| Reducing the Risk
for Cardiovascular Disease With Nutritional Supplements (1992)
Rath M. Journal of Orthomolecular Medicine, 7:153-162.
Summary
Reducing the risk for cardiovascular disease (CVD) is a primary
goal of any health care system in the industrialized world. The
success of this world-wide effort will largely depend on the proper
understanding of the mechanisms responsible for development of
this disease.
This paper marshals the scientific evidence for
the predominant pathomechanisms of CVD and presents new therapeutic
approaches. Human atherosclerotic lesions are primarily composed
of lipoprotein(a). The extracellular deposition of this lipoprotein
directly parallels the extent of the atherosclerotic lesion. The
frequency of this pathomechanism today is directly related to
its efficacy as a defense mechanism during the evolution of man,
particularly in stabilizing the vascular wall during ascorbate
deficiency. The deposition of lipoprotein(a) in form of largely
intact particles implies the reversibility of this mechanism.
On the basis of an improved understanding about
the pathogenesis of CVD new therapeutic approaches are defined.
Certain vitamins and amino acids are of particular importance
for these approaches. Ascorbate is essential for preserving and
restoring the integrity and stability of the vascular wall. Niacin
and ascorbate were reported to lower lipoprotein(a) plasmalevels.
It is proposed that this effect is mediated by NADPH.
The amino acids L-lysine and L-proline competitively
interfere with the binding of lipoprotein(a) to constituents of
the vascular wall and atherosclerotic lesions. The therapeutic
use of these amino acids could prevent further buildup of lipoprotein(a)
accumulation in the vascular wall. More importantly, optimum concentrations
of L-lysine and L-proline could release deposited lipoprotein(a)
but also other atherogenic lipoproteins form the vascular wall.
This paper defines a new therapeutic goal: The
pharmaceutical, non-invasive reversal of existing CVD with nutritional
supplements.
Full study
Introduction
Cardiovascular Disease (CVD) is the most frequent cause of death
in the industrialized world. In a series of recent papers I have
contributed to an improved understanding about the pathogenesis
of human CVD. It was shown that ascorbate deficiency is an important
underlying factor and that all mechanisms known today leading
to CVD can be triggered by ascorbate deficiency. This remarkable
fact reflects the strong pressure during the evolution of man
after loss of endogenous ascorbate synthesis. This pressure favored
genetic and metabolic features contributing to avoidance of the
fatal consequences of ascorbate deficiency and scurvy. The different
mechanisms of human CVD known today therefore all compensate for
impaired integrity and stability of the vascular wall caused by
chronically low dietary ascorbate intake. If these mechanisms
overshoot, heart attack, stroke and other forms of CVD develop.
1,2
In the first part of this paper I will marshal
the evidence for the most frequent of these pathomechanisms. I
will focus here on mechanisms related to lipid and lipoprotein
deposition in the vascular wall and re-evaluate existing hypotheses.
This re-evaluation is particularly necessary since cholesterol
lowering concepts have become dominant factors in the public health
debate. I will show that the most important among these overshooting
defense mechanisms is the extracellular deposition of lipoprotein(a)
in the vascular wall. On the basis of an improved understanding
of these pathomechanisms I will present new therapeutic approaches
including the reversibility of existing atherosclerotic deposits.
Finally I will marshal the evidence for the particular value of
nutritional supplements to achieve this therapeutic aim.
Lipoprotein(a), not LDL,
is the Primary Risk Factor for CVD in Plasma
Present theories of human CVD are based on the concept
that low-density lipoprotein (LDL) or LDL-cholesterol is the primary
risk factor for CVD in plasma.3,4 A closer look at the available
epidemiological data challenges this assumption. Lipoprotein(a),
not LDL is the primary risk factor for CVD in human plasma. Lipoprotein(a)
is a unique particle essentially composed of a LDL particle and
an additional adhesive protein designated apoprotein(a) (apo(a)).
The adhesive properties of apo(a) are the cause for the selective
retention of lipoprotein(a) in the vascular wall and for the accumulation
of lipids and lipoproteins inside the wall (Figure 1).
Lipoprotein(a) is an independent risk factor for
CVD. None of the epidemiological studies thus far assessing the
plasma risk profile for CVD showed any correlation between lipoprotein(a)
levels and total-cholesterol or LDL-cholesterol levels. The most
conclusive study that lipoprotein(a), not LDL, is the primary
risk factor for CVD was carried out in a genetically defined cohort
of LDL-receptor deficient patients.5 This genetic disorder is
characterized by significantly elevated plasma LDL levels and
was thought to lead almost invariably to premature CVD. Surprisingly,
60% of these LDL-receptor deficient patients had no clinical signs
of CVD, while 40% had developed CVD. Both groups did not differ
in their extremely high plasma levels of LDL-cholesterol (above
300 mg/dl) or of total cholesterol (390 mg/dl). The two groups
differed, however, significantly in their lipoprotein(a) plasma
levels and CVD patients had on average three-fold higher plasma
lipoprotein(a) levels. This study in a large group of patients
selected to minimize genetic variations allows the following conclusions:
Elevated plasma lipoprotein(a) is the primary risk
factor for CVD.
Increased LDL levels, in addition to elevated lipoprotein(a) levels,
increase the risk for CVD. High plasma LDL levels alone are not
associated with an increased risk for CVD.
Figure 1.
Equally strong evidence that lipoprotein(a), not
LDL, is the primary risk factor for CVD comes from a recent re-evaluation
of the Framingham Heart Study, one of the largest prospective
epidemiological studies determining the risk profile for CVD.
Lipoprotein(a) ranked among the most prevalent risk factors for
heart attacks. Moreover, a given quantity of lipoprotein(a) in
the blood conferred as much added risk for CVD as does 10 times
the quantity of LDL.6 Lipoprotein(a) was discovered 30 years ago.7
The negligent exclusion of this important risk factor from previous
epidemiological studies deserves an explanation. It may in part
be provided by methodological difficulties as a result of the
structural similarity between lipoprotein(a) and LDