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Supplement: 5th Amino Acid Assessment Workshop: Session III

The Many Facets of Hyperhomocysteinemia: Studies from the Framingham Cohorts^1,2

Vitamin Metabolism and Aging Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111

³ To whom correspondence should be addressed. E-mail: jacob.selhub{at}tufts.edu.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of 2 pathways: remethylation, which requires folic acid and B-12 coenzymes, and transsulfuration, which requires pyridoxal-5'-phosphate, the B-6 coenzyme. Data from several studies suggest that mild elevations of homocysteine in plasma are a risk factor for occlusive vascular disease. In the Framingham studies we have shown that plasma total homocysteine concentration is inversely related to the intake and plasma levels of folate and vitamin B-6 as well as vitamin B-12 plasma levels. Almost two-thirds of the prevalence of high homocysteine is attributable to low vitamin status or intake. Elevated homocysteine concentrations in plasma are a risk factor for prevalence of extracranial carotid artery stenosis of at least 25% in both men and women. Prospectively elevated plasma homocysteine is associated with increased total and CVD mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer's disease, increased incidence of bone fracture, and higher prevalence of chronic heart failure. This multitude of relationships between elevated plasma total homocysteine and diseases that afflict the elderly point to the existence of a common denominator that may be responsible for these diseases. Whether this denominator is homocysteine itself or whether homocysteine is merely a marker remains to be determined.

KEY WORDS: • total homocysteine • folate • vitamin B-12 • vitamin B-6 • cardiovascular disease • stenosis • stroke • dementia • bone fractures • chronic heart failure

The initial link between homocysteine and vascular disease was made by McCully over 35 y ago (1). He observed that an infant who died as a result of a rare genetic condition of abnormal cobalamin metabolism with homocystinuria exhibited widespread, severe arteriosclerosis analogous to the lesions seen in cases of homocystinuria caused by a genetic cystathionine ß-synthase deficiency. Because hyperhomocysteinemia was the only condition common to these 2 metabolic disorders, McCully proposed that hyperhomocysteinemia resulted in arteriosclerotic disease.

Although McCully's hypothesis did not gain immediate support, the association between plasma homocysteine concentration and arteriosclerosis has more recently become the subject of a number of clinical studies. In 1976, Wilcken and Wilcken showed that the concentration of homocysteine-cysteine mixed disulfide after a methionine load was slightly higher in coronary heart disease (CHD)⁴ patients than in respective age- and sex-matched controls (2). This pioneering work has led to many studies that have been the subject of a number of important review articles. The first by Ueland et al. (3) summarized 17 studies that presented fasting homocysteine concentrations for 1500 patients with various forms of vascular disease and a similar number of normal controls. Fasting homocysteine concentrations were consistently elevated among patients with all types of vascular disease and averaged 31% greater than concentrations among controls. Abnormal homocysteine metabolism was also measured in some studies by presenting individuals with a large oral dose of methionine, which is a homocysteine precursor. Frequencies of abnormal homocysteine response to methionine loading were higher (24%) in patients with vascular disease than in healthy controls (2%).

The meta-analysis by Boushey et al. (4) in 1995 involved 27 studies including prospective and population-based case-control studies. These studies concluded that elevations of plasma total homocysteine (tHcy) were considered an independent graded risk factor for arteriosclerotic vascular disease with odds ratios for 5µmol/L increase in plasma tHcy that ranged from 1.5 to 1.8 for men and women with CHD, cerebrovascular or peripheral vascular diseases.

In recent years, however, there has been a debate on whether tHcy elevation is truly a risk factor or an epiphenomenon resulting from kidney disease that is often an integral part of any atherosclerotic disease (5,6). This debate was also extended to those studies that failed to show any relation between homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, which is associated with mild elevations of plasma tHcy and atherosclerotic disease (7).

