Nutritional Supplement Program Halts Progression of Early Coronary Atherosclerosis
Documented by Ultrafast Computed Tomography
Matthias Rath M.D. and Aleksandra Niedzwiecki Ph.D.
Documented by Ultrafast Computed Tomography
According to the World-Health Organization, over 12 million people die
every year from heart attacks, strokes and other forms of cardiovascular
disease.1 The direct and indirect costs for treatment of cardiovascular
disease are the single largest health care expense in every industrialized
country of the world. Despite modest success in some countries in lowering
the mortality rate from heart attacks and strokes, the cardiovascular
epidemic is still expanding on a worldwide scale.
Current concepts of the pathogenesis of cardiovascular disease focus
on elevated plasma risk factors damaging the vascular wall and thereby
initiating atherogenesis and cardiovascular disease.2-4 Accordingly,
drugs lowering cholesterol and modulating other plasma risk factors have
become a predominant therapeutic approach in the prevention of cardiovascular
A new scientific rationale about the initiation of atherosclerosis and
cardiovascular disease was proposed by one of us5,6.It can be summarized
as follows: cardiovascular disease is primarily caused by chronic deficiencies
of vitamins and other essential nutrients with defined biochemical properties,
such as coenzymes, cellular energy carriers, and antioxidants.7,8 Chronic
depletion of these essential nutrients in endothelial and vascular smooth
muscle cells impairs their physiological function. For example, chronic
ascorbate deficiency, similar to early scurvy, leads to morphological
impairment of the vascular wall and endothelial microlesions, histological
hallmarks of early atherosclerosis. 9-11 Consequently, atherosclerotic
plaques develop as the result of an overcompensating repair mechanism
comprising deposition of systemic plasma factors as well local cellular
responses in the vascular wall.5,6 This repair mechanism is primarily
exacerbated at sites of hemodynamic stress, explaining the predominantly
local development of atherosclerotic plaques in coronary arteries and
myocardial infarction as the most frequent clinical manifestation of
Animal studies have confirmed this scientific rationale resulting in
patents for the combination of ascorbate with other essential nutrients
in the prevention and treatment of cardiovascular disease.12 Based on
this patented technology, we have developed a nutritional supplement
program, which was tested in this study in patients with coronary heart
Subjects and Methods
A total of 55 patients, 50 men and 5 women, with documented coronary
artery disease assessed by Ultrafast CT, were recruited for the study.
The inclusion criterion was the availability of a high quality Ultrafast
CT scan from a previous visit to the Heart Scan facility in South San
Francisco. At the beginning of the study each patient completed a comprehensive
questionnaire, which was updated after six months and after 12 months.
This questionnaire included medical history, previous cardiac events,
and cardiovascular risk factors, as well as individual life style data.
Specific questions related to the patientsÕ regular diet, such
as strictly vegetarian diet, predominantly fruits and vegetables, predominantly
meat, fish or poultry; the daily intake of different vitamins and other
essential nutrients; and the frequency of physical exercise by the patient.
The laboratory tests available documented a heterogeneous population
with respect to plasma cholesterol and triglycerides. About half of the
patients were taking different types of prescription medication, including
calcium antagonists, nitrates, betablockers, and cholesterol-lowering
drugs. Before entering the study, the patients were instructed not to
change their diet or lifestyle other than adding the nutritional supplement
program tested. Any changes were to be documented in their questionnaires.
Compliance with the nutritional supplement program was monitored in the
questionnaires, through telephone calls and during the control visits.
Composition and Administration of Nutritional Supplement Program
The following daily dosages of nutritional supplements were taken for
a period of one year: Vitamins: Vitamin C 2700 mg, Vitamin E(d-Alpha-Tocopherol)
600 IU, Vitamin A (as Beta-Carotene) 7,500 IU, Vitamin B-1 (Thiamine)
30 mg, Vitamin B-2 (Riboflavin) 30 mg, Vitamin B-3 (as Niacin and Niacinamide)
195 mg, Vitamin B-5 (Pantothenate) 180 mg, Vitamin B-6 (Pyridoxine) 45
mg, Vitamin B-12 (Cyanocobalamin) 90 mcg, Vitamin D (Cholecalciferol)
600 IU. Minerals: Calcium 150 mg, Magnesium 180 mg, Potassium 90 mg,
Phosphate 60 mg, Zinc 30 mg, Manganese 6 mg, Copper 1500 mcg, Selenium
90 mcg, Chromium 45 mcg, Molybdenum 18 mcg. Amino acids: L-Proline 450
mg, L-Lysine 450 mg, L-Carnitine 150 mg, L-Arginine 150 mg, L-Cysteine
150 mg. Coenzymes and other nutrients: Folic Acid 390 mcg, Biotin 300
mcg, Inositol 150 mg, Coenzyme Q-10 30 mg, Pycnogenol 30 mg, and Citrus
Bioflavonoids 450 mg. Further information at: http://www.drrath.com/.
