Increased dietary micronutrients decrease serum homocysteine
concentrations in patients at high risk of cardiovascular disease1–3
Alan Chait, M Rene Malinow, David N Nevin, Cynthia D Morris, Rebecca L Eastgard, Penny Kris-Etherton,
F Xavier Pi-Sunyer, Suzanne Oparil, Lawrence M Resnick, Judith S Stern, R Brian Haynes, Daniel C Hatton, Jill A Metz,
Sharon Clark, Margaret McMahon, Scott Holcomb, Molly E Reusser, Geoffrey W Snyder, and David A McCarron
KEY WORDS
Homocysteine, dietary folate, vitamin B-12,
vitamin B-6, cardiovascular disease, randomized clinical trial,
humans
INTRODUCTION
An elevated serum total homocysteine (tHcy) concentration is
now recognized as an important, independent risk factor for
cardiovascular disease (1–3). A rapidly growing number of case-
control (1), retrospective (1, 3–5), and prospective (6–10)
studies have reported a relation between elevated tHcy concentrations and early-onset vascular disease in coronary, cerebral,
and peripheral arteries. Graham et al (11) detected hyperhomocysteinemia in 42% of patients with cerebrovascular disease,
28% with peripheral vascular disease, and 30% with coronary
vascular disease. From the Physicians’ Health Study, it was
reported that baseline tHcy concentrations were markedly higher
in men who later had myocardial infarctions than in matched control subjects, and that <7% of cases could be attributed to elevated tHcy concentrations (7). In a Framingham cohort that was
older and more representative of the US population, the prevalence of high tHcy concentrations was 29% (12). More recently,
Nygard et al (10) observed a strong, graded association between
plasma tHcy concentrations and overall mortality in patients with
angiographically confirmed coronary artery disease.
Elevated tHcy concentrations can be the result of genetic disorders (13, 14) or vitamin deficiencies (15, 16). Observational
1
From the Division of Metabolism, Endocrinology, and Nutrition, the
Department of Medicine, and the Interdisciplinary Nutrition Sciences Program, University of Washington, Seattle; the Laboratory of Cardiovascular
Diseases, Oregon Regional Primate Research Center, Beaverton; the Division
of Nephrology, Hypertension, and Clinical Pharmacology, the Department of
Medicine, Oregon Health Sciences University, Portland; the Nutrition
Department, College of Health and Human Development, Pennsylvania State
University, University Park; the Division of Endocrinology, Diabetes, and
Nutrition, St Luke’s–Roosevelt Hospital, Columbia University, New York; the
Hypertension Program, University of Alabama at Birmingham; the Division
of Endocrinology/Hypertension, Wayne State University Medical Center,
Detroit; the Division of Clinical Nutrition, the Department of Nutrition and
Metabolism, University of California, Davis Medical Center, Davis; the
Department of Clinical Epidemiology and Biostatistics, McMaster University,
Hamilton, Canada; and the Clinical Research Group of Oregon, Portland.
2
Supported by Campbell’s Center for Nutrition and Wellness, Campbell
Soup Company, Camden, NJ.
3
Address reprint requests to DA McCarron, Division of NephrologyPP262, Oregon Health Sciences University, 3314 SW US Veterans Hospital
Road, Portland, OR 97201-2940. Address correspondence to A Chait, Division of Metabolism, Endocrinology, and Nutrition, Box 356426, University
of Washington, Seattle, WA 98195-6426. E-mail: [email protected].
Received October 30, 1998.
Accepted for publication March 22, 1999.
Am J Clin Nutr 1999;70:881–7. Printed in USA. © 1999 American Society for Clinical Nutrition
881
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ABSTRACT
Background: Elevated blood homocysteine is a risk factor for
cardiovascular disease. A 5-mmol/L increase is associated with
an <70% increase in relative risk of cardiovascular disease in
adults. For patients with established risk factors, this risk is
likely even greater.
Objective: Effects of increased dietary folate and recommended
intakes of vitamins B-12 and B-6 on serum total homocysteine
(tHcy) were assessed in individuals at high risk of cardiovascular disease.
Design: This trial was conducted at 10 medical research centers in the United States and Canada and included 491 adults
with hypertension, dyslipidemia, type 2 diabetes, or a combination thereof. Participants were randomly assigned to follow a
prepared meal plan (PMP; n = 244) or a self-selected diet
(SSD; n = 247) for 10 wk, which were matched for macronutrient content. The PMP was fortified to provide ≥ 100% of the
recommended dietary allowances for 23 micronutrients, including folate.
