A Unified Theory of Human
Cardiovascular Disease Leading the Way to the Abolition of This Disease as a
Cause for Human Mortality
Matthias Rath M.D. and Linus Pauling
"An important scientific innovation rarely, makes its way by gradually
winning over and converting its opponents. What does happen is that its
opponents gradually die out and that the growing generation is familiar with
the idea from the beginning." -Max Planck
This paper is dedicated to the young physicians and the medical students of
Until now therapeutic concepts for human cardiovascular disease (CVD) were
targeting individual pathomechanisms or specific risk factor,. On the basis of
genetic, metabolic, evolutionary, and clinical evidence we present here a
unified pathogenetic and therapeutic approach. Ascorbate deficiency is the
precondition and common denominator of human CVD. Ascorbate deficiency is the
result of the inability of man to synthesize ascorbate endogenously in
combination with insufficient dietary intake. The invariable morphological
consequences of chronic ascorbate deficiency in the vascular wall are the
loosening of the connective tissue and the loss of the endothelial barrier
function. Thus human CVD is a form of pre-scurvy. The multitude of
pathomechanisms that lead to the clinical manifestation of CVD are primarily
defense mechanisms aiming at the stabilization of the vascular wall. After the
loss of endogenous ascorbate production during the evolution of man these
defense mechanisms became life-saving. They counteracted the fatal
consequences of scurvy and particularly of blood loss through the scorbutic
vascular wall. These countermeasures constitute a genetic and a metabolic
level. The genetic level is characterized by the evolutionary advantage of
inherited features that lead to a thickening of the vascular wall, including a
multitude of inherited diseases.
The metabolic level is characterized by the close connection of ascorbate with
metabolic regulatory systems that determine the risk profile for CVD in
clinical cardiology today. The most frequent mechanism is the deposition of
lipoproteins, particularly lipoprotein (a) [Lp(a)], in the vascular wall. With
sustained ascorbate deficiency, the result of insufficient ascorbate uptake,
these defense mechanisms overshoot and lead to the development of CVD.
Premature CVD is essentially unknown in all animal species that produce high
amounts of ascorbate endogenously. In humans, unable to produce endogenous
ascorbate, CVD became one of the most frequent diseases. The genetic mutation
that rendered all human beings today dependent on dietary ascorbate is the
universal underlying cause of CVD- Optimum dietary ascorbate intake will
correct this common genetic defect and prevent its deleterious consequences.
Clinical confirmation of this theory should largely abolish CVD as a cause for
mortality in this generation and future generations of mankind.
Ascorbate, vitamin C, cardiovascular disease, lipoprotein (a), hypercholesteroleinia. hypertriglyceridemia, hypoalphalipoproteinemia,
We have recently presented ascorbate deficiency as the primary cause of
human CVD. We proposed that the most frequent pathomechanism leading to the
development of atherosclerotic plaques is the deposition of Lp(a) and
fibrinogen/fibrin in the ascorbate-deficient vascular wall. In the course of
this work we discovered that virtually every pathomechanism for human CVD
known today can be induced by ascorbate deficiency. Beside the deposition of
Lp(a) this includes such seemingly unrelated processes as foam cell formation
and decreased reverse-cholesterol
transfer, and also peripheral angiopathies in diabetic or homocystinuric
patients. We did not accept this observation as a coincidence. Consequently we
proposed that ascorbate deficiency is the precondition as well as a common
denominator of human CVD. This farreaching conclusion deserves an explanation;
it is presented in this paper. We suggest that the direct connection of
ascorbate deficiency with the development of CVD is the result of
extraordinary pressure during the evolution of man. After the loss of the
endogenous ascorbate production in our ancestors, severe bloodloss through the
scorbutic vascular wall became a life-threatening condition. The resulting
evolutionary pressure favored genetic and metabolic mechanisms predisposing to
The Loss of Endogenous Ascorbate Production in the Ancestor of Man
With few exceptions all animals synthesize their own ascorbate by
conversion from glucose. In this way they manufacture a daily amount of
ascorbate that varies between about 1 gram and 20 grams, when compared to the
human body weight. About 40 million years ago the ancestor of man lost the
ability for endogenous ascorbate production. This was the result of a mutation
of the gene encoding for the enzyme L-gulono-g-lactone oxidase (GLO), a key
enzyme in the conversion of glucose to ascorbate. As a result of this mutation
all descendants became dependent on dietary ascorbate intake.