A meta-analysis in 1998 showed that the C677T mutation of the MTHFR gene is a weak risk factor for cardiovascular disease (8). A major shortcoming of this review, however, lies in the fact that the prevalence of this mutation is different in various ethnic groups. It is practically nonexistent in blacks and can reach as high as 35% homozygosity in indigenous Mexicans (9). Many of the studies may have not chosen the proper control population. Another factor that influences the result is likely to be the folate status of the population: Klerk et al. (9) showed in a more recent meta-analysis that the odds of CHD in European populations having the TT genotype compared with the CC genotype were 1.14 (95% C.I. 1.01–1.28), whereas in North America the odds were 0.87 (0.73–1.05). The overall result from this meta-analysis is that individuals with the TT genotype have odds of 1.16 (1.05–1.28) of CHD, almost exactly the predicted increase from the observed elevation in plasma tHcy in those with the TT genotype (6). In an approach based on the concept of Mendelian randomization, the observed increase in risk of stroke among individuals homozygous for the MTHFR T allele was close to that predicted from the differences in tHcy concentration conferred by this variant (1.93 µmol/L higher in TT genotype than in CC genotype) (10). A meta-analysis in 2002 showed that the relation between elevated plasma tHcy and vascular disease is stronger in retrospective than in prospective studies (11) . In the prospective population, a 25% lower tHcy level (about 3 µmol/L) is associated with an 11% lower risk of ischemic heart disease and about 19% lower stroke risk. The authors concluded that elevated tHcy is at most a modest independent predictor of ischemic heart disease and stroke in a healthy population.

The Framingham Study

Our interest in homocysteine was prompted by the possibility that plasma tHcy may serve as an indicator of the status and perhaps the intake of a number of vitamins, including folic acid, vitamin B-12, and vitamin B-6. This possibility derived from the large number of studies that implied that methionine metabolism is tightly regulated and from other studies that showed that deficiencies in the above vitamins are often associated with hyperhomocysteinemia (12). We examined members of the original Framingham Heart Study cohort, a population-based sample of 5209 men and women originally examined in 1948–1952 (13) to study heart disease and followed prospectively to the present to assess the occurrence of vascular disease. Our first study was based on 1401 survivors of the original cohort who participated in the 20th biennial examination (1989–90). Total homocysteine and carotid ultrasound measures were available for 1041 individuals (418 men and 623 women), aged 67 to 96 y at the time of data collection (14,15). The main findings of these studies were as follows.

Total homocysteine distribution and prevalence of high tHcy concentrations

The mean tHcy concentration for all subjects was 11.9 µmol/L (median 11.6 µmol/L). Values ranged from 3.5 to 66.9 µmol/L. Total homocysteine concentration was higher in men than in women and increased with age (14,15) . The increase with age remained highly significant (P < 0.001) for men and women after adjustment for plasma vitamin concentrations, but the difference between men and women was no longer statistically significant.

We defined high tHcy as the concentration greater than the 90th percentile among subjects with all plasma vitamin levels above the 70th percentile (14.0 µmol/L). Prevalence of high tHcy was 29.3% for the entire cohort and over 40% for individuals aged 80 y and older.

Mean tHcy concentration by vitamin status and intake

    Folate. Mean plasma tHcy concentrations for subjects in the 2 lowest deciles of plasma folate (below 4.8 nmol/L) were 15.6 and 13.7 µmol/L, respectively. These were significantly greater than the mean for subjects in the highest decile, which was 11.0 µmol/L (P < 0.01). Mean tHcy concentrations for subjects in the 3 lowest deciles of folate intake (<253 µg/day) were 13.7, 12.9, and 13.2 µmol/L, respectively, and were significantly greater than the mean for subjects in the highest intake decile, which was 10.4 µmol/L (P < 0.01).

    Vitamin B-12. Mean tHcy concentrations were significantly elevated for subjects in the lowest decile for vitamin B-12 relative to subjects in the highest decile (P < 0.01). Mean tHcy concentrations were 15.4 and 10.9 µmol/L for subjects in the lowest and highest vitamin B-12 deciles, respectively. Subjects in the lowest vitamin B-12 decile had vitamin B-12 concentrations below 139 pmol/L. Vitamin B-12 intake appeared unrelated to mean tHcy concentration even though subjects in the fifth decile had significantly higher tHcy concentrations than subjects in the highest decile (P < 0.05).