Results: Mean folate intakes at 10 wk were 601 ± 143 mg/d with
the PMP and 270 ± 107 mg/d with the SSD. With the PMP, serum
tHcy concentrations fell from 10.8 ± 5.8 to 9.3 ± 4.9 mmol/L
(P < 0.0001) between weeks 0 and 10 and the change was associated with increased intakes of folate, vitamin B-12, and vitamin B-6 and with increased serum and red blood cell folate and
serum vitamin B-12 concentrations. tHcy concentrations did not
change significantly with the SSD.
Conclusions: The PMP resulted in increased intakes and serum
concentrations of folate and vitamin B-12. These changes were
associated with reduced serum tHcy concentrations in persons
at high risk of cardiovascular disease.
Am J Clin Nutr
1999;70:881–7.
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CHAIT ET AL
studies have reported an inverse correlation between serum tHcy
concentrations and blood concentrations or dietary intakes of
folate and vitamins B-12 and B-6 (12, 17, 18), which are cofactors in the metabolic processing of homocysteine. Morrison et al
(19) reported a significant inverse relation between serum folate
concentrations and risk of fatal coronary artery disease. Clinical
studies have shown that folate and vitamin B supplementation
can reduce elevated tHcy concentrations (15, 20–23) and have
generally concluded that administration of supplemental folate
or a combination of folate, vitamin B-6, and vitamin B-12 is an
effective means of improving hyperhomocysteinemia.
In the present study, we examined the effects of increased
dietary folate and B vitamins as part of a prepared meal plan
(PMP) or self-selected diet (SSD) on serum tHcy concentrations
in persons with hypertension, dyslipidemia, type 2 diabetes, or a
combination of these disorders who were participants in the Cardiovascular Risk Reduction Dietary Intervention Trial (24). The
PMP consisted of prepackaged, nutritionally balanced meals fortified to provide ≥ 100% of the National Academy of Sciences
recommended dietary allowance (RDA) for 22 vitamins and
minerals, including vitamins B-12 and B-6, and twice the RDA
for folate (25). The SSD consisted of foods chosen by the participants based on the exchange list system. Both interventions
were designed to meet the macronutrient recommendations of
major government and health organizations. As reported previously (24), a PMP produced greater improvements in systolic
blood pressure (SBP), diastolic blood pressure (DBP), and
weight loss than did an SSD, whereas reductions in cholesterol
and glucose were comparable with both interventions.
≤ 200% of the median normal value (≤ 15.4%), or have been stabilized [HbA1c concentration 100–175% of the median for assay
(7.7–13.4%)] for ≥ 1 mo before the study after taking oral hypoglycemic agents.
Those subjects who had other chronic or life-threatening diseases (including renal disease), who were receiving insulin treatment, who refused to discontinue vitamin or mineral supplement
use, or who had an alcohol- or substance-abuse problem and
women who were pregnant or lactating or not practicing a medically approved method of birth control were excluded.
SUBJECTS AND METHODS
This study was part of a larger trial to evaluate the effects of a
PMP and SSD on traditional cardiovascular disease risk factors.
Results of that study were reported elsewhere (24). The trial was
conducted at 10 clinical centers after approval of the protocol by
the institutional review board at each of the centers. Written,
informed consent was obtained from each participant.
Randomization
Subjects
Participants consumed either the PMP or SSD (described
below) for 10 wk and were seen every 2 wk for measurements of
blood pressure and weight and collection of 3-d food records.
Fasting blood samples were collected at weeks 0 and 10 for
measurement of serum tHcy, folate, and vitamin concentrations,
and were frozen at 220 8C until analyzed.
Baseline period
A 4-wk baseline period (week 24 to week 0) preceded the 10wk treatment period. During this time, participants were advised
to maintain their usual diets, completed two 3-d food records, and
were seen weekly for blood pressure and weight measurements.
