Solution to the Puzzle of Human Cardiovascular Disease: Its Primary Cause
is Ascorbate defiency, leading to the deposition of lipoprotein(a) and fibrinogen
/ fibrin in the vascular wall
Matthias Rath and Linus Pauling
My dear Kepler, what do you say of the leading philosophers
here to whom I have offered a thousand times of my own accord to
studies, but who, with the lazy obstinacy of a serpent who has
eaten his fill,
have never consented to look at the planets, or moon, or telescope?
Verily, just as serpents close their eyes, so do men close their
eyes to the
light of truth."
Galileo Galilei in a letter
to Johannes Kepler ca. 1630
We recently formulated the concept that lipoprotein(a), Lp(a), is a surrogate
for ascorbate, vitamin C. (1) This concept revealed the physiological
role of Lp(a) as well as new therapeutic approaches. On the basis of
earlier work and additional experimental and clinical evidence we now
present a detailed theory of human CVD. The primary cause of human
CVD is a deficiency in ascorbate leading to the deposition of Lp(a)
and fibrinogen/fibrin in the vascular wall. We elucidate the interaction
of ascorbate and Lp(a) and present a pathomechanism that differs from
existing concepts (2,3,4) in that it is able to explain the unique
features of human atherosclerosis. We also present prophylactic and
therapeutic considerations that open new pathways to prevention and
treatment of CVD.
The Pivotal Role of Lp(a) in Human Cardiovascular Disease
Lp(a) was discovered by Kare Berg in 1963. (5) It is closely similar
to LDL, the main difference being that a glycoprotein, apo(a), is attached
by a disulfide bond to the apoprotein of LDL, apo B, giving a larger
surface area to the lipoprotein sphere. The c-DNA sequence of apo(a)
shows a striking homology to that of plasminogen (6), with multiple
repeats of kringle 4, one kringle 5 and a protesase domain. Because
of the homology of apo(a) with plasminogen Lp(a) has been called the
missing link between atherogenesis and thrombogenesis (7).
Evidence that Lp(a), not LDL, is the primary lipoprotein responsible
for initiating the development of atherosclerosis was reported by one
of us and his colleagues at Hamburg University (8,9,10). In the most
comprehensive studies assessing the role of Lp(a) in human vascular wall
yet reported it was found that Lp(a), not LDL accumulates selectively
in the vascular wall of CVD patients. Moreover the extracellular accumulation
of Lp(a) was closely correlated to the development of atherosclerotic
Most importantly, in several hundreds of histological cross sections
from the human coronary arteries and the aorta immunostaining for apoB,
without congruent staining for apo(a) was a rare event, indicating that
the vascular wall deposition of LDL alone occurs rarely (9). The deposition
of Lp(a) in the vascular wall as determined by immuno-morphometric analysis
because extraction methods overestimate the role of LDL: a major fraction
of Lp(a) is found dissociated in the vascular wall into apo(a) and the
LSDL-like particle particularly under post-mortem conditions. (8) Earlier
investigators have evidently failed to differentiate between LDL and
Lp(a) so that the initiation of atherosclerotic lesions was incorrectly
attributed to LDL.
This conclusion was recently confirmed by a study determining plasma
risk factors in patients with inherited LDL-receptor defects. In these
familial hypercholesterolemic patients the incidence of CVD was significantly
determined by the Lp(a) plasma concentration, with total cholesterol
and LDL cholesterol in plasma not related to the clinical manifestation
There is now strong clinical and experimental evidence that Lp(a) is
a more important risk factor than total cholesterol or LDL-cholesterol
for coronary heart disease (12), stroke (13), as well as restenosis of
vein grafts after coronary bypass surgery (14). We therefore conclude
that Lp(a) is the lipoprotein primarily responsible for the initiation
of human CVD. The role of LDL is best characterized as an aggravating
risk factor for CVD in patients with simultaneously elevated Lp(a) plasma
The Ascorbate-Lp(a) Connection
We observed that Lp(a) has mainly been detected in the plasma of man,
other primates and a few other species that have lost the ability to
synthesize ascorbate and consequently have low ascorbate levels compared
to animals with endogenous ascorbate production. We do not exclude,
however, that small amounts of Lp(a) will also be found in other species.