The precondition for the mutation of the GLO gene was a sufficient supply of
dietary ascorbate. Our ancestors at that time lived in tropical regions. Their
diet consisted primarily of fruits and other forms of plant nutrition that
provided a daily dietary ascorbate supply in the range of several hundred
milligrams to several grams per day. When our ancestors left this habitat to
settle in other regions of the world the availability of dietary ascorbate
dropped considerably and they became prone to scurvy.
Fatal Blood Loss Through the Scorbutic Vascular Wall - An Extraordinary
Challenge to the Evolutionary Survival of Man
Scurvy is a fatal disease. It is characterized by structural and metabolic
impairment of the human body, particularly by the destabilization of the
connective tissue. Ascorbate is essential for an optimum production and
hydroxylation of collagen and elastin, key constituents of the extracellular
matrix. Ascorbate depletion thus leads to a destabilization of the connective
tissue throughout the body. One of the first clinical signs of scurvy is
perivascular bleeding. The explanation is obvious: Nowhere in the body does
there exist a higher pressure difference than in the circulatory system,
particularly across the vascular wall. The vascular system is the first site
where the underlying destabilization of the connective tissue induced by
ascorbate deficiency is unmasked, leading to the penetration of blood through
the permeable vascular wall. The most vulnerable sites are the proximal
arteries, where the systolic blood pressure is particularly high. The
increasing permeability of the vascular wall in scurvy leads to petechiae and
ultimately hemorrhagic blood loss.
Scurvy and scorbutic blood loss decimated the ship crews in earlier centuries
within months. It is thus conceivable that during the evolution of man periods
of prolonged ascorbate deficiency led to a great death toll. The mortality
from scurvy must have been particularly high during the thousands of years the
ice ages lasted and in other extreme conditions, when the dietary ascorbate
supply approximated zero. We therefore propose that after the loss of
endogenous ascorbate production in our ancestors, scurvy became one of the
greatest threats to the evolutionary survival of man. By hemorrhagic blood
loss through the scorbutic vascular wall our ancestors in many regions may
have virtually been brought close to extinction.
The morphologic changes in the vascular wall induced by ascorbate deficiency
are well characterized: the loosening of the connective tissue and the loss of
the endothelial barrier function. The extraordinary pressure by fatal blood
loss through the scorbutic vascular wall favored genetic and metabolic
countermeasures attenuating increased vascular permeability.
Ascorbate Deficiency and Genetic Countermeasures
The genetic countermeasures are characterized by an evolutionary advantage
of genetic features and include inherited disorders that
are associated with atherosclerosis and CVD. With sufficient ascorbate supply
these disorders stay latent. In ascorbate deficiency, however, they become
unmasked, leading to an increased deposition of plasma constituents in the
vascular wall and other mechanisms that thicken the vascular wall. This
thickening of the vascular wall is a defense measure compensating for the
impaired vascular wall that had become destabilized by ascorbate deficiency.
With prolonged insufficient ascorbate intake in the diet these defense
mechanisms overshoot and CVD develops.
The most frequent mechanism to counteract the increased permeability of the
ascorbate-deficient vascular wall became the deposition of lipoproteins and
lipids in the vessel wall. Another group of proteins that generally accumulate
at sites of tissue transformation and repair are adhesive proteins such as
fibronectin, fibrinogen, and particularly apo(a). It is therefore no surprise
that Lp(a), a combination of the adhesive protein apo(a) with a low density
lipoprotein (LDL) particle, became the most frequent genetic feature
counteracting ascorbate deficiency.' Beside lipoproteins, certain metabolic
disorders, such as diabetes and homocystinuria, are also associated with the
development of CVD. Despite differences in the underlying pathomechanism, all
these mechanisms share a common feature: they lead to a thickening of the
vascular wall and thereby can counteract the increased permeability in
ascorbate deficiency. In addition to these genetic disorders, the evolutionary
pressure from scurvy also favored certain metabolic countermeasures.