Monitoring of Coronary Artery Disease
The extent of coronary calcification was measured non-invasively with
an Imatron C-100 Ultrafast CT scanner in the high-resolution volume mode,
using a 100- millisecond exposure time. ECG triggering was used so that
each image was obtained at the same point in the diastole, corresponding
to 80% of the RR interval. In each scan, 30 consecutive images were obtained
at 3-mm intervals beginning 1 cm below the carina and progressing caudally
to include the entire length of the coronary arteries. The scans at study
entry and after 6 and 12 months of the study included a second scan sequence
of 30 images at 3 mm intervals across the entire heart. The 30 images
of the second scan were taken between the 3 mm intervals of the first
scan resulting in a scanning of the heart at an interval of 1.5 mm. Total
radiation exposure using this technique was <1rad per patient (<.01Gy).
The scan threshold was set at 130 Hounsfield units (Hu) for identification
of calcified lesions. The minimum area to differentiate calcified lesions
from CT artifact was 0.68 mm2. The lesion score, also designated Coronary
Artery Scanning (CAS) score, was calculated by multiplying the lesion
area by a density factor derived from the maximal Hounsfield unit within
this area.13 The density factor was assigned in the following way: 1
for lesions with a maximal density with 130-199 Hu, 2 for lesions with
200-299 Hu, 3 for lesions with 300-399 Hu and 4 for lesions > 400
Hu. The total calcium areas and CAS scores of each Ultrafast CT scan
were determined by summing individual lesion areas or scores from the
left main, left anterior descending, circumflex, and right coronary artery.
Several studies have confirmed an excellent correlation of the extent
of coronary artery disease as assessed by Ultrafast CT scanning when
compared to angiographic and histomorphometric methods.13-15 Considering
the accuracy and the non-invasive approach, Ultrafast CT was the method
of choice for an intervention study that included early, asymptomatic
stages of coronary artery disease.
The growth rate of coronary calcifications was calculated as the quotient
of the differences in the calcification areas or CAS scores between two
scans divided by the months between these scans according to the formula
(Area2-Area1):(Date2-Date1), or (CAS score2-CAS score1):(Date2-Date1)
respectively. The data were analyzed using standard formulas for means,
medians, and standard error of the means (SEM). PearsonÕs correlation
coefficient was used to determine the association between continuous
variables. One tailed Student t-test was used to analyze differences
between mean values, with a significance defined at <0.5. Progression
of calcification was predicted by linear extrapolation. The distribution
of the growth rate of CAS scores was described by a smooth curve resulting
from a third order polynominal fit (y=a + bx3, where a = 0.9352959, b
= 8.8235 x 10-5).
The aim of this study was to determine the effect of a defined nutritional
supplement program on the natural progression of coronary artery calcification
particularly in its initial stages as measured by Ultrafast CT. We therefore
evaluated the results of the entire study group (n=55) and of a subgroup
of 21 patients with early coronary artery calcification, as defined by
a CAS score of <100.
Table 2 separately lists the characteristics of the study population
assessed by the questionnaire for all patients and for a subgroup with
early coronary artery disease.
This is the first intervention study using Imatron's Ultrafast CT technology.
One of the first aims of this study was to determine the rate of natural
progression of coronary calcium deposits in situ , without the intervention
of the nutritional supplement program. Figure 1 shows the distribution
of the monthly progression of calcifications in the coronary arteries
of all 55 patients in relation to their CAS score at study entry.