    Vitamin B-6. Mean tHcy concentrations were significantly elevated for subjects in the lowest decile of pyridoxal-5'-phosphate (PLP) relative to subjects in the highest decile for this vitamin (P < 0.01). Mean tHcy concentrations were 14.3 and 10.9 µmol/L for subjects in the lowest and highest PLP deciles. Subjects in the lowest decile had PLP concentrations below 18.1 nmol/L. For vitamin B-6 intake, mean tHcy concentrations were significantly elevated in the lowest 2 deciles (P < 0.01) and the third decile (P < 0.05). Mean tHcy concentrations were 13.4, 12.4, and 12.3 µmol/L for subjects in the lowest 3 deciles; the mean in the highest decile was 10.1 µmol/L. Subjects in the lowest 3 intake deciles reported consuming less than 1.75 mg/day.

Total homocysteine concentrations by overall vitamin status

We divided the population into 5 categories based on their overall vitamin status. Category 1 represents those people whose vitamin status was greater than the 70th percentile for all 3 of the vitamins (folate, B-6, and B-12), which includes many of those who are taking vitamin supplements. The fifth category represents those whose vitamin status is below the 30th percentile, whereas categories in between represent those whose vitamin status was between the first and the fifth categories. Mean tHcy and the prevalence of high tHcy increased dramatically across categories of the B-vitamin index. Mean tHcy concentration was 75% greater in the lowest relative to the highest index categories. The prevalence of high tHcy was almost 6-fold greater among subjects in the lowest index category compared with subjects in the highest category for plasma index. Sixty-seven percent of the cases of high tHcy in this cohort of older subjects were associated with at least 1 vitamin concentration below the 70th percentile. Although the prevalence of high tHcy was substantially greater in lower vitamin categories (4 and 5) than in the middle category, this latter category contributed the largest share of cases of high tHcy for the index because it included the largest proportion of the cohort.

Relation between plasma tHcy and disease in the Framingham Study

    Relation between tHcy and extracranial carotid artery stenosis. The prevalence of extracranial carotid stenosis over 25% was 43% and 34% in men and women, respectively. In men, the prevalence of stenosis over 25% was 27% (95% confidence interval 17 to 38%) in the lowest tHcy quartile and 58% (95% confidence interval 49 to 67%) in the highest quartiles (P_trend < 0.001). The relation in women was not as striking as that in men: prevalence of stenosis at least 25% ranged from 31% (95% confidence interval 24 to 38%) to 39% (95% confidence interval 31 to 47%) across tHcy quartiles (P_trend = 0.03). Whereas the risk of stenosis appeared to increase in the second tHcy quartile (9.1 to 11.3 µmol/L) among men, it did not appear to increase until the third tHcy quartile (11.4 to 14.3 µmol/L) among women. Although the prevalence of stenosis appeared somewhat greater among men than women in the upper quartiles of tHcy, a test of interaction between sex and tHcy indicated that the trends for prevalence of stenosis over 25% were not significantly different for men and women (P = 0.07).

    Relation between tHcy and stroke incidence. In this study (16), we examined the prospective relation between baseline plasma tHcy levels and stroke incident after a 9.9 y of follow-up. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other 3 quartiles were as follows: quartile 2 compared with quartile 1, RR 1.32 (95% CI 0.81 to 2.14); quartile 3 compared with quartile 1, RR 1.44 (CI 0.89 to 2.34); quartile 4 compared with quartile 1, RR 1.82 (CI 1.14 to 2.91). The linear trend across the quartiles was significant (P < 0.001). These data are consistent with the notion that tHcy levels are an independent risk factor for incident stroke.

    Relation between tHcy and mortality. In this study (17), we examine baseline plasma tHcy levels and all-cause and CVD mortality during a median follow-up of 10.0 y. There were 653 total deaths and 244 CVD deaths during this period. Proportional hazards modeling revealed that tHcy levels of 14.26 µmol/L or greater (the upper quartile) versus <14.26 µmol/L (the lowest 3 quartiles) were associated with relative risk estimates of 2.18 (95% CI 1.86–2.56) and 2.17 (95% CI 1.68–2.82) for all-cause and CVD mortality, respectively. The relative risk estimates after adjustment for age, sex, systolic blood pressure, diabetes, smoking, and total and high-density lipoprotein cholesterol levels attenuated these associations, but they remained significant: 1.54 (95% CI 1.31–1.82) for all-cause mortality; 1.52 (95% CI 1.16–1.98) for CVD mortality. These data suggest that elevated plasma tHcy levels are independently associated with increased rates of all-cause and CVD mortality in the elderly.

