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, J. Orthomolecular
Medicine, 6:125-134, (1991).
Summary
Human cardiovascular disease (CVD) is the result of the accumulation of
lipoprotein (a), Lp(a), rather than of low density lipoprotein (LDL), in the
vascular wall. It is generally not the consequence of plasma LDL levels, but
rather of the level of Lp(a), which is formed in the liver in amounts largely
determined by the rate of synthesis of apo (a). This
rate is increased by low ascorbate concentrations.
Human CVD is primarily a degenerative disease caused by ascorbate
deficiency. This deficiency is the result of the inability of humans to
synthesize endogenous ascorbate combined with an
insufficient dietary ascorbate intake. The deficiency
is
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
show my 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
Introduction
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 colle
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 of CVD.
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
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
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
Moreover, we proposed that Lp(a) strengthens the vascular wall, particularly in ascorbate deficiency. At low ascorbate
concentrations the synthesis of coll
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 to CVD.
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 dam
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
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
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. Coll
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
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 cardiology.
The Roles of Lp(a) and Fibrinogen in the Vascular Wall
In the
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 dam
Figure a.
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 plaques
develop.
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
wall.
Figure b.
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) plasma levels
Figure c.
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
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 dam
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 dam
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 CVD patients.
Prophylaxis.
Ascorbate, a potent reducing and hydroxylating
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.
Therapeusis.
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 wall.
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
Conclusion
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
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 sites 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
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
References
Rath M & Pauling
L (1990): Proceedings of the National
Brown MS & Goldstein JL (1984):
Scientific American 251, 58-66.
Ross R (1986):
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 (
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):
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
Carlson LA, Hamsten
A & Asplund A (1989): Journal of Internal
Medicine 226, 271-276.
Pauling L (1968): Science 160, 265-271.
Aulinskas TH,
Harwood HJ Jr,
Greene YJ & Stacpoole PW (1986): Journal of
Biological Chemistry 261, 7127-7135.
Frei B,
Ginter E (1973): Science 179, 702-704.
Beetens J, Coene
M-C, Verheyen A, Zonnekyn L
& Herman
Loscalzo J, Weinfeld
M, Fless GM & Scanu AM
(1990): Arteriosclerosis 10, 240-245.
Harpel PC, Gordon BR & Parker TS (1989):
Proceedings of the National
Smith EB & Cochran S (1990): Atherosclerosis
84, 173-181.
Miles LA, Fless
GM, Levin EG, Scanu AM & Plow EF (1989): Nature
339, 301-303.
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 &
Willis GC, Light AW & Gow WQS (1954): Canadian Medical Association Journal 71, 562-568.