Nutrition prescriptions
At week 22, before randomization, a nutrition prescription
was calculated for each patient by using the Harris-Benedict
equation (26) to estimate the individual’s energy needs for
weight maintenance or loss. Each energy intake prescription
had an 840-kJ window; the minimum prescription was 5040–
5876 kJ/d. Weight loss was limited to 1 kg/wk and to a total of
11 kg for the intervention. Participants not desiring weight loss
were prescribed an isoenergetic diet. Nutrition counseling was
provided to all participants at weeks 0 and 2, but no further dietspecific instruction was provided.
At week 22, 560 participants were randomly assigned by the
coordinating center at Oregon Health Sciences University to either
the PMP or SSD, stratified by clinic site and 4 diagnostic categories: 153 with hypertension, 162 with dyslipidemia, 148 with
type 2 diabetes, and 97 with any combination of these disorders.
Treatment period
Dietary intervention
Both diets provided <20% of energy as fat, 55–60% as carbohydrate, and 15–20% as protein. The meals were produced by
the Campbell Soup Company (Camden, NJ) and included
6 breakfasts, 8 lunches, 10 dinners, and 6 snack selections. Participants ordered meals at clinic visits, and the meals were delivered to their homes.
Prepared meal plan
The PMP met nutritional guidelines for sodium, total and saturated fat, cholesterol, refined sugars, fiber, and complex carbohydrates and was fortified with vitamins and minerals to provide
400 mg folate/d (twice the RDA) and ≥ 100% of the RDA for
adults (25, 27, 28) for 22 nutrients, with the exceptions of vitamin D and copper (77% and 91% of the RDA, respectively).
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Adult men and women were recruited through outpatient clinics and advertisements. To be eligible for the study, subjects had
to be 25–70 y of age, have a body mass index (BMI; in kg/m 2)
≤ 42, and have hypertension, dyslipidemia, type 2 diabetes, or a
combination thereof.
Subjects with hypertension had to be taking no antihypertensive medication and have an average sitting SBP and DBP of
140–180 and 90–105 mm Hg, respectively, or have been stabilized (average sitting SBP and DBP of 135–180 and 85–100 mm
Hg, respectively) for ≥ 1 mo before the study after taking antihypertensive medication. Subjects with dyslipidemia had to be taking no lipid-lowering medication and have a total cholesterol
concentration of 5.7–7.8 mmol/L (220–300 mg/dL), a triacylglycerol concentration of 2.3–11.3 mmol/L (200–1000 mg/dL), or
both, or have been stabilized for ≥ 1 mo before the study after
taking lipid-lowering medication and a cholesterol concentration
of 5.2–6.7 mmol/L (200–260 mg/dL), a triacylglycerol concentration of 2.3–11.3 mmol/L (200–1000 mg/dL), or both. Subjects
with type 2 diabetes had to be taking no hypoglycemic agents
and have a fasting blood glucose concentration > 7.8 mmol/L
(140 mg/dL) and a glycated hemoglobin (Hb A 1c) concentration
Study design
DIETARY MICRONUTRIENTS AND HOMOCYSTEINE
883
TABLE 1
Dietary effects on folate, vitamin B-6, and vitamin B-12
Serum folate (nmol/L)
RBC folate (nmol/L)
Serum vitamin B-62
RBC vitamin B-62
Serum vitamin B-12 (pmol/L)
1–
x ± SD.
2
Week 0
Prepared meal plan
(n = 244)
Week 10
Difference
P
Week 0
17.5 ± 10.0
567 ± 338
1.9 ± 1.2
2.5 ± 1.9
367 ± 168
31.3 ± 12.7 14.1 ± 13.4
931 ± 424
367 ± 403
1.8 ± 0.7 20.1 ± 1.3
2.4 ± 1.7 20.1 ± 2.6
465 ± 199
98 ± 173
< 0.0001
< 0.0001
0.52
0.53
< 0.0001
16.8 ± 9.5
555 ± 315
1.8 ± 1.0
2.3 ± 1.1
380 ± 202
Self-selected diet
(n = 247)
Week 10
Difference
15.2 ± 8.2
621 ± 329
1.8 ± 0.8
2.4 ± 1.2
359 ± 159
21.6 ± 8.4
66 ± 333
0 ± 1.3
0.1 ± 1.6
222 ± 168
P
P for change
between
treatments
< 0.01
< 0.01
0.59
0.21
< 0.05
< 0.0001
< 0.0001
0.41
0.23
0.0001
Coefficient ratio.