Plasma tHcy as a risk factor for dementia and Alzheimer's disease

In cross-sectional studies (18), elevated plasma tHcy levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required to establish whether the elevated tHcy levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. We examined the relation of the plasma tHcy level measured at baseline and that measured 8 years earlier in the Framingham Study Original Cohort to the risk of newly diagnosed dementia on follow-up. Over a median follow-up period of 8 years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95% confidence interval 1.1 to 1.9) for each increase of 1 SD in the log-transformed tHcy value either at baseline or 8 years earlier. The relative risk of Alzheimer's disease was 1.8 (95% confidence interval 1.3 to 2.5) per increase of 1 SD at baseline and 1.6 (95% confidence interval, 1.2 to 2.1) per increase of 1 SD 8 years before baseline. With a plasma tHcy level >14 µmol/L, the risk of Alzheimer's disease nearly doubled. These data suggest that an increased plasma tHcy level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.

Homocysteine as a predictive factor for hip fracture in older persons

The increased prevalence of osteoporosis among people with homocystinuria suggests that a high serum tHcy concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture (19). We examined the association between the tHcy concentration and the risk of hip fracture in men and women enrolled in the Framingham Study. We studied 825 men and 1174 women, ranging in age from 59 to 91 y, from whom blood samples had been obtained between 1979 and 1982 to measure plasma tHcy. The participants in our study were followed from the time that the sample was obtained through June 1998 for incident hip fracture. Sex-specific, age-adjusted incidence rates of hip fracture were calculated for quartiles of tHcy concentrations. Cox proportional-hazards regression was used to calculate hazard ratios for quartiles of tHcy values.

The mean (±SD) plasma tHcy concentration was 13.4 ± 9.1 µmol/L in men and 12.1 ± 5.3 µmol/L in women. The median duration of follow-up was 12.3 y for men and 15.0 y for women. There were 41 hip fractures among men and 146 among women. The age-adjusted incidence rates per 1000 person-years for hip fracture, from the lowest to the highest quartile for tHcy, were 1.96 (95% confidence interval 0.52 to 3.41), 3.24 (0.97 to 5.52), 4.43 (1.80 to 7.07), and 8.14 (4.20 to 12.08) for men and 9.42 (5.72 to 13.12), 7.01 (4.29 to 9.72), 9.58 (6.42 to 12.74), and 16.57 (11.84 to 21.30) for women. Men and women in the highest quartile had a greater risk of hip fracture than those in the lowest quartile: the risk was almost 4 times as high for men and 1.9 times as high for women.

These findings suggest that the tHcy concentration is an important risk factor for hip fracture in older persons.

Plasma tHcy and risk for congestive heart failure in adults without prior myocardial infarction

In this study (20), we examined prospectively the association between plasma tHcy and incidence of CHF in 2491 adults (mean age 72 y, 1547 women) who participated in the Framingham Heart Study during the 1979–1982 and 1986–1990 examinations and were free of CHF or prior myocardial infarction (recognized or unrecognized) at baseline.

During an 8-y follow-up period, 156 subjects (88 women) developed CHF. In multivariable analyses controlling for established risk factors for CHF including the occurrence of myocardial infarction (recognized or unrecognized) during follow-up, plasma tHcy levels higher than the sex-specific median value were associated with an adjusted hazards ratio for heart failure of 1.93 in women (95% confidence interval 1.19–3.14) and 1.84 in men (95% confidence interval 1.06–3.17). The relation of plasma tHcy levels to CHF risk was more continuous in women than in men. In analyses restricted to participants without any manifestation of coronary heart disease at baseline, the association of plasma tHcy levels with risk of CHF was maintained in men and women.

These data suggest that an increased plasma tHcy level independently predicts risk of the development of CHF in adults without prior myocardial infarction.