We found that the higher the CAS score was initially, without intervention,
the faster the coronary calcification progressed. Accordingly, the average
monthly growth rate of coronary calcifications ranged from 1 CAS score
per month in patients with early coronary heart disease to more than
15 CAS score per month in patients with advanced stages of coronary calcifications.
The growth pattern of coronary calcifications can be described as a third
order polynomial fit curve. The exponential shape of this curve signifies
a first quantification of the aggressive nature of coronary atherosclerosis
and emphasizes the importance of early intervention.
The changes in the natural progression rate of coronary artery calcification
before the nutritional supplement program (-NS) and after one year on
this program (+NS) are shown in Figure 2. The results are presented separately
for the calcified area and the CAS score.
As presented in Figure 2.a. the average monthly growth of calcified
areas for all 55 patients decreased from 1.24 mm2/month (SEM +/- 0.3)
before the nutritional supplement program (-NS) to 1.05 mm2/month (+/-
0.2) after one year on this program (+NS).For patients with early coronary
artery disease (Figure 2b), the average monthly growth of the calcified
area decreased from 0.49 mm2/month (+/- 0.16) before taking the nutritional
supplements (-NS) to 0.28 mm2/month (+/- 0.09) after one year on this
As shown in Figure 2.c the average monthly changes in the total CAS
score (calcified area X density of calcium deposits) for all 55 patients
had decreased after one year on the nutritional supplement program by
11%, from 4.8 CAS score/month (SEM +/-0.97) before the program (-NS)
to 4.27 CAS score /month(+/- 0.87) (+NS). In patients with early coronary
artery disease (Figure 2.d) the average monthly growth of the total CAS
score decreased during the same time by as much as 65%, from 1.85 CAS
score /month (+/-0.49) before the nutritional supplement program (-NS)
to 0.65 CAS score /month (+/- 0.36) on this program (+NS). The slow-down
of the progression of coronary calcification during this nutritional
supplement intervention for CAS scores of patients with early coronary
artery disease was statistically significant (p<0.05)(Figure 2.d).
For the other three sets of data the decrease of coronary calcifications
with the nutritional supplement program was evident; however, largely
due to the wide range of calcification values at study entry reflecting
the different stages of coronary artery disease, it did not reach statistical
It is noteworthy that the decrease in the CAS scores during intervention
with nutritional supplements were more pronounced than for the calcified
areas. This indicates a decrease in the density of calcium in addition
to a reduction in the area of coronary calcium deposits during nutritional
Ultrafast CT scans at the beginning of the study and after 12 months
on the nutritional supplement program, were complemented by a control
scan after 6 month, allowing for additional insight into the time required
for the nutritional supplements to exert their therapeutic effect. This
additional evaluation was particularly important for early forms of coronary
artery disease, because any therapeutic approach that can halt progression
of early coronary calcification would ultimately prevent myocardial infarctions.
Figure 3 shows the average coronary calcification areas (Figure 3.a)
and total CAS scores (Figure 3.b) for patients with early coronary artery
disease measured during different scanning dates before and during the
course of the study. The actual coronary calcification values for areas
and total CAS scores during nutritional supplement intervention are compared
to the predicted values obtained from linear extrapolation of the growth
rate without intervention. The letters A to D mark the different time
points at which Ultrafast CT scans were performed. AB represents the
changes in coronary calcification before intervention with nutritional
supplement for the areas (Figure 3.a) and CAS scores (Figure 3.b). Accordingly,
BC represents calcification changes during the first six months on the
nutritional supplement program and CD changes during the second six months
on the program. The calculated progression rate for coronary calcifications
without therapeutic intervention by the nutritional supplement program
is marked by a dotted line (B through F).
As seen in Figure 3.a without the nutritional supplement program, the
average area of coronary calcifications in patients with early coronary
artery disease increased from 17.62 mm2 (+/- 1.0) at time point A to
23.05 mm2 (+/- 1.8) at time point B. Thus, the annual extension of calcified
areas without intervention was assessed with 31 %. At this progression
rate, the average calcified area would reach 26.3 mm2 after six months
(point E) and 29.8 mm2 after twelve months (point F). The nutritional
supplement intervention, resulted in an average calcified area of 25.2
mm2 (+/-2.2) after six months and of 27.0 mm2 (+/-1.7) after 12 months,
reflecting a 10% decrease compared to the predicted value.