Self-selected diet
The SSD group was instructed to consume a fixed number of
servings from each of the exchange lists of the American
Dietetic and American Diabetes Associations (29), consisting
primarily of breads and starches, fruit, low-fat milk, vegetables,
and lean meats. The number of servings was determined by
the individual’s nutrition prescription. Participants were also
allowed to select one serving daily from the bonus list. Participants received a weekly monetary food allowance to compensate
for the free food given to the PMP group.
Outcome measurements
Serum tHcy concentrations were determined by HPLC and
electrochemical detection by using the method of Smolin and
Schneider (30), as modified by Malinow et al (31), at the Oregon
Regional Primate Research Center, Beaverton. Serum and red
blood cell (RBC) vitamin concentrations were determined at the
University of California at Davis Vitamin and Mineral Laboratory. Folate and vitamin B-12 concentrations were measured by
radioimmunoassay (Bio-Rad Laboratories, Richmond, CA) and
vitamin B-6 by spectrophotometry with an automated analyzer
and AST/GOT kit (Sigma Diagnostics, St Louis). For vitamin B6, the enzymatic activity of D-alanine transaminase was measured in the absence and presence of added pyridoxine, and vitamin B-6 status (coefficient ratio) was reported as the ratio of
activity with and without pyridoxine (32). The nutrient composition of the foods listed on the dietary records was determined by
using a licensed copy of the University of Minnesota Nutrition
Coordinating Center database in Minneapolis (NDS, version 2.8,
1995) and the product content of the prepackaged meals was provided by the Campbell Soup Company.
Statistical analysis
The study was part of a parallel intervention study to compare
the efficacy of a PPM with that of an SSD in producing clinically
relevant changes in the major endpoints associated with hypertension, dyslipidemia, and type 2 diabetes (24). Regression
relations were tested by analysis of covariance, with diet as a
fixed-effect factor, and were followed by post hoc tests of correlations both within and between diets. The effect of the diets on
endpoints was tested by repeated-measure analysis of variance.
SAS software (SAS Institute Inc, Cary, NC) was used for the
analysis. Data are presented as means ± SDs.
RESULTS
Of the 560 participants randomly assigned in the main trial,
12 dropped out of the study before beginning dietary therapy. Of
the remaining 548 participants (PMP: n = 274; SSD: n = 274),
sufficient serum samples for tHcy analysis at weeks 0 and 10
were available from 491 subjects (PMP: n = 244; SSD: n = 247).
This group included 130 with hypertension, 143 with dyslipidemia, 132 with type 2 diabetes, and 86 with a combination of
these disorders. Losses due to insufficient sample availability
were similar across diagnostic categories and treatments. In the
PMP group, tHcy concentrations fell from 10.8 ± 5.8 mmol/L at
week 0 to 9.3 ± 4.9 mmol/L at week 10 (P < 0.0001). In the SSD
group, tHcy concentrations did not change significantly between
weeks 0 (11.0 ± 5.6 mmol/L) and 10 (11.1 ± 5.9 mmol/L).
With the PMP, dietary intakes of folate and vitamins B-6
and B-12 increased significantly: folate from 293 ± 109 to
692 ± 132 mg/d (P < 0.0001), vitamin B-12 from 5.4 ± 4.7 to
12.8 ± 2.8 mg/d (P < 0.0001), and vitamin B-6 from 1.9 ± 0.6 to
4.0 ± 0.7 mg/d (P < 0.0001). With the SSD, folate intakes
increased slightly (from 290 ± 116 to 358 ± 139 mg/d; P < 0.0001),
as did vitamin B-6 (from 1.9 ± 0.7 to 2.2 ± 0.8 mg/d; P < 0.0001),
whereas vitamin B-12 intakes tended to decrease from 5.3 ± 4.3
to 4.9 ± 2.9 mg/d (P = 0.11) between weeks 0 and 10. For all
3 vitamins, the increase in intakes over 10 wk with the PMP differed significantly from intakes with the SSD (P < 0.0001).
Differences were also observed in serum and RBC concentrations of folate and in serum concentrations of vitamin B-12
(Table 1). With the PMP, serum and RBC folate nearly doubled.
With the SSD, serum folate decreased by 9%, whereas RBC folate
increased by 12%. Despite an increased vitamin B-6 intake with
the PMP, neither serum nor RBC vitamin B-6 concentrations
changed significantly with either diet. Serum vitamin B-12
increased by 27% in the PMP group and decreased by 6% with the
SSD. The change in serum and RBC folate and serum B-12 with
the PMP differed significantly from the change with the SSD.