The loss of ascorbate synthesis is the result of a genetic mutation
in the gene for L-gulono-c -lactone oxidase; this mutation occurred
40 million years ago in an ancestor of the primates. Subsequently,
Lp(a) became a major plasma constituent in primates and man. We therefore
proposed that Lp(a) is a surrogate for ascorbate. Vice versa, ascorbate
is a surrogate for Lp(a), since in most species Lp(a) is replaced by
ascorbate without any disadvantage.
Previously, it has been assumed that Lp(a) is primarily a pathogenic
particle and that Lp(a) plasma concentrations are primarily determined
by genetic factors. Our publication of the Lp(a)-ascorbate connection
marked a turning point in research directions and suggested numerous
investigations. Subsequently, it was shown that ascorbate, the strongest
reducing agent normally present in the body, and also synthetic reducing
agents such as N-acetylcysteine (15), decrease Lp(a) plasma levels. In
a clinical trial in CVD patients an increased intake of ascorbate lowered
the plasma Lp(a) level (unpublished observations).
Moreover, we proposed that Lp(a) strengthens the vascular wall, particularly
in ascorbate deficiency. At low ascorbate concentrations the synthesis
of collagen and elastin is impaired and the deposition of Lp(a) helps
to control the resulting instability of the vessel wall and to contain
disease progression. Apo(a), a macromolecule, would compensate for this
impairment and its demonstrated binding to glycosaminoglycans and other
compounds of the extracellular matrix would be beneficial. Moreover,
apo(a) has been shown top bind with high affinity to proline and hydroxyproline
and is likely to bind to collagen and elastin, macromolecules that are
enriched in these amino acid residues. Increased intake of ascorbate
eliminates the need for Lp(a) to strengthen the blood vessels and thus
ascorbate can replace Lp(a).
We have recently been able to confirm that ascorbate can replace Lp(a)
at the site of the disease process. In this pilot study we used the hypoascorbemic
guinea pig , an animal like man, unable to synthesize ascorbate but able
to synthesize apo(a). When fed dietary ascorbate in small amounts, corresponding
approximately to the usual human intake, these animals rapidly develop
atherosclerotic plaques and deposit Lp(a) in the vascular wall. Larger
intakes of ascorbate inhibited the deposition of Lp(a) in the arterial
wall and prevented the development of atherosclerosis. (16)
Ascorbate and the Regulation of Plasma Lp(a)
Lp(a) plasma levels among individuals vary by as much as 1000 fold. This
considerable variation is to a large extent the result of genetic factors
determining the synthesis of apo(a), but also those of apoB and lipids.
It may be that the modifying genes controlling apo(a) synthesis at
the optimum level have not yet become fully effective, so that in some
individuals this synthesis has overshot the mark, predisposing them
Beside genetic factors, Lp(a) plasma concentrations are also regulated
by dietary factors, one of them being niacin, which has been shown to
lower plasma Lp(a) levels (17). Another dietary factor is ascorbate. We
have obtained preliminary results that ascorbate decreases apo(a) synthesis
in human hepatoma cells in vitro. Ascorbate may also decrease the assembly
of the Lp(a) particle by reducing the disulfide formation between apo(a)
and apo B in the liver.
Ascorbate Defiency, the Risk Profile for CVD and Lp(a)
Ascorbate depletion is the common metabolic denominator of endogenous
and exogenous risk factors for CVD. Many genetic defects are associated
with ascorbate deficiency. As a result of a genetic defect the rate-constants
of certain enzyme-controlled metabolic reactions are decreased. These
rate constants can be increased towards normal values by increasing
the concentrations of certain cofactors (18). In the attempt to normalize
these decreased rate constants, ascorbate and other essential cofactors
for metabolic reactions are depleted. Ascorbate, a potent reducing
and hydroxylating molecule, is destroyed in these reactions. Accordingly,
in the effort to control the damage done by the genetic defect the
level of ascorbate is decreased, exacerbating the general deleterious
effects of ascorbate deficiency.