Analogous observations were made for the total CAS before and during
the nutritional supplement program. Figure 3.b shows that the CAS score
before the nutritional supplement program increased by 44% per year,
from 45.8 (+/- 3.2) (point A) to 65.9 mm2 (+/- 5.2) (point B). At this
progression rate the total CAS score, without the nutritional supplement
program, would reach an average of 77.9 after six months (point E) and
of 91 (point F) after twelve months. In contrast to this trend the actual
CAS score values measured with the nutritional supplement program were
75.8 (+/-6.2) after 6 months (point C) and 78.1 (+/-5.1) after 12 months
(point D). Thus, the progression of coronary calcification as determined
by the total CAS scores decreased significantly during the second six
months of nutritional supplement intervention (CD). The total score after
twelve months on the nutritional supplement program was only 3% higher
than after six months (CD), as compared to the projected increase of
17% (EF), indicating that during the second six months on the nutritional
supplement program the process of coronary calcification has practically
Figure 4 shows the actual Ultrafast CT scans of a 51 year old patient
with early, asymptomatic, coronary artery disease. The patientsÕ first
Ultrafast CT scan was performed in 1993 as part of an annual routine
check-up. The scan film revealed small calcifications in the left anterior
descendent coronary artery as well as in the right coronary artery. The
second CT scan was performed one year later at which time the initial
calcium deposits had further increased. Figure 4.a shows two Ultrafast
CT scan images taken before the nutritional supplement program. Subsequently,
the patient started on the nutritional supplement program. About one
year later the patient received a control scan. At this time point, coronary
calcifications were not found (Figure 4b), indicating the natural reversal
of coronary artery disease.
This is the first study that provides quantifiable data from in situ
measurements about the natural progression rate of coronary artery disease.
Although atherosclerotic plaques have a complex histomorphological composition,
calcium dispersion within these plaques has been shown to be an excellent
marker for their advancement.11,13 Our study determined that the calcified
vascular areas expand at a rate between 5 mm2 (early atherosclerotic
lesions) and 40 mm2 (advanced atherosclerotic lesions). Before the nutritional
supplement program the average annual increase of total coronary calcification
was 44% (Figure 1). Considering the exponential increase of coronary
calcification, it is evident that the control of cardiovascular disease
has to focus on early diagnosis and early intervention.
Today, the diagnostic assessment of individual cardiovascular risk is
largely confined to the measurement of plasma cholesterol and other risk
factors with little correlation to the extent of atherosclerotic plaques.
More accurate methods, such as coronary angiography, are confined to
advanced, symptomatic, stages of coronary artery disease. Ultrafast CT
provides the diagnostic option to quantify coronary artery disease non-invasively
in its early stages.14,15
The most important finding of this study is that coronary artery disease
can be effectively prevented and treated by natural means. This nutritional
supplement program was able to decrease the progression of coronary artery
disease within the relatively short time of one year, irrespective of
the stage of this disease. Most significantly, in patients with early
coronary calcifications this nutritional supplement program was able
to essentially stop its further progression. In individual cases with
small calcified deposits, nutritional supplement intervention led to
their complete disappearance (Figure 4).