    Relations of plasma tHcy to left ventricular structure and function. In this study (21), we investigated if tHcy promotes left ventricular (LV) remodeling. We examined cross-sectional relations of plasma tHcy to echocardiographic LV structure and function in 2697 Framingham Offspring Heart Study participants (mean age 58 y, 58% women) free of heart failure and previous myocardial infarction. Adjusted for age and height, plasma tHcy was positively related to LV mass, wall thickness, and relative wall thickness in women (P = 0.0004–0.04), but not in men (P = 0.28–0.68). Adjusted additionally for other clinical covariates, the relations of plasma tHcy to LV mass and wall thickness in women remained statistically significant, but the relation to relative wall thickness became of borderline significance (1.92 g, 0.01 cm, and 0.29% increase, respectively, for a 1-SD increase in ln{tHcy}, P = 0.01–0.08). LV mass and wall thickness were higher in the fourth quartile of plasma tHcy compared to the lower 3 in all models in women (P = 0.0003–0.02), but not in men (P = 0.25–0.78). Plasma tHcy was not related to left atrial size or LV fractional shortening in either sex.

These data suggest that in our community-based sample, plasma tHcy was directly related to LV mass and wall thickness in women but not in men.

The many facets of hyperhomocysteinemia

This review of the studies done on the Framingham Cohorts relating plasma tHcy to mortality and various diseases that afflict the elderly is an example of the ever-expanding studies on the relation of elevated plasma tHcy and diseases. Although many of these relationships were begun with observations from homocystinuric patients, it is important to point out the difference between these patients whose tHcy concentrations could reach as high as 400 µmol/L and those with mild elevations of tHcy, where the concentrations do not exceed 35 µmol/L and the difference between disease and control population can be as low as 1–2 µmol/L.

Given these many relationships between mild elevations of tHcy in plasma and a variety of diseases, a most likely interpretation is that these elevations of plasma tHcy represent unfavorable conditions that resulted in increased plasma tHcy level. The fact that many in vitro and in vivo animal studies have demonstrated direct "toxic effects" of tHcy does not pose a conflict with the above interpretation. These toxic effects are attained under conditions and at concentrations that are not comparable to these epidemiological observations. Knockout mice with CBS and MTHFR deficiencies did not exhibit characteristic vascular disease as seen in humans (22,23) . Studies using excess methionine intake as a model for hyperhomocysteinemia (24–30) neglect the fact that methionine per se is highly toxic, and this toxicity is unrelated to elevated plasma tHcy levels (31). Our group has recently shown that in the ApoE-null mice, hyperhomocysteinemia induced by vitamin deficiency alone caused no increase in aortic plaque area beyond what was seen in mice fed the control diet (32). On the other hand, feeding excess methionine with or without vitamin deficiency did result in significantly higher plaque area in the aorta, even when plasma tHcy was the same as in control mice. High tHcy did, however, appear to affect behavior in these mice as determined by water maze escape latency (A. Troen, unpublished data).

Results from recently finished intervention trials appear to be consistent with the above possibility. The VISP (Vitamin Intervention for Stroke Prevention) trial is a randomized, "placebo-controlled" trial that involved close to 3800 patients with nondisabling cerebral stroke. One group was supplemented for 2 years with a daily dose of a high-vitamin mixture (25 mg B-6, 2.5 mg FA, 0.4 mg B-12); the second group was supplemented for 2 years with a daily dose with a low-vitamin mixture (0.2 mg B-6, 0.02 mg FA, 0.006 mg B-12). The initial data from the 2-year follow-up showed no difference between groups with respect to ischemic stroke, coronary disease, or death (33). Most recently, Spence et al. (34) have reanalyzed the data from the VISP trial using the argument that the fortification of food with folate has blunted the efficacy of folate in preventing recurrent events, and hence, one should analyze the data based on B-12 as the major nutritional determinant of tHcy. To do so they excluded those with low B-12 with the idea that they are probably not absorbing this vitamin; those patients who have been taking supplemental vitamin B-12 that was not included in the mix; and those with renal insufficiency because B-12 would be ineffective in reducing plasma tHcy. Analysis for efficacy among those that were not excluded (n = 2175) demonstrated that those receiving the high-vitamin mix had 21% fewer events than those who received the lower-vitamin mix (P = 0.05 before and 0.058 after adjusting for confounding factors). Furthermore, this analysis also showed that those whose baseline B-12 is above the median and were assigned to the high-vitamin group had significantly fewer events than those whose baseline B-12 level was below the median and who received the low-vitamin mix.