Ascorbate Deficiency and Metabolic Countermeasures
The metabolic countermeasures are characterized by the regulatory role of
ascorbate for metabolic systems determining the clinical risk profile for CVD.
The common aim of these metabolic regulations is to decrease the vascular
permeability in ascorbate deficiency. Low ascorbate concentrations therefore
induce vasoconstriction and hemostasis and affect vascular wall metabolism in
favor of atherosclerogenesis. Towards this end ascorbate interacts with
lipoproteins. coagulation factors, prostaglandins, nitric oxide, and second
messenger systems such as cyclic monophosphates. It should be noted that
ascorbate can affect these regulatory levels in a multiple way- In lipoprotein
metabolism low density lipoproteins (LDL), Lp(a), and very low density
lipoproteins (VLDL) are inversely correlated with ascorbate concentrations,
whereas ascorbate and HDL levels are positively correlated. Similarly, in
prostaglandin metabolism ascorbate increases prostacyclin and prostaglandin E
levels and decreases the thromboxane level. In general, ascorbate deficiency
induces vascular constriction and hemostatis, as well as cellular and
extracellular defense measures in the vascular wall.
In the following sections we shall discuss the role of ascorbate for frequent
and well established pathomechanisms of human CVD. In general, the inherited
disorders described below are polygenic. Their separate description, however,
will allow the characterization of the role of ascorbate on the different
genetic and metabolic levels.
Apo(a) and Lp(a), the Most Effective and Most Frequent Countermeasure
After the loss of endogenous ascorbate production, apo(a) and Lp(a) were
greatly favored by evolution. The frequency of occurrence of elevated Lp(a)
plasma levels in species that had lost the ability to synthesize ascorbate is
so great that we formulated the theory that apo(a) functions as a surrogate
for ascorbate.' There are several genetically determined isoforms of apo(a).
They differ in the number of kringle repeats and in their molecular size. An
inverse relation between the molecular size of apo(a) and the synthesis rate
of Lp(a) particles has been established. Individuals with the high molecular
weight apo(a) isoform produce fewer Lp(a) particles than those with the low
apo(a) isoform. In most population studies the genetic pattern of high apo(a)
isoform/low Lp(a) plasma level was found to be the most advantageous and
therefore most frequent pattern. In ascorbate deficiency Lp(a) is selectively
retained in the vascular wall. Apo(a) counteracts increased permeability by
compensating for collagen, by its binding to fibrin, as a proteinthiol
antioxidant, and as an inhibitor of plasmin-induced proteolysis. Moreover, as
an adhesive protein apo(a) is effective in tissue-repair processes (8).
Chronic ascorbate deficiency leads to a sustained accumulation of Lp(a) in the
vascular wall. This leads to the development of atherosclerotic plaques and
premature CVD, particularly in individuals with genetically determined high
plasma Lp(a) levels. Because of its association with apo(a), Lp(a) is the most
specific repair particle among all lipoproteins. Lp(a) is predominantly
deposited at predisposition sites and it is therefore found to be
significantly correlated with coronary, cervical, and cerebral atherosclerosis
but not with peripheral vascular disease.
The mechanism by which ascorbate resupplementation prevents CVD in any
condition is by maintaining the integrity and stability of the vascular wall.
In addition, ascorbate exerts in the individual a multitude of metabolic
effects that prevent the exacerbation of a possible genetic predisposition and
the development of CVD. If the predisposition is a genetic elevation of Lp(a)
plasma levels the specific regulatory role of ascorbate is the decrease of
apo(a) synthesis in the liver and thereby the decrease of Lp(a) plasma levels.