A significant inverse relation was shown between the change in
serum tHcy concentrations and the change in dietary folate and
vitamin B-6 in the PMP group (Figure 1). The change in vitamin
B-12 did not correlate with the change in tHcy in either group. The
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Subjects were instructed to consume daily one breakfast, one
lunch, and one dinner, including at least one serving each of
fruit, vegetables, and low-fat dairy products. Prepared snacks or
additional meals were used to adjust the energy content of the
diet. One food selection was allowed daily from a bonus list; the
list included one alcoholic beverage or the energy equivalent in
fruit, vegetables, or low-fat dairy products.
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CHAIT ET AL
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FIGURE 1. Relation between changes in serum total homocysteine (tHcy) concentrations and dietary folate and vitamin B-6 intakes in participants
consuming the prepared meal plan.
DIETARY MICRONUTRIENTS AND HOMOCYSTEINE
DISCUSSION
In this study, the consumption of the PPM, which contained
natural foods fortified with vitamins and minerals to provide
twice the RDA for folate and the RDA for vitamins B-6 and B-12,
was associated with a greater decrease in serum tHcy concentrations than was the consumption of the SSD, which was designed
to meet typical nutritional recommendations for individuals at
high cardiovascular disease risk. Serum tHcy concentrations fell
on average by 1.5 mmol/L in the PMP group, but did not change
significantly in those consuming the traditional “risk reduction”
diet (ie, the SSD) for 10 wk.
The 400-mg/d concentration of folate in the PMP was chosen in
light of observations that the current RDA for folate may not pro-
vide optimal intakes with respect to tHcy reduction (1, 12). In their
recent meta-analysis of studies of homocysteine and cardiovascular disease risk, Boushey et al (1) showed that homocysteine concentrations decreased as dietary intakes of folate increased from
200 to 400 mg/d and that homocysteine concentrations reached a
plateau at folate intakes > 400 mg/d. In our study, it appeared that
serum tHcy concentrations continued to fall as folate intakes
exceeded 400 mg/d because a higher prevalence of tHcy concentrations > 15 mmol/L was observed in participants consuming
< 400 mg folate/d (17%) than in those consuming > 400 mg/d (8%;
P < 0.01). Although only a small number of participants (n = 41)
consumed > 800 mg folate/d, no difference in the prevalence of
hyperhomocysteinemia was observed relative to those consuming
< 600 mg/d. With use of the predicted equation for the line in Figure 1 (top), one would expect a 1.4-mmol/L decrease in tHcy with
a 400-mg/d increase in folate intake and a 2.2-mmol/L decrease in
tHcy with a 600-mg/d increase in folate. For the PMP group, estimates of folate intake far exceeded the amount of folate fortification (400 mg/d) as a result of the intake of the vegetable and fruit
allowances included in this plan. No relation between the change
in dietary intake of folate and the change in serum tHcy was
observed with the SSD. This may be a result of the relatively small
change in the intake of folate that occurred in this group or
because folate was not as bioavailable in the SSD as it was in the
fortified foods included in the PMP.
The estimated intake of vitamin B-6 also more than doubled
with the PMP, although no changes in either serum or RBC vitamin B-6 concentrations were observed. The cause of this lack of
an observable effect may have been due to the vitamin B-6 assay
used for these measurements. Both the dietary intake and the
serum concentrations of vitamin B-12 increased with the PMP
and these increases may have contributed to the observed reduction in serum tHcy concentrations. Fortification in the PMP was
provided by a prepared mix and therefore it is not possible to statistically separate the effects on tHcy of one vitamin from
another because of multicollinearity.
The meta-analysis of Boushey et al (1) suggested that homocysteine concentrations decreased by 2 mmol/L for every 100-mg/d
FIGURE 2. Response of serum total homocysteine (tHcy) concentrations to diet in relation to baseline serum tHcy concentrations. Participants consuming either the prepared meal plan (PMP) or the self-selected diet (SSD) were divided into quartiles on the basis of their serum tHcy concentrations
at week 0.