The NORVIT trial (35), which has been recently completed but not yet reported in full, involved 3749 patients, age 30 to 84, from 35 Norwegian hospitals. Trial participants were randomized to 1 of 4 study groups: a combination folic-acid/B-12 and vitamin-B-6 group, a folic-acid/B-12-only group, a vitamin-B-6 group, and a placebo group. Doses used for each group were 0.8 mg daily for folic acid and 40 mg daily for vitamin B-6; 0.4 mg of vitamin B-12 was given with the folic-acid dose. The primary endpoint of the trial was a combination of nonfatal and fatal MI and stroke after 3.5 y. Secondary endpoints included death, stroke, MI, need for PCI/CABG, and hospitalization for unstable angina. No differences in fatal or nonevents were found between the folate/B-12 and the B-6 groups compared to the placebo group. The group who received the combination of 3 vitamins, however, seems to have experienced slightly higher rates of events (P < 0.05). This is despite the fact that tHcy had decreased in the latter group by as much as 31%.

Two other trials on restenosis after angioplasty appear to yield different results. A placebo-controlled trial by Schnyder et al. has shown that daily supplementation for 6 months with a vitamin mix containing 1 mg folic acid, 0.4 mg B-12, and 10 mg B-6 in patients after successful coronary angioplasty was associated with decreased rate of restenosis and revascularization need of the target lesion (36).

The second placebo-controlled trial by Lange et al. involved 636 patients who had coronary stenting who received for 6 mo either a daily dose of 48 mg B-6, 1.2 mg folic acid, and 0.06 mg B-12 or placebo (37). Data from this trial have shown that the vitamin group has experienced smaller mean minimal luminal diameter, greater late luminal loss, higher restenosis rate, and higher percentage of patients required repeated target-vessel revascularization.

Concluding remarks

The relationships between tHcy and disease are too strong to be ignored, despite the many uncertainties. Many of these uncertainties are attributable to the hypothesis that tHcy is the cause for the disease. Our data on the pleiotropic relation between tHcy and various diseases, and the fact that in the majority of cases differences in tHcy concentrations between healthy and disease populations are small, are supportive of the idea that tHcy is a marker, rather than the cause for the respective disease. This would imply that not all cases of elevated tHcy in plasma contribute to a disease risk. For example, high niacin intake to lower blood lipids results in hyperhomocysteinemia because of "detoxification" of niacin through methylation by SAM (38). There is no evidence that this increase in tHcy poses any risk.

It is therefore important to understand what elevated tHcy in plasma represents. Deficiency of folate and other related vitamins provides more reasonable bases for relating pleiotropic relationships with diseases. Observed discrepancies between the outcomes of the intervention trials should be used to understand what works and what doesn't. Both the NORVIT trial (35) and that by Lange et al. (37) used large amounts of vitamin B-6 (40–48 mg/d). Could these high doses be detrimental? It is important to point out that vitamins are micronutrients, not drugs, and should be used as such.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented at the conference "The Fifth Workshop on the Assessment of Adequate Intake of Dietary Amino Acids" held October 24–25, 2005 in Los Angeles. The conference was sponsored by the International Council on Amino Acid Science (ICAAS). The organizing committee for the workshop and guest editors for the supplement were David H. Baker, Dennis M. Bier, Luc Cynober, Yuzo Hayashi, Motoni Kadowaki, and Andrew G. Renwick. Guest editors disclosure: all editors received travel support from ICAAS to attend the workshop.

² This material is based on work supported by the U.S. Department of Agriculture, under agreement No. 1950-51520-008. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author and do not necessarily reflect the view of the U.S. Dept of Agriculture.

⁴ Abbreviations used: CHD, coronary heart disease; CHF, congestive heart failure; LV, left ventricular; PLP, pyridoxal-5'-phosphate; tHcy, total homocysteine.

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