One of the genetic defects where the ascorbate depleting steps are well
characterized is the LDL receptor defect. All the expressions of LDL
receptors (19) the inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme
A reductase in the synthesis of cholesterol (20), the protection of LDL
against oxidative modification (21) and the stimulation of 7a -hydroxylase
in the catabolism of cholesterol to bile acids (22). We suggest that
it is ascorbate deficiency that is the real cause of the premature CVD
associated with this inherited disease, exacerbated by the genetic defect.
In this context the recent study in familial hypercholesterolemic patients
by Seed et al. (11) is of interest. In this study elevated LDL or the
underlying genetic defect of the LDL-receptor were not correlated with
CVD. Thus this genetic defect leading to ascorbate deficiency in combination
with the genetic deposition for high Lp(a) levels significantly increased
the risk of premature CVD.
As do genetic defects, exogenous risk factors for CVD lead to ascorbate
depletion. The observed correlation between a high fat diet or cigarette
smoking and CVD can also be explained as the result of induced ascorbate
deficiency, caused by destruction of ascorbate in the catabolism of lipids
and the effort to detoxify the substances in the smoke. With insufficient
dietary ascorbate resupplementation, both endogenous and exogenous risk
factors for CVD aggravate ascorbate deficiency and accelerate CVD development.
Ascorbate Deficiency and the Vascular Wall
Ascorbemia, the total depletion of ascorbate in scurvy, leads to a complete
loss of the integrity and stability of the vascular wall and to the
extravasation of blood into the perivascular area. Hypoascorbemia,
leads to early forms of this impairment.
The vascular endothelium is directly affected by ascorbate deficiency.
Characteristic features are changes in the cellular morphology and the
presence of large intercellular gaps. These changes lead to the loss
of the function of the endothelium as a barrier between the blood and
the vascular wall, to increased permeability, and consequently to increased
infiltration of plasma constituents into the vascular wall.
The extracellular matrix of the wall is affected. Collagen and elastin,
the principal macromolecules of this matrix, are made from their precursors,
procollagen, and proelastin, by hydroxylation of prolyl and lysyl residues.
Ascorbate deficiency leads to an incomplete hydroxylation and thus weakens
the extracellular matrix. Alterations of the endothelium and loose connective
tissue are known to be characteristic features of atherosclerotic plaques.
To limit the fatal consequences of prolonged ascorbate deficiency metabolic
counter measures were developed under strong evolutionary pressure.
Ascorbate Deficiency and Metabolic Countermeasurs
To limit the consequences of prolonged ascorbate deficiency metabolic
countermeasures were developed under strong evolutionary pressure.
The most detrimental effect of ascorbate depletion is blood loss. Thus
ascorbate deficiency, to prevent the extravasation of blood, triggers
a whole series of metabolic reactions, with the primary aim of inducing
vasoconstriction and hemostasis.
It is therefore not surprising that ascorbate deficiency induces virtually
all the risk factors predisposing to atherogenesis and thrombogenesis,
most of them with immediate clinical significance. In the first line
of defense against the danger of perivascular bleeding increased levels
of thromboxane and decreased levels of prostacyclin (23) and prostaglandin
E lead to vasoconstriction and hemostasis. We have shown that prolonged
ascorbate deficiency increases fibrinogen and Lp(a) plasma levels and
in this situation the antifibrinolyitic properties of Lp(a) become beneficial.
We are aware that there is no one-to-one relation between ascorbate
and Lp(a). Lp(a) is a rather late part in a sequence of acute-phase reactants,
or risk factors induced by ascorbate deficiency. Because of its lipid
deposition in the vascular wall, however, Lp(a) is particularly detrimental.