Moreover, ascorbate decreases the retention of Lp(a) in the vascular wall by
lowering fibrinogen synthesis and by increasing the hydroxylation of lysine
residues in vascular wall constituents, thereby reducing the affinity for
In about half of the CVD patients the mechanism of Lp(a) deposition
contributes significantly to the development of atherosclerotic plaques. Other
lipoprotein disorders are also frequently part of the polygenic pattern
predisposing the individual patient to CVD in the individual.
Other Lipoprotein Disorders Associated with CVD
In a large population study Goldstein et al. discussed three frequent
lipid disorders, familial hypercholesterolemia, familial hypertriglyceridemia,
and familial combined hyperlipidemia. Ascorbate deficiency unmasks these
underlying genetic defects and leads to an increased plasma concentration of
lipids (e.g. cholesterol, triglycerides) and lipoproteins (e.g. LDL, VLDL) as
well as to their deposition in the impaired vascular wall. As with Lp(a), this
deposition is a defense measure counteracting the increased permeability. It
should, however, be noted that the deposition of lipoproteins other than Lp(a)
is a less specific defense mechanism and frequently follows Lp(a) deposition.
Again, these mechanisms function as a defense only for a limited time. With
sustained ascorbate deficiency the continued deposition of lipids and
lipoproteins leads to atherosclerotic plaque development and CVD. Some
mechanisms will now be described in more detail.
Hypercholesterolemia, LDL-receptor defect
A multitude of genetic defects lead to an increased synthesis and/or a
decreased catabolism of cholesterol or LDL. A well characterized although rare
defect is the LDL receptor defect. Ascorbate deficiency unmasks these
inherited metabolic defects and leads to an increased plasma concentration of
cholesterol-rich lipoproteins, e.g. LDL, and their deposition in the vascular
wall. Hypercholesterolemia increases the risk for premature CVD primarily when
combined with elevated plasma levels of Lp(a) or triglycerides.
The mechanisms by which ascorbate supplementation prevents the exacerbation of
hypercholesterolemia and related CVD include an increased catabolism of
cholesterol. In particular, ascorbate is known to stimulate 7-a-hydroxylase, a
key enzyme in the conversion of cholesterol to bile acids and to increase the
expression of LDL receptors on the cell surface. Moreover, ascorbate is known
to inhibit endogenous cholesterol synthesis as well as oxidative modification
Hypertriglyceridemia, Type III hyperlipidemia
A variety of genetic disorders lead to the accumulation of triglycerides
in the form of chylomicron remnants, VLDL, and intermediate density
lipoproteins (IDL) in plasma. Ascorbate deficiency unmasks these underlying
genetic defects and the continued deposition of triglyceride-rich lipoproteins
in the vascular wall leads to CVD development. These triglyceride-rich
lipoproteins are particularly subject to oxidative modification, cellular
lipoprotein uptake, and foam cell formation. In hypertriglyceridemia
nonspecific foam-cell formation has been observed in a variety of
organs." Ascorbate-deficient foam cell formation, although a less
specific repair mechanism than the extracellular deposition of Lp(a), may have
also conferred stability .
Ascorbate supplementation prevents the exacerbation of CVD associated with
hypertriglyceridemia, Type III hyperlipidemia, and related disorders by
stimulating lipoprotein lipases and thereby enabling a normal catabolism of
triglyceride-rich lipoproteins. Ascorbate prevents the oxidative modification
of these lipoproteins, their uptake by scavenger cells and foam cell
formation. Moreover, we propose here that, analogous to the LDL receptor,
ascorbate also increases the expression of the receptors involved in the
metabolic clearance of triglyceride-rich lipoproteins, such as the chylomicron
The degree of build-up of atherosclerotic plaques in patients with lipoprotein
disorders is determined by the rate of deposition of lipoproteins and by the
rate of the removal of deposited lipids from the vascular wall. It is
therefore not surprising that ascorbate is also closely connected with this
Hypoalphalipoproteinemia is a frequent lipoprotein disorder characterized by a
decreased synthesis of HDL particles. HDL is part of the
'reverse-cholesterol-transport' pathway and is critical for the transport of
cholesterol and also other lipids from the body periphery to the liver. In
ascorbate deficiency this genetic defect is unmasked, resulting in decreased
HDL levels and a decreased reverse transport of lipids from the vascular wall
to the liver. This mechanism is highly effective and the genetic disorder
hypoalphalipoproteinemia was greatly favored during evolution. With ascorbate
supplementation HDL production increases, leading to an increased uptake of
lipids deposited in the vascular wall and to a decrease of the atherosclerotic
lesion. A look back in evolution underlines the importance of this mechanism.
