S PAULING-RATH THERAPY.pdf

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 Ph.D. 1

"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. "

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.

Max Planck

This paper is dedicated to the young physicians

and the medical students of this world.

Abstract

Until now therapeutic concepts for human

cardiovascular disease (CVD) were targeting

individual pathomechanisms or specific risk

factors. On the basis of genetic, metabolic,

evolutionary, and clinical evidence we present

here a unified pathogenetic and therapeutic

approach. Ascorbate deficiency is the precon-

dition 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 ascor-

bate 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.

Key words

Ascorbate, vitamin C, cardiovascular disease,

lipoprotein(a),hypercholesterolemia,

hypertriglyceridemia, hypoalphalipoprotein-emia,

diabetes, homocystinuria.

Introduction

We have recently presented ascorbate defi-

ciency as the primary cause of human CVD. We

proposed that the most frequent pathome-chanism

leading to the development of atherosclerotic

plaques is the deposition of Lp(a) and

fibrinogen/fibrin in the ascorbate-deficient

vascular wall. 1.2 In the course of this work we

discovered that virtually every patho-mechanism

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

1. Linus Pauling Institute of Science and Medicine, 440 Page Mill

Road, Palo Alto. CA 94306.

Journal of Orthomolecular Medicine Vol. 7, No. 1, 1992

transfer, and also peripheral angiopathies in

diabetic or homocystinuric patients. We did not

accept this observation as a coincidence.

Consequently we proposed that ascorbate de-

ficiency is the precondition as well as a common

denominator of human CVD. This far-reaching

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 blood-loss

through the scorbutic vascular wall became a life-

threatening condition. The resulting evolutionary

pressure

of the connective tissue. Ascorbate is essential for

an optimum production and hydroxy-lation 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 ap-

proximated 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.

favored

genetic

and

metabolic

mechanisms predisposing to CVD.

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.

Ascorbate Deficiency and Genetic

Countermeasures

The genetic countermeasures are characterized

by an evolutionary advantage of genetic features

and include inherited disorders that

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

A Unified Theory of Human Cardiovascular Disease

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

coun-teracting ascorbate deficiency. 1 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.

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 pro-

duction, 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. 6 There are

several genetically determined isoforms of apo(a).

They differ in the number of kringle repeats and

in their molecular size. 7 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 (1).

Moreover, as an adhesive protein apo(a) is

effective in tissue-repair processes (8). Chronic

ascorbate

Ascorbate Deficiency and Metabolic

Countermeasures

The metabolic countermeasures are charac-

terized 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

deficiency

leads

sustained

messenger

systems

such

cyclic

accumulation of Lp(a) in

monophosphates (for review see 1, 3-5). It

Journal of Orthomolecular Medicine Vol. 7, No. 1, 1992

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

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 sup-

plementation 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 of

LDL (for review see 1).

cerebral

atherosclerosis

but

not

with

peripheral vascular disease.

The mechanism by which ascorbate

resupplementation prevents CVD in any con-

dition 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 Lp(a) binding. 1

In about half of the CVD patients the mecha-

nism 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.

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. 10 Ascorbate-deficient foam cell

formation, although a less specific repair

mechanism than the extracellular deposition of

Lp(a), may have also conferred stability .

Other Lipoprotein Disorders Associated with

CVD

In a large population study Goldstein et al.

discussed three frequent lipid disorders, familial

hypercholesterolemia, familial hyper-

triglyceridemia, and familial combined

hyperlipidemia. 9 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,

A Unified Theory of Human Cardiovascular Disease

Ascorbate supplementation prevents the

exacerbation of CVD associated with

hypertriglyceridemia, Type III hyperlipide-mia,

and related disorders by stimulating lipoprotein

lipases and thereby enabling a normal catabolism

of triglyceride-rich lipoproteins. 11 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 in-

volved in the metabolic clearance of triglyceride-

rich lipoproteins, such as the chylomicron remnant

receptor.

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 reverse pathway.

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. 13

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, 14 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 ascorbate-deficient vascular wall.

We illustrate this principle for diabetic and

homocystinuric angiopathy.

Hypoalphalipoproteinemia

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, l2 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

Diabetic 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. 15,16

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 requirement. 17

Homocystinuric angiopathy

Homocystinuria is characterized by the ac-

cumulation 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. 18 Elevated plasma

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