The therapeutic implications are evident: ascorbate supplementation
increases the levels of prostacyclin and potentially EDRF, the endothelial
derived relaxing factor. This potent vasodilative factor is identical
with nitric oxide and ascorbate may preserve the active form of EDRF
by inhibiting oxidation to nitrogen dioxide. Simultaneously, ascorbate
decreases the levels of thromboxane, fibrinogen, and Lp(a) and thereby
contributes to a fundamental improvement of the risk profile in clinical
The Roles of Lp(a) and Fibrinogen in the Vascular Wall
In the Hamburg studies Lp(a) was found mainly deposited together with
fibrinogen/fibrin (10). Moreover, Lp(a) has been shown to bind to immobilized
fibrinogen/fibrin (25) and evidence for a direct binding of Lp(a) to
fibrinogen/fibrin in the vascular wall was reported (9). All these
observations can now be explained. In ascorbate deficiency the need
for increased plasma concentrations of Lp(a) and fibrinogen, for binding
of Lp(a) to fibrinogen/ fibrin in the vascular wall, and for its selective
retention become evident.
The hemostatic properties of Lp(a) and fibrinogen are needed to counteract
the deleterious consequences of ascorbate deficiency. Lp(a) also has
functions in the containment of diseases and the repair of tissues. Free-radical-induced
and plasmin-induced tissue degradation are established pathways.
We have suggested that apo(a), because of many disulfide groups that
can be reduced by ascorbate to thiols, can itself function as an antioxidant
(1). Moreover, we now suggest that because of its homology to plasmin
Lp(a) also inhibits plasmin-induced tissue degradation. The lipid content
of the Lp(a) particle simultaneously provides the substrate for cell repair.
In order to exert its physiological functions Lp(a) is deposited as an
intact lipoprotein particle and can be isolated from the vascular wall
(8). The extracellular accumulation of Lp(a) in the vascular wall is an
independent pathomechanism of human CVD which is at variance with concepts
suggesting the cellular uptake and degradation of lipoproteins by scavenger
cells is a prerequisite for atherogenesis (2,4).
A Theory for Human Cardiovascular Disease
We are now able to present a novel pathomechanism for human cardiovascular
disease. This disease is primarily a degenerative disease caused by
chronic ascorbate deficiency. The extracellular deposition of Lp(a)
and fibrinogen is a defense mechanism to limit the damage done by this
deficiency. Under chronic conditions this defense may, however, turn
into a pathologic process leading to the continued accumulation of
Lp(a) and fibrinogen/fibrin in the vascular wall. Thus Lp(a) and fibrinogen/fibrin
become the hallmarks of the atherosclerotic lesion (see figure).
The impairment of the integrity of the vascular wall in ascorbate deficiency
leads to increased infiltration of plasma constituents and to intimal
thickening throughout the vascular system but not necessarily to the
development of atherosclerotic plaques. If, however, altered hemodynamic
conditions reveal the underlying impairment of the vascular wall these
This theory explains why human atherosclerosis develops mainly at sites
of altered hemodynamic conditions such as the branching regions of coronary,
cervical and cerebral arteries. It explains why the primary manifestations
of human CVD is myocardial infarction and stroke, and also the increased
risk of CVD associated with hypertension, where an increased systemic
pressure extensively unmasks the underlying impairment of the vascular
It is unlikely that Lp(a) primarily exerts its atherogenicity by binding
to the plasminogen receptor on endothelial cells (27). These receptors
are present throughout the vascular system so that such a pathomechanism
would lead to increased incidence of peripheral vascular diseases and
venous thrombi, which are not necessarily associated with elevated Lp(a)
Peripheral Forms of Atherosclerosis
We are now able to account for another phenomenon associated with human
CVD: The principle difference in the pathomechanisms leading on the
one hand to atherosclerosis at predisposition sites and on the other
hand to peripheral vascular disease (PVD). Myocardial infarction and
stroke are by far the most frequent manifestations of CVD. The localized
development of atherosclerotic plaques in these patients can only be
explained if the instability of the vascular wall is the main risk
factor. Elevated concentrations of plasma risk factors, e.g., cholesterol
or LDL, can not explain the phenomenon of localized manifestation of
CVD. They may, however, play an aggravating role in the development
of CVD in the individual.