We postulate that the nutritional supplement program tested in this
study initiates the reconstitution of the vascular wall. Restructuring
of the vascular matrix is facilitated by several nutrients tested, such
as ascorbate (vitamin C), pyridoxine (vitamin B-6), L-lysine, and L-proline,
as well as the trace element copper. Ascorbate is essential for the synthesis
and hydroxylation of collagen and other matrix components,16-18 and can
be directly and indirectly involved in a variety of regulatory mechanisms
in the vascular wall from cell differentiation to distribution of growth
factors.19,20 Pyridoxine and copper are essential for the proper cross-linking
of matrix components.8 L-lysine and L-proline are important substrates
for the biosynthesis of matrix proteins; they also competitively inhibit
the binding of lipoprotein(a) to the vascular matrix, facilitating the
release of lipoprotein(a) and other lipoproteins from the vascular wall.5,12,21
Ascorbate and -tocopherol have been shown to inhibit the proliferation
of vascular smooth muscle cells.22-24 Moreover, tocopherols, beta-carotene,
ascorbate, selenium and other antioxidants scavenge free radicals and
protect plasma constituents, as well as vascular tissue, from oxidative
damage.25,26 In addition, nicotinate, riboflavin, pantothenate, carnitine,
coenzyme Q-10, as well as many minerals and trace elements, function
as cellular cofactors in form of NADH, NADPH, FADH, Coenzyme A and other
cellular energy carriers.8 The results of this study confirm that maintaining
the integrity and physiological function of the vascular wall is the
key therapeutic target in controlling cardiovascular disease. This also
corroborates early angiographic findings that supplemental vitamin C
may halt the progression of atherosclerosis in femoral arteries.27
These conclusions are even more relevant since deficiencies of essential
nutrients are common.28,29 Moreover, many epidemiological and clinical
studies have already documented the benefits of individual nutrients
in the prevention of cardiovascular disease.30-35 Compared to the high
dosages of vitamins used in some of these studies the amounts of nutrients
used in this study are moderate, indicating the synergistic effect of
In this context, it seems appropriate to critically review some of the
approaches currently used in the primary and secondary prevention of
cardiovascular disease, including the extensive use of cholesterol-lowering
drugs. An intervention study including lovastatin was performed with
a highly selected group of hyperlipidemic patients, representing only
an extremely narrow fraction of a normal population.36 More recently,
the reduction of myocardial infarctions and other cardiac events in patients
taking simvastatin, led to recommendations for its long-term use even
by normolipidemic patients.37 However, because of their potential side-effects,
the recommended use of these drugs has now been restricted to patients
at high short term risk for coronary heart disease.38
Similarly, certain natural approaches to prevention of cardiovascular
disease deserve a critical review. A program of rigorous diet and exercise
program claims to be able to reverse coronary heart disease.39 However,
the published study does not provide compelling evidence documenting
the regression of coronary atherosclerosis. Thus, the improved myocardial
perfusion shown in that study, was likely the result of the physical
training program, leading to an increased ventricular ejection fraction
and an increased coronary perfusion pressure.
Considering the urgent need for effective and safe public health measures
towards the control of cardiovascular disease, the validity of this study
is of particular importance. In light of this, the following study elements
1 The patients in this study served as their own controls before and
during nutritional supplement intervention, thereby minimizing undesired
co-variables such as age, gender, genetic predisposition, diet or medication.
2 Ultrafast CT has been extensively validated to assess the degree of
coronary atherosclerosis, and it allowed quantification of coronary atherosclerotic
plaques in situ.13-15 This diagnostic technique also minimizes errors
as they occur in angiography studies in which vasospasms, formation or
lysis of thrombi, and other events cannot be differentiated from progression
or regression of atherosclerotic plaques. Moreover, Ultrafast CT provides
valuable information about the morphological changes during progression
and regression of atherosclerotic plaques, by quantifying not only the
area of coronary calcifications but also their density. Furthermore,
the automatic CT measurements of coronary calcifications eliminates human
error in the evaluation of the data.
In summary, the results of this study imply that coronary heart disease
is a preventable and essentially reversible condition. This study documents
that coronary artery disease could be halted in its early stages by following
this nutritional supplement program. These results were achieved within
one year, suggesting that additional therapeutic benefits in patients
with advanced coronary artery disease can be obtained by an extended
use of this program. The continuation of this study is currently under
way to document these effects. This nutritional supplement program signifies
an effective and safe approach for the prevention and adjunct therapy
of cardiovascular disease. This study should encourage public health
policy makers and health care providers to redefine health strategies
towards the control of cardiovascular disease.
We are grateful to Jeffrey Kamradt for his help in coordinating this
study. Douglas Boyd Ph.D., Lew Meyer Ph.D. from Imatron/HeartScan., South
San Francisco, for helping to plan the study and providing the HeartScan
facility; Lauranne Cox, Susan Brody, and Tom Caruso for their collaboration
in conducting the heart scans. Dr. Roger Barth and Bernard Murphy for
their assistance in planning the study, as well as to Martha Best for
her secretarial assistance.
