years (SD, 1.1) (n=1,317). Total brain volume (TBV), hippocampal volume (HPV), white matter hyperintensity volume (WMHV), expressed as a percentage of total cranial volume, and presence of SBIs were assessed from MRI scans. We used multivariable linear (TBV, HPV and WMHV) and logistic (SBIs) regressions for the cross-sectional analyses, and we analyzed the annualized change of TBV and HPV as atrophy measures using multivariable linear regression. Results: In cross-sectional analyses, higher MIND diet scores were significantly associated with larger TBV (β±SE, +0.09±0.04; p=0.03) after adjustment for basic demographic factors, total daily energy intake, and APOE e4 allele status, but was not associated with HPV (+0.001±0.001; p=0.09), WMHV (-0.01±0.01; p=0.27), SBIs (OR (95%CI), +1.01, 0.92:1.10; p=0.61) or atrophy (TBV, -0.001±0.01; p=0.88; HPV, -0.0003±0.001; p=0.62). After additional adjustments for cardiovascular risk factors the association with TBV was attenuated (+0.05±0.04; p=0.17). Significant interactions were observed for HPV by APOE ε4 status and BMI in the basic model. After stratification by APOE ε4 status, higher MIND diet scores were significantly associated with higher HPV among APOE ε4 non-carriers (+0.002±0.001; p=0.01) but not carriers (n=412). After stratification by BMI, higher adherence to the MIND diet was associated with larger HPV among participants with a BMI above 25 (+0.002±0.001; p=0.01), but not among participants with a BMI below 25. Conclusions: Higher adherence to the MIND diet was not independently associated with brain volume measures, SBIs or brain atrophy in our community cohort as the associations appeared to be mediated by cardiovascular risk factors. In addition, we observed that adherence to the diet was associated with larger brain volume measures in sub groups. Replication is needed to confirm our findings.

Introduction: Ceramides are a class of sphingolipid that have been implicated in the pathogenesis of cardiometabolic diseases, and their circulating concentrations may be affected by foods that can alter hepatic lipid metabolism. We hypothesized that sugar-sweetened beverage (SSB) consumption may influence plasma concentrations of three ceramide species. Methods: Framingham Offspring cohort participants (N=2142; mean age, 65 years; 57% women) were categorized based on SSB consumption, as non-consumers (0 to < 1 serving/month), occasional consumers (1 serving/month to Results: Approximately 49% of participants were non-consumers, 20% occasional consumers, 25% frequent consumers, and 6% daily consumers, of SSBs. On average daily SSB consumers were younger, more likely to be men, more likely to smoke, had a lower diet quality, and were slightly more physically active (P trend trend trend trend Conclusion: In our cross-sectional community-based sample of middle-aged adults, SSB consumption was positively associated with plasma concentrations of several ceramide species but not with ceramide ratios. This study may help to elucidate mechanisms mediating the association between SSB consumption and higher risk of cardiometabolic diseases.

Background— Vitamin D receptors have a broad tissue distribution that includes vascular smooth muscle, endothelium, and cardiomyocytes. A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. Methods and Results— We studied 1739 Framingham Offspring Study participants (mean age 59 years; 55% women; all white) without prior cardiovascular disease. Vitamin D status was assessed by measuring 25-dihydroxyvitamin D (25-OH D) levels. Prespecified thresholds were used to characterize varying degrees of 25-OH D deficiency (P =0.01) for incident cardiovascular events compared with those with 25-OH D ≥15 ng/mL. This effect was evident in participants with hypertension (hazard ratio 2.13, 95% confidence interval 1.30 to 3.48) but not in those without hypertension (hazard ratio 1.04, 95% confidence interval 0.55 to 1.96). There was a graded increase in cardiovascular risk across categories of 25-OH D, with multivariable-adjusted hazard ratios of 1.53 (95% confidence interval 1.00 to 2.36) for levels 10 to P for linear trend=0.01). Further adjustment for C-reactive protein, physical activity, or vitamin use did not affect the findings. Conclusions— Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