In the development of PVD, however, these plasma risk factors play a
much more prominent role, exerting a direct or indirect noxious effect
on the vascular wall. Consequently, this leads to atherosclerosis in
the vascular periphery where the contact between noxious plasma constituents
and the endothelium is prolonged. Triglyceride-rich lipoproteins, because
of their enhanced susceptibility to peroxidation, are such potential
challengers, leading to vascular damage in the periphery.
This theory explains the peripheral form of CVD associated with Type-III
hyperlipidemia, a metabolic disorder in which triglyceride-rich lipoproteins
accumulate in the plasma as very low-density lipoproteins (VLDL) and
intermediate-density lipoproteins (IDL). These conditions are also characterized
by a further pathomechanism of lipid deposition in the vascular wall.
In addition to the extracellular deposition of Lp(a) described above,
the cellular uptake of oxidatively modified lipoproteins by scavenger
cells plays a more prominent role. This can also explain why foam cells
are found much more frequently in the vascular wall of patients with
these metabolic disorders.
A similar pathomechanism is involved in PVD associated with cigarette
smoking, Oxygen free radicals from the cigarette smoke damage the endothelium
directly or via oxidative modification of lipoproteins. It is noteworthy
that ascorbate, the strongest antioxidant normally present in the human
body, is also a potent inhibitor of these pathomechanisms.
In general, inherited metabolic disorders resulting in an elevated concentration
of potentially noxious plasma constituents are frequently associated
with PVD, e.g., in homocystinuria.
Of particular interest is the pathogenesis of PVD in diabetes mellitus.
The glucose and ascorbate molecules share structural similarities and
compete for the same transport system for cellular uptake. Elevated glucose
levels competitively inhibit an optimum tissue uptake of ascorbate, leading
also to a chronic ascorbate depletion of the vascular wall and its impairment.
Therefore, dietary supplementation of ascorbate should lead to an effective
control of diabetic angiopathy.
The different pathomechanisms leading on the one hand to CVD at predisposition
sites and on the other hand to PVD are frequently interrelated. Nevertheless,
their discrimination described here may prove helpful for future therapeutic
approaches. Independent of the different pathomechanisms involved, ascorbate
deficiency is a common denominator of human CVD.
Prophylactic and Therapeutic Considerations
The theory presented in this paper immediately suggests effective prophylactic
and therapeutic treatments for most individuals at risk CVD and for
Ascorbate, a potent reducing and hydroxylating agent has been shown
to be effective in achieving critical prophylactic aims: lowering the
plasma Lp(a) level, preventing Lp(a) deposition in the vascular wall
(16), decreasing elevated LDL levels (28), increasing HDL levels (29),
preventing oxidative modification of lipoproteins, protecting against
oxidative damage by scavenging oxygen free radicals and by regenerating
tocopherol, [ppteventing the oxidative modification of lipoproteins (30),
and, above all, preserving the integrity of the vascular wall and preventing
the formation of atherosclerotic plaques (16).
Moreover ascorbate hits all these therapeutic targets at the same time.
It will be hard for any pharmaceutical product to surpass ascorbate, a
substance that has been developed and improved by nature over billions
of years. Premature atherosclerosis is essentially unknown in most animals,
whereas millions of humans, with chronic ascorbate deficiency, die of
atherosclerosis and related diseases each year.
Ascorbate is able not only to prevent the formation of atherosclerotic
lesion but also to reduce existing plaques. It is well-established that
ascorbate increases HDL plasma levels, thereby promoting reverse cholesterol
transport by uptake of intra- and extracellular lipid from the vascular
On the basis of our finding that plaque development is paralleled by
the extracellular deposition of Lp(a) it is evident that a major focus
of therapeutic development is the release of Lp(a) or its lipid component
from the arterial wall. Ascorbate may be involved in two ways: by dissociating
apo(a) from the LDL-like component of Lp(a), thus enhancing the lipoprotein
efflux from the vascular wall and by converting lysyl residues in this
wall into hydroxylysyl residues, thereby decreasing the binding affinity
to components of the vascular wall by way of the lysyl haptenic group.