Note by the Authors
This publication was originally submitted to the Journal of the American
Medical Association (JAMA) on August 5, 1996 and referred to Charles
B. Clayman, MD Contributing Editor of JAMA, by Editor in Chief, George
D. Lundberg, MD.Ê
In his letter dated August 23, 1996, Dr. Clayman rejected publication
of this paper without further comments. Apparently the contents of this
paper challenged the interests of the pharmaceutical industry and their
gatekeepers in the administration of the American Medical association.
While thousands of doctors in America and millions of patients were waiting
for this life-saving information it was deliberately blocked and sabotaged
by special interest groups inside the American Medical Association.
The background: This study delivered indisputable proof that heart attacks
the number one killer in America are vitamin deficiency conditions
that can be prevented naturally by an optimum intake of essential nutrients.
The publication of this study threatens a multi-billion dollar market
in cholesterol-lowering drugs and other unnecessary pharmaceuticals currently
marketed for heart conditions.
Following the provocative rejection of this paper by the American Medical
Association JournalÕs office, we immediately submitted our manuscript
to the Journal of Applied Nutrition whose reviewers understood the importance
of this study for the health and life of every human being on earth as
well as for future generations. They immediately accepted this study
Following this decision, Dr. Rath received a letter from the JAMA office
asking for a resubmission of the study for reconsideration of its publication.
Apparently, the American Medical Association had realized its grave mistake.
But it was too late. The credit for publishing this important study will
go forever to the Journal of Applied Nutrition.Ê
As for the American Medical Association, thousands of doctors in America
will have to hold their elected officers responsible for their unethical
actions which were taken for no other reason than to serve special interests
from the pharmaceutical industry. If the doctors in America do not clean
up their house, the American people must see their organization as a
puppet of the Pharma-Cartel. If the doctors of America donÕt act
now, the American Medical Association will loose all remaining credibility
that it serves the health interests of the American people.
1. World Health Statistics, World Health Organization, Geneva, 1994.
2. Brown MS, Goldstein JL. How LDL receptors influence cholesterol and
atherosclerosis. Scientific American 1984;251:58-66.
3. Steinberg D, Parthasarathy S, Carew TE, Witztum JL. Modifications
of low-density lipoprotein that increase its atherogenicity. N Engl J
4. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med.
5. Rath M, Pauling L. A unified theory of human cardiovascular disease
leading the way to the abolition of this diseases as a cause for human
mortality. J Ortho Med. 1992;7:5-15.
6. Rath M, Pauling L. Solution to the puzzle of human cardiovascular
disease: Its primary cause is ascorbate deficiency, leading to the deposition
of lipoprotein(a) and fibrinogen/fibrin in the vascular wall. J Ortho
7. Rath M. Reducing the risk for cardiovascular disease with nutritional
supplements. J Ortho Med 1992;3:1-6.
8. Stryer l. Biochemistry, 3rd ed. New York: W.H.Freeman and Company;
9. Stary HC. Evolution and progression of atherosclerotic lesions in
coronary arteries of children and young adults. Atherosclerosis (Suppl.)
10. Constantinides P. The role of arterial wall injury in atherogenesis
and arterial thrombogenesis. Zentralbl allg Pathol pathol Anat. 1989;135:517-530Ê Stolman
JM, Goldman HM, Gould BS. Ascorbic acid in blood vessels. Arch Pathol.
1961;72:59-68 Ê 11. US Patent #5,278,189
12. Agatston AS, Janowitz WR, Kaplan G, Gasso J, Hildner F, Viamonte
M. Ultrafast computed tomographyÑdetected coronary calcium reflects
the angiographic extent of coronary arterial atherosclerosis. Am J Cardiology.
13. Budoff MJ, Georgiou D, Brody A, et al. Ultrafast computed tomography
as a diagnostic modality in the detection of coronary artery disease.
Circulation. 1996; 93:898-904.
14. Mautner SI, Mautner GC, Froehlich J, et al. Coronary artery disease:
prediction with in vitro electron beam CT. Radiology. 1994;192:625-630.