Background— The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors. Methods and Results— We measured 8 circulating biomarkers reflecting inflammation (C-reactive protein), hemostasis (plasminogen activator inhibitor-1, fibrinogen), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide), and endothelial dysfunction (homocysteine) in 2292 Framingham Offspring Study participants (mean age, 57 years; 56% women). We related the biomarker panel to incidence of MetS on follow-up initially and then related biomarkers associated with incident MetS to longitudinal change in its components. On follow-up (mean, 2.9 years), 282 participants (of 1473 participants without prevalent MetS at baseline) developed MetS. After adjustment for clinical risk factors, the biomarker panel was associated with incident MetS ( P =0.008). On backward elimination, plasminogen activator inhibitor-1 and aldosterone remained associated with incident MetS (multivariable-adjusted odds ratio per 1-SD increment log marker, 1.31 [ P =0.004] and 1.21 [ P =0.015], respectively). In multivariable analyses evaluating longitudinal change in MetS components (analyzed as continuous variables), plasminogen activator inhibitor-1 was significantly and positively associated with changes in fasting glucose, systolic blood pressure, and triglycerides (all P P =0.023) and inversely with change in high-density lipoprotein cholesterol ( P =0.001). Conclusions— Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk.

Background— Increased arterial stiffness and higher plasma natriuretic peptide and homocysteine levels are associated with elevated risk for cardiovascular disease. Little is known about the relations of natriuretic peptides and homocysteine to arterial wall stiffness in the community. Methods and Results— We assessed the relations of plasma N-terminal atrial natriuretic peptide, B-type natriuretic peptide, adrenomedullin, and homocysteine concentrations to arterial stiffness in participants in the Framingham Heart Study. Central pulse pressure, forward pressure wave, reflected pressure wave, carotid-femoral pulse wave velocity, and carotid-radial pulse wave velocity were assessed by tonometry in 1962 participants (mean age, 61 years; 56% women) in the Framingham Heart Study. Central systolic and diastolic blood pressures were 123/75 mm Hg in men and 119/66 mm Hg in women. After adjustment for age and clinical covariates, N-terminal atrial natriuretic peptide and B-type natriuretic peptide were associated with carotid-femoral pulse wave velocity (men: partial correlation, 0.069, P =0.043 and r =0.115, P ≤0.001, respectively; women: r =−0.063, P =0.037 and r =−0.062, P =0.040), and carotid-radial pulse wave velocity (men: r =−0.090, P =0.009 and r =−0.083, P ≤0.015; women: r =−0.140, P ≤0.001 and r =-0.104, P =0.001, respectively). In men, N-terminal atrial natriuretic peptide and B-type natriuretic peptide also were associated with forward and reflected wave and carotid pulse pressure. In men, adrenomedullin was associated with mean arterial pressure ( r =0.089, P =0.009), and homocysteine was associated with carotid-femoral pulse wave velocity ( r =0.072, P =0.036), forward pressure ( r =0.079, P =0.02), and central pulse pressure ( r =0.072, P =0.035). Interaction tests indicated sex differences in the relations of several biomarkers to measures of arterial stiffness. Conclusions— Plasma natriuretic peptide, adrenomedullin, and homocysteine levels are associated with alterations in conduit vessel properties that differ in men and women.

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 μmol/L). This difference was largely attributable to lower plasma vitamin B 12 levels in the Israeli population. Male case offspring had higher adjusted tHcy than did controls (1.9 μmol/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.