During the winter seasons, with low ascorbate intake, our ancestors became
dependent on protecting their vascular wall by the deposition of lipoproteins
and other constituents. During spring and summer seasons the ascorbate content
in the diet increased significantly and mechanisms were favored that decreased
the vascular deposits under the protection of increased ascorbate
concentration in the vascular tissue. It is not unreasonable for us to propose
that ascorbate can reduce fatty deposits in the vascular wall within a
relatively short time. In an earlier clinical study it was shown that 500 mg
of dietary ascorbate per day can lead to a reduction of atherosclerotic
deposits within 2 to 6 months."
This concept, of course, also explains why heart attack and stroke occur today
with a much higher frequency in winter than during spring and summer, the
seasons with increased ascorbate intake.
Other Inherited Metabolic Disorders Associated with CVD
Beside lipoprotein disorders many other inherited metabolic diseases are
associated with CVD. Generally these disorders lead to an increased
concentration of plasma constituents that directly or indirectly damage the
integrity of the vascular wall. Consequently these diseases lead to peripheral
angiopathies as observed in diabetes, homocystinuria, sickle-cell anemia (the
first molecular disease described," and many other genetic disorders.
Similar to lipoproteins the deposition of various plasma constituents as well
as proliferative thickening provided a certain stability for the
ascorbatedeficient vascular wall. We illustrate this principle for diabetic
and homocystinuric angiopathy.
The pathomechanism in this case involves the structural similarity between
glucose and ascorbate and the competition of these two molecules for specific
cell surface receptors." Elevated glucose levels prevent many cellular
systems in the human body, including endothelial cells, from optimum ascorbate
uptake- Ascorbate deficiency unmasks the underlying genetic disease,
aggravates the imbalance between glucose and ascorbate, decreases vascular
ascorbate concentration, and thereby triggers diabetic angiopathy.
Ascorbate supplementation prevents diabetic angiopathy by optimizing the
ascorbate concentration in the vascular wall and also by lowering insulin
Homocystinuria is characterized by the accumulation of homocyst(e)ine and
a variety of its metabolic derivatives in the plasma, the tissues and the
urine as the result of decreased homocysteine catabolism." Elevated
plasma concentrations of homocyst(e)ine and its derivatives damage the
endothelial cells throughout the arterial and venous system. Thus
homocystinuria is characterized by peripheral vascular disease and
thromboembolism. These clinical manifestations have been estimated to occur in
30 per cent of the patients before the age of 20 and in 60 per cent of the
patients before the age of 40.
Ascorbate supplementation prevents homocystinuric angiopathy and other
clinical complications of this disease by increasing the rate of homocysteine
Thus, ascorbate deficiency unmasks a variety of individual genetic
predispositions that lead to CVD in different ways. These genetic disorders
were conserved during evolution largely because of their association with
mechanisms that lead to the thickening of the vascular wall. Moreover, since
ascorbate deficiency is the underlying cause of these diseases, ascorbate
supplementation is the universal therapy.
The Determining Principles of This Theory
The determining principles of this comprehensive theory are schematically
summarized in Figures I to 3 (pages 13 to 15).
1. CVD is the direct consequence of the inability for endogenous ascorbate
production in man in combination with low dietary ascorbate intake.
2. Ascorbate deficiency leads to increased permeability of the vascular wall
by the loss of the endothelial barrier function and the loosening of the
vascular connective tissue.