15. Murad S, Grove D, Lindberg KA, Reynolds G, Sivarajah A, Pinnell
SR. Regulation of collagen synthesis by ascorbic acid. Proc Natl Acad
16. De Clerck YA, Jones PA. The effect of ascorbic acid on the nature
and production of collagen and elastin by rat smooth muscle cells. Biochem
17. Schwartz E, Bienkowski RS, Coltoff-Schiller B, Goldfisher S, Blumenfeld
OO. Changes in the components of extracellular matrix and in growth properties
of cultured aortic smooth muscle cells upon ascorbate feeding. J Cell
18. Francheschi RT. The role of ascorbic acid in mesenchymal differentiation.
Nutr Rev. 1992;50:65-70 Ê 19. Dozin B, Quatro R, Campanile g, Cancedda
R. In vitro differentiation of mouse embryo chondrocytes: requirement
for ascorbic acid. Eur J Cell Biol. 1992;58:390-394.
20. Trieu VN, Zioncheck TF, Lawn RM, McConathy WJ. Interaction of apolipoprotein(a)
with apolipoprotein B-containing lipoproteins. J Biol Chem. 1991; 226:5480-5485. Ê 21.
Boscoboinik D, Szewczyk A, Hensey C, Azzi A. Inhibition of cell proliferation
by -tocopherol. Role of protein kinase C. J Biol Chem. 1991; 266:6188-6194.
22. Ivanov V, Niedzwiecki A. Direct and extracellular matrix mediated
effects of ascorbate on vascular smooth muscle cells proliferation. 24th
AAA (Age) and 9th Am Coll Clin Gerontol Meeting, Washington DC, 1994;Oct14-18.
23. Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis MB, King SB,
Berk BC. Combination of vitamins C and E alters the response to coronary
balloon injury in the pig. Arteriosclerosis, Thrombosis and Vascular
Biology. 1995; 15:156-165.
24. Retsky KL, Freeman MW, Frei B. Ascorbic acid oxidation product(s)
protect human low density lipoprotein against atherogenic modification.
Anti- rather than prooxidant activity of vitamin C in the presence of
transition metal ions. J Biol Chem. 1993;268:1304-1309.
25. Sies H, Stahl W. Vitamins E and C, -carotene and other carotenoids
as antioxidants. Am J Clin Nutr. 1995;62(Suppl);1315S-1321S.
26. Willis GC, Light AW, Gow WS. Serial arteriography in atherosclerosis.
Can Med Ass J. 1954;71:562-568.
27. Levine M, Contry-Caritilena C, Wang Y, et al. Vitamin C pharmacokinetics
in healthy volunteers: Evidence for a recommended daily allowance. Proc
Natl Acad Sci. 1996;93:3704-3709.
28. Naurath HJ, Joosten E, Riezler R. Effects of vitamin B12, folate,
and vitamin B6 supplements in elderly people with normal serum vitamin
concentrations. The Lancet. 1995;346:85-89.
29. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among
a sample of the United States population. Epidemiology. 1992; 3: 194-202.
30. Riemersma RA, Wood DA, Macintyre CCA, Elton RA, Gey KF, Oliver MF.
Risk of angina pectoris and plasma concentrations of vitamin A, C, and
E and carotene. The Lancet. 1991;337:1-5.
31. Hodis HN, Mack WJ, LaBree L, et al. Serial coronary angiographic
evidence that antioxidant vitamin intake reduces progression of coronary
artery atherosclerosis. JAMA. 1995; 273:1849-1854.
32. Morrison HI, Schaubel D, Desmeules M, Wigle DT. Serum folate and
risk of fatal coronary heart disease. JAMA. 1996; 275:1893-1896.
33. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled
trial of vitamin E in patients with coronary disease: Cambridge Heart
Antioxidant Study (CHAOS). The Lancet. 1996;347:781-786.
34. Heitzer T, Just H, MŸnzel T. Antioxidant vitamin C improves
endothelial dysfunction in chronic smokers. Am Heart Assoc. 1996;comm:6-9.
35. Brown BG, Albers JJ, Fisher LD, Schafer SM, Lin J-T, et al. Regression
of coronary artery disease as a result of intensive lipid-lowering therapy
in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.
36. Scandinavian Simvastatin Survival Study Group. Randomised trial
of cholesterol lowering in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study (4S). The Lancet 1994;344:1383-1389.
37. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA.
38. Gould KL, Ornish D, Scherwitz L, et al. Changes in myocardial perfusion
abnormalities by positron emission tomography after long-term, intense
risk factor modification. JAMA 1995;274:894-901.