Objective: To describe the influence of type of dietary fat on the activity of metabolic pathways, as measured by gene expression profiles, and the relation to plasma lipids. Background: Metabolic studies have demonstrated strong associations of dietary fatty acid composition with plasma lipids. Relatively little is known about the pathways and gene expression changes that mediate these relationships in the general population. Methods: We analyzed self-reported dietary intake of fatty acids, plasma lipid levels, and genome-wide gene expression data from Framingham Heart Study Offspring and Third Generation cohort participants. We excluded participants on lipid therapy. Multivariable linear regression models were conducted with plasma lipids as separate outcomes, energy-adjusted residuals of dietary fats as predictors, and adjustment for clinical and dietary covariates. Normalized gene expression from whole blood derived RNA was similarly modeled with additional adjustment for cell count and batch effects. Results: Among 3681 participants, higher polyunsaturated fatty acid (PUFA) intake is associated with lower LDL-C (estimated β [regression coefficient] = -0.5, p=0.002), higher HDL-C (β= 0.4, pFigure 1 ). Conclusions: Higher PUFA intake is associated with a less atherogenic lipid profile and higher ABCA1 expression with inverse associations for higher SFA intake. Gene expression analysis reveals important links between dietary fat type, specific cholesterol metabolism pathways, and lipids in a community cohort.

Background: Heritability measures the proportion of phenotypic variation attributable to genetic factors. Reliable heritability estimates are used to determine the necessary sample size and power for subsequent genetic studies of susceptibility genes. In addition to a shared nuclear genetic component, common environmental factors and maternal or mitochondrial inheritance may have strong effects on some phenotypes. Failure to account for necessary variance components may give rise to biased heritability estimates. Aims: Our primary goal was to investigate how heritability estimates are biased in the presence of common environmental or/and maternal effects. The second goal was to estimate mitochondrial inheritance for a number of common phenotypes. Methods: We employed variance component methods to account for additional variance components using both simulated and Framingham Heart Study (FHS) pedigree data to revisit heritability estimates in the presence of common environmental and maternal effects. Results: Using both simulated families and actual FHS extended pedigrees, we demonstrated that heritability is greatly overestimated when key variance components are not properly accounted for. The inflation in heritability ranged from 9% to 214% across several anthropometric, metabolic and life-style phenotypes when we compared models that consider correct variance components and simple models that only consider familial relationships (Table 1). Maternal inheritance was observed in most phenotypes investigated. The estimated maternal inheritance ranged from ~1 to 5%, which is considerable because the mitochondrial genome is about the size of an average gene. Conclusion/Discussion: We systematically investigated the influence of common environmental effects and maternal inheritance in heritability estimates using extended pedigrees. Our findings may explain, in part, the missing heritability for some traits and may facilitate further collaborations in the genetic study of mitochondrial DNA in disease susceptibility for common phenotypes.

Background— Several biological pathways are activated in ventricular remodeling and in overt heart failure (HF). There are no data, however, on the incremental utility of a parsimonious set of biomarkers (reflecting pathways implicated in HF) for predicting HF risk in the community. Methods and Results— We related a multibiomarker panel to the incidence of a first HF event in 2754 Framingham Heart Study participants (mean age, 58 years; 54 women) who were free of HF and underwent routine assays for 6 biomarkers (C-reactive protein, plasminogen activator inhibitor-1, homocysteine, aldosterone-to-renin ratio, B-type natriuretic peptide, and urinary albumin-to-creatinine ratio). We estimated model c statistic, calibration, and net reclassification improvement to assess the incremental predictive usefulness of biomarkers. We also related biomarkers to the incidence of nonischemic HF in participants without prevalent coronary heart disease. On follow-up (mean, 9.4 years), 95 first HF events occurred (54 in men). In multivariable-adjusted models, the biomarker panel was significantly related to HF risk ( P =0.00005). On backward elimination, B-type natriuretic peptide and urinary albumin-to-creatinine ratio emerged as key biomarkers predicting HF risk; hazards ratios per 1-SD increment in log marker were 1.52 (95 confidence interval, 1.24 to 1.87) and 1.35 (95 confidence interval, 1.11 to 1.66), respectively. B-type natriuretic peptide and urinary albumin-to-creatinine ratio significantly improved the model c statistic from 0.84 (95 confidence interval, 0.80 to 0.88) in standard models to 0.86 (95 confidence interval, 0.83 to 0.90), enhanced risk reclassification (net reclassification improvement=0.13; P =0.002), and were independently associated with nonischemic HF risk. Conclusion— Using a multimarker strategy, we identified B-type natriuretic peptide and urinary albumin-to-creatinine ratio as key risk factors for new-onset HF with incremental predictive utility over standard risk factors.