3. After the loss of endogenous ascorbate production scurvy and fatal blood
loss through the scorbutic vascular wall rendered our ancestors in danger of
extinction. Under this evolutionary pressure over millions of years genetic
and metabolic countermeasures were favored that counteract the increased
permeability of the vascular wall.
4. The genetic level is characterized by the fact that inherited disorders
associated with CVD became the most frequent among all genetic
predispositions. Among those predispositions lipid and lipoprotein disorders
occur particularly often.
5. The metabolic level is characterized by the direct relation between
ascorbate and virtually all risk factors of clinical cardiology today.
Ascorbate deficiency leads to vasoconstriction and hemostasis and affects the
vascular wall metabolism in favor of atherosclerogenesis.
6. The genetic level can be further characterized. The more effective and
specific a certain genetic feature counteracted the increasing vascular
permeability in scurvy, the more advantageous it became during evolution and,
generally, the more frequently this genetic feature occurs today
7. The deposition of Lp(a) is the most effective, most specific, and therefore
most frequent of these mechanisms. Lp(a) is preferentially deposited at
predisposition sites. In chronic ascorbate deficiency the accumulation of
Lp(a) leads to the localized development of atherosclerotic plaques and to
myocardial infarction and stroke.
8. Another frequent inherited lipoprotein disorder is
hypoalphalipoproteinemia. The frequency of this disorder again reflects its
usefulness during evolution. The metabolic upregulation of HDL synthesis by
ascorbate became an important mechanism to reverse and decrease existing lipid
deposits in the vascular wall.
9. The vascular defense mechanisms associated with most genetic disorders are
nonspecific. These mechanisms can aggravate the development of atherosclerotic
plaques at predisposition sites. Other nonspecific mechanisms lead to
peripheral forms of atherosclerosis by causing a thickening of the vascular
wall throughout the arterial system. This peripheral form of vascular disease
is characteristic for angiopathics associated with Type III hyperlipidemia,
diabetes, and many other inherited metabolic diseases.
10. Of particular advantage during evolution and therefore particularly
frequent today are those genetic features that protect the ascorbate-deficient
vascular wall until the end of the reproduction age. By favoring these
disorders nature decided for the lesser of two evils: the death from CVD after
the reproduction age rather than death from scurvy at a much earlier age. This
also explains the rapid increase of the CVD mortality today from the 4th
11. After the loss of endogenous ascorbate production the genetic mutation
rate in our ancestors increased significantly- This was an additional
precondition favoring the advantage not only of apo(a) and Lp(a) but also of
many other genetic countermeasures associated with CVD.
12. Genetic predispositions are characterized by the rate of ascorbate
depiction in a multitude of metabolic reactions specific for the genetic
disorder." The overall rate of ascorbate depletion in an individual is
largely determined by the polygenic pattern of disorders. The earlier the
ascorbate reserves in the body are depleted without being resupplemented, the
earlier CVD develops.
13. The genetic predispositions with the highest probability for early
clinical manifestation require the highest amount of ascorbate supplementation
in the diet to prevent CVD development. The amount of ascorbate for patients
at high risk should be comparable to the amount of ascorbate our ancestors
synthesized in their body before they lost this ability: between 10,000 and
20,000 milligrams per day.
14. Optimum ascorbate supplementation prevents the development of CVD
independently of the individual predisposition or pathomechanism. Ascorbate
reduces existing atherosclerotic deposits and thereby decreases the risk for
myocardial infarction and stroke. Moreover, ascorbate can prevent blindness
and organ failure in diabetic patients, thromboembolism in homocystinuric
patients, and many other manifestations of CVD.
In this paper we present a unified theory of human CVD. This disease is
the direct consequence of the inability of man to synthesize ascorbate in
combination with insufficient intake of ascorbate in the modem diet. Since
ascorbate deficiency is the common cause of human CVD, ascorbate
supplementation is the universal treatment for this disease. The available
epidemiological and clinical evidence is reasonably convincing. Further
clinical confirmation of this theory should lead to the abolition of CVD as a
cause of human mortality for the present generation and future generations of