The efficiency of releasing Lp(a) from its bonds to fibrinogen/fibrin
in the vascular wall may be considerably enhanced by administration also
of small prophylactic doses of one or more inhibitors that compete with
the lysyl haptenic groups [lysine, 6-aminohexanoic acid, p-aminomethylbenzoic
acid, trans-4-aminomethylcyclohexane carboxylic acid, and others].
For patients with advanced cardiovascular disease therapeutic amounts
of these inhibitors, together with ascorbate and as adjuncts to appropriate
conventional therapy, might be prescribed, once their therapeutic effect
has been clinically proved.
It might be argued that this class of substances, which are generally
used as anti-fibrinolytic agents, might induce coagulative complications.
These substances are, however, protease inhibitors and inhibit activation
of fibrinolysis as well as the activation of coagulation (31). These
substances have been used in long-term studies for different indications
without compromising side effects. We have, however, not found any earlier
recommendation of the use of these substances in the pharmacological
treatment of cardiovascular disease. The combination of these substances
with ascorbate may be considered ideal since ascorbate reduces the need
for further Lp(a) deposition in the vascular wall and the inhibitors
would enhance the release of already deposited Lp(a). Moreover, ascorbate
is known to have anti-coagulative (32) and profibrinolytic properties.
The concept presented here offers for the first time a conclusive explanation
for the unique features of human CVD. It can answer the questions that
have remained yet unexplained by presently available hypotheses on
the development of CVD (1,2,3) Ascorbate deficiency is a precondition
as well as a common denominator of CVD. With rare exceptions CVD is
a degenerative disease. Its leading risk factor is the instability
of the vascular wall rather than any plasma constituents, and its primary
pathomechanism is the deposition of Lp(a) and fibrinogen/fibrin in
the vascular wall.
We can now explain why the strongest downward trend in CVD mortality
of all industrialized countries occurred in the USA, the country with
the highest vitamin C consumption. Moreover, we now understand why these
two developments exactly parallel each other. On the basis of the scientific
concept presented in this publication it is now possible to achieve a
similar success also in other countries.
The pathomechanisms described here and the therapeutic conclusions presented
are the solution to the puzzle of human cardiovascular disease.
We have discussed the following points in detail:
- the cause of today's most important disease by ascorbate deficiency,
the result of a genetic defect in combination with inadequate intake
of supplementary ascorbate;
- the regulation of plasma Lp(a) levels by ascorbate and the reasons
why Lp(a) and ascorbate are found alternatively in most animal species;
- the identification of ascorbate deficiency as a common denominator
of endogenous and exogenous risk factors for CVD;
- the conditions under which a physiological defense mechanism designed
by nature to limit the deleterious effects of ascorbate deficiency
can turn into a pathological process;
- the extracellular deposition of Lp(a) and fibrinogen/fibrin as
the primary mechanism of human atherogenesis;
- the details of a comprehensive theory of human cardiovascular
disease; and the difference between atherosclerosis at predisposition
and peripheral vascular disease;
- finally, we presented prophylactic and therapeutic recommendations
made on the basis of these discoveries, which may lead
to a breakthrough for
the prevention and treatment of human CVD.
50 years ago ascorbate deficiency was established as a prominent risk
factor in CVD (33), and 37 years ago ascorbate was shown in preliminary
angiographic studies to reduce atherosclerotic plaques in man (34).
There is no rational explanation why these early observations of the
value of ascorbate were ignored and did not become common knowledge
in the medical profession long ago.
Our publications have initiated further clinical trials. The evidence
of the beneficial effects of ascorbate available now is already convincing
but comprehensive clinical confirmation should soon end the decades of
reluctance and skepticism. We are convinced that before long ascorbate
will become the treatment of first choice for cardiovascular disease.