Background— Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial. Methods and Results— In 3120 Framingham cohort participants (mean age 58.4±9.7 years, 54% women), we related 10 biomarkers that represented inflammation (C-reactive protein and fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP] and N-terminal proatrial natriuretic peptide), oxidative stress (homocysteine), the renin-angiotensin-aldosterone system (renin and aldosterone), thrombosis and endothelial function (D-dimer and plasminogen activator inhibitor type 1), and microvascular damage (urinary albumin excretion; n=2673) to incident AF (n=209, 40% women) over a median follow-up of 9.7 years (range 0.05 to 12.8 years). In multivariable-adjusted analyses, the biomarker panel was associated with incident AF ( P P P P =0.004) were chosen. The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95% confidence interval 0.75 to 0.81) to 0.80 (95% confidence interval 0.78 to 0.83) and showed an integrated discrimination improvement of 0.03 (95% confidence interval 0.02 to 0.04, P Conclusions— BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention requires further investigation.

Background— Arterial stiffness increases with age and contributes to the pathogenesis of systolic hypertension and cardiovascular disease in the elderly. Knowledge about the pathophysiological processes that determine arterial stiffness may help guide therapeutic approaches. Methods and Results— We related 7 circulating biomarkers representing distinct biological pathways (C-reactive protein, aldosterone-to-renin ratio, N-terminal proatrial natriuretic peptide and B-type natriuretic peptide, plasminogen activator inhibitor-1, fibrinogen, and homocysteine) to 5 vascular function measures (central pulse pressure, carotid-femoral pulse-wave velocity, mean arterial pressure, forward pressure wave amplitude [all measures of conduit artery stiffness], and augmented pressure, an indicator of wave reflection) in 2000 Framingham Offspring Study participants (mean age, 61 years; 55% women). Tonometry measures were obtained on average 3 years after the biomarkers were measured. In multivariable linear regression models adjusting for covariates, the biomarker panel was significantly associated with all 5 vascular measures ( P P ≤0.002 for all). In addition, C-reactive protein was positively related to augmented pressure ( P =0.0003), whereas plasminogen activator inhibitor-1 was positively associated with mean arterial pressure ( P =0.003), central pulse pressure ( P =0.001), and forward pressure wave ( P =0.01). Conclusions— Our cross-sectional data on a community-based sample suggest a distinctive pattern of positive associations of biomarkers of renin-angiotensin-aldosterone system activation with pan-arterial vascular stiffness, plasminogen activator inhibitor-1 with central vascular stiffness indices, and C-reactive protein with wave reflection. These observations support the notion of differential influences of biological pathways on vascular stiffness measures.

Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine. Methods and Results To assess the potential interaction between this mutation and vitamin coenzymes in homocysteine metabolism, we screened 365 individuals from the NHLBI Family Heart Study. Among individuals with lower plasma folate concentrations (P Conclusions Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.

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 P 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.