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change in serum tHcy was also inversely related to the change in
the concentrations of serum folate (r = 20.22, P < 0.0001) and
RBC folate (r = 20.14, P < 0.01) in the overall population. There
were no significant relations between changes in serum tHcy and
changes in serum or RBC vitamin B-6 or serum vitamin B-12 concentration. The change in tHcy was best explained by a model that
included changes in serum folate as well as in serum vitamins B-12
and B-6 (r = 20.26, P < 0.001). This suggests that serum measurements of vitamins B-12 and B-6 explained a small proportion
of the variance in tHcy, along with serum folate. None of these
relations were significantly different between treatments.
As shown in Figure 2, the change in serum tHcy concentrations in response to the 2 diets correlated significantly with
baseline concentrations. Individuals in the highest quartile for
baseline tHcy had the greatest change in response to diet. However, differences in the tHcy response to the 2 diets were
observed in all 4 quartiles. Approximately 14% of participants
had baseline serum tHcy concentrations > 15 mmol/L, which is
generally regarded as high (6). In subjects with baseline concentrations > 15 mmol/L, serum tHcy concentrations fell 5.7 ± 5.0
mmol/L (P < 0.001) with the PMP and 2.3 ± 10.0 mmol/L
(P = 0.26) with the SSD. At 10 wk, 9% of the PMP group and
14% of the SSD group had tHcy concentrations > 15 mmol/L.
885
886
CHAIT ET AL
The following institutions and individuals participated in this study: Oregon Health Sciences University (Portland)—D McCarron, C Morris, J Metz,
D Hatton, J Roullet, G McMillan, P Cook, P Rufolo, G Snyder, S Holcomb,
and P Bartholomew; University of Alabama (Birmingham)—S Oparil, A Hammond, and S Hood; University of California Davis—J Stern, M Haan, S Wesley, and S Young; Wayne State University (Detroit)—L Resnick, M Krempasky, J Roszler; St Luke’s–Roosevelt Hospital (Columbia University, New
York)—X Pi-Sunyer, N Mezitis, E Bauza, and N Aronoff; McMaster University and Hamilton Hospital (Hamilton, Canada)—R Haynes, A McKibbon,
M Pim, M Gray, G Sweeney, M McQueen, and T Mahoney; Pennsylvania
State University (University Park)—P Kris-Etherton, W Evans, J Ulbrecht,
and N Pletcher; University of Washington (Seattle)—A Chait, D Nevin, and
R Eastgard; Clinical Research Group of Oregon (Portland)—S Clark, M McMahon, C Gaboury, P de Garmo, L Chester, and S Hackney; and Oregon
Regional Primate Research Center (Beaverton)—M Malinow.
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increase in dietary folate, which was a greater change than seen
in the present study. This difference may have been due in part
to the shorter duration of our study or to the fact that most of the
participants in our study had baseline tHcy concentrations within
the normal range. The greatest change in tHcy concentrations in
response to the PMP was seen in subjects in the upper quartile of
tHcy concentration, in which the baseline concentrations of
some participants were > 15 mmol/L, a generally accepted upper
limit of normal (5).
With an increase in tHcy concentrations of 5 mmol/L, the relative risk of cardiovascular disease has been estimated to
increase by <60% for men and 80% for women (1). In individuals
with baseline tHcy concentrations > 15 mmol/L, concentrations
fell by 5.7 mmol/L with the PMP. A change of this magnitude
may markedly decrease cardiovascular risk in the presence of the
more traditional and commonly clustered risk factors of hypertension, dyslipidemia, and type 2 diabetes (33, 34).
This study showed that an adequate intake of nutrients known
to beneficially influence tHcy concentrations, including folate
and vitamins B-12 and B-6, can effectively decrease tHcy concentrations in persons with concomitant risk factors for cardiovascular disease and that appropriate intakes of these nutrients
can be achieved by fortifying a prepared diet that is low in fat,
cholesterol, and sodium. We showed that a comprehensive meal
plan that meets all dietary recommendations of major health
organizations for reducing cardiovascular risk (28, 35–38)
offers an alternative and more simplified approach to dietary
therapy intended to improve cardiovascular risk factors, including serum tHcy. The effectiveness of the PMP in reducing serum
tHcy concentrations, in addition to improving other risk factors,
including hypertension, dyslipidemia, and hyperglycemia (24),
may confer further potential benefit to persons at high risk of
cardiovascular disease.
DIETARY MICRONUTRIENTS AND HOMOCYSTEINE
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