The therapeutic significance of our discovery is not limited to CVD;
Lp(a) and ascorbate are involved in cancer, inflammatory disease, and
other diseases, including the process of aging. The deposition of Lp(a)
in the vicinity of disease can be conceived as a defense mechanism to
contain the progression of disease, particularly at low ascorbate concentrations.
The Lp(a)-ascorbate connection is a regulatory principle of nature that
directly affects human health. Abolition of ascorbate deficiency may
profoundly improve human health and increase life expectancy of human
Rath M & Pauling L (1990): Proceedings of the National Academy of
Sciences USA 87, 6204-6207.
Brown MS & Goldstein JL (1984): Scientific American 251, 58-66.
Ross R (1986): New England Journal of Medicine 314, 488-500.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, & Witztum JL (1989):
New England Journal of Medicine 320, 915-924.
Berg K (1963): Acta Pathologica 59, 369-382.
McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, Fless GM, Scanu
AM & Lawn RM (1987): Nature 300, 132-137.
Brown MS & Goldstein JL (1987): Nature (London) 330, 113-114.
Rath M, Niendorf A, Reblin T, Dietel M, Krebber HJ & Beisiegel U
(1989): Arteriosclerosis 9, 579-592.
Niendorf A, Rath M, Wolf K, Peters S, Arps H, Beisiegel U & Dietel
M (1990): Virchows Archiv. A. Pathol. Anat. 417, 105-111.
Beisiegel U, Niendorf A, Wolf K, Reblin T & Rath M (1990): European
Heart Journal 11, Suppl. E., 174-183.
Seed BM, Hoppichler F, Reaveley D, McCarhty S, Thompson GR, Boerwinkle
E & Utermann G (1990): New England Journal of Medicine 322, 1494-1499.
Dahlen GH, Guyton JR, Attar M, Farmer JA, Kautz JA & Gotto AM Jr.
(1986): Circulation 74, 758-765.
Zenker G, Koltringer P, Bone G, Kiederkorn K, Pfeiffer K & Jurgens
G (1986): Stroke 17, 942-945.
Hoff HF & Gaubatz JW (1982): Atherosclerosis 42: 273-297.
Gavish D & Breslow JL (1991): Lancet 337, 203-204.
Rath M & Pauling L (1990): Proceedings of the National Academy of
Sciences USA 87, 9388-9390.
Carlson LA, Hamsten A & Asplund A (1989): Journal of Internal Medicine
Pauling L (1968): Science 160, 265-271.
Aulinskas TH, Van der Westerhuyzen DR & Coetzee GA (1983): Atherosclerosis
Harwood HJ Jr, Greene YJ & Stacpoole PW (1986): Journal of Biological
Chemistry 261, 7127-7135.
Frei B, England L & Ames BN (1989): Proceedings of the National
Academy of Sciences USA 86, 6377-6381.
Ginter E (1973): Science 179, 702-704.
Beetens J, Coene M-C, Verheyen A, Zonnekyn L & Herman AG (1986):
Prostaglandins 32, 335-352.
Loscalzo J, Weinfeld M, Fless GM & Scanu AM (1990): Arteriosclerosis
Harpel PC, Gordon BR & Parker TS (1989): Proceedings of the National
Academy of Sciences USA 86, 3847-3851.
Smith EB & Cochran S (1990): Atherosclerosis 84, 173-181.
Miles LA, Fless GM, Levin EG, Scanu AM & Plow EF (1989): Nature
Ginter E (1979): Wld. Rev. Nutr. Diet. 33, 104-141.
Bates CJ, Mandal AR, Cole TJ (1977): Lancet 3, 611.
Jialal I, Vega GL & Grundy SM (1990): Atherosclerosis 82, 185-191.
Aoki N, Naito K & Yoshida N (1978): Blood 1, 1-12.
Bordia A & Verma SD (1985): Clinical Cardiology 8, 552-554.
Paterson JC (1941): Canadian Medical Association Journal 44, 114-120.
Willis GC, Light AW & Gow WQS (1954): Canadian Medical
Association Journal 71, 562-568.