Background —The hyperhomocysteinemia regularly found in hemodialysis patients is largely refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high-dose l -5-methyltetrahydrofolate–based regimen provided improved total homocysteine (tHcy)–lowering efficacy in chronic hemodialysis patients. Methods and Results —We block-randomized 50 chronic, stable hemodialysis patients on the basis of their screening predialysis tHcy levels, sex, and dialysis center into 2 groups of 25 subjects treated for 12 weeks with oral folic acid at 15 mg/d (FA group) or an equimolar amount (17 mg/d) of oral l -5-methyltetrahydrofolate (MTHF group). All 50 subjects also received 50 mg/d of oral vitamin B 6 and 1.0 mg/d of oral vitamin B 12 . The mean percent reductions (±95% CIs) in predialysis tHcy were not significantly different: MTHF, 17.0% (12.0% to 22.0%); FA, 14.8% (9.6% to 20.1%); P =0.444 by matched ANCOVA adjusted for pretreatment tHcy. Final on-treatment values (mean with 95% CI) were MTHF, 20.0 μmol/L (18.8 to 21.2 μmol/L); FA, 19.5 μmol/L (18.3 to 20.7 μmol/L). Moreover, neither treatment resulted in “normalization” of tHcy levels (ie, final on-treatment values P =0.490. Conclusions —Relative to high-dose folic acid, high-dose oral l -5-methyltetrahydrofolate–based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (ie, >90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution.

P85 Background:The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high dose L-folinic acid based regimen provided improved total homocysteine (tHcy) -lowering efficacy in chronic hemodialysis patients, as suggested by a recent uncontrolled report. Methods and Results: We block randomized 48 chronic, stable hemodialysis patients based on their screening pre-dialysis tHcy levels, sex, and dialysis center, into 2 groups of 24 subjects treated for 12-weeks with oral folic acid (FA) at 15 mg/day, or an equimolar amount (20 mg/day) of oral L-folinic acid(FNA)[L-5-formyltetrahydrofolate]. All 48 subjects also received 50 mg/day of oral vitamin B6, and 1.0 mg/day of oral vitamin B12. The mean percent (%) reductions (with 95% confidence intervals) in pre-dialysis tHcy were not significantly different: FNA= 22.1% (11.8-31.4%) ; FA=20.7% (11.7-30.5%) ; P= 0.950 by paired t-test. Final on-treatment values (mean with 95% confidence interval) were, FNA: 15.9 μmol/L (14.0-18.0); FA: 16.9 μmol/L (14.8-18.8). Moreover, in those subjects with baseline tHcy levels ≥14 μmol/L, neither treatment resulted in normalization of tHcy levels (i.e., final on-treatment values < 12 μmol/L) among a significantly different, or clinically meaningful number of patients: FNA= 2/22 (9.1%); FA= 2/24 (8.3%); Fisher s exact test of between groups difference, P=1.000. Conclusions: Relative to high dose folic acid, high dose oral L-folinic acid -based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (i.e., > 90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen.

P86 Background: The prevalence of both deficient plasma folate status, and elevated total (t) plasma levels of the putatively atherothrombotic amino acid homocysteine (Hcy), have been dramatically reduced since the recent advent of fortification of all enriched cereal grain flour products with physiological amounts (i.e., 140 μg/ 100 g flour) of folic acid. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid based B-vitamin supplementation among stable coronary artery disease (CAD) patients. Methods and Results: Using a 2x2 factorial design, we randomly assigned 131 stable CAD patients (mean age 60.1 years; 29.8 % women) to folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d [ FA group] or FA placebo [PL] , ± B6 [ B6 group] 50 mg/d or B6 placebo[PL], for 12 weeks of treatment. All pre-treatment and final on-treatment analyte values were based on the average of two blood collections performed within 1-week. Geometric mean pre-treatment, on-treatment, and pre-treatment minus on-treatment change in (Δ) tHcy levels (μmol/L), were- FA, B6 (n=31): 8.7 (pre-), 7.4 (on-), Δ= -1.3; B6, PL (n=32): 8.7 (pre-), 9.1 (on-), Δ= + 0.4; FA, PL (n=34): 9.0 (pre-), 8.0 (on-), Δ= - 1.0; PL, PL (n=34): 8.4 (pre-), 8.5 (on-), Δ= + 0.1. ANCOVA adjusted for baseline tHcy levels revealed that the very modest (i.e., ∼ 1.0 μmol/L) reductions in fasting values afforded by the FA containing treatments were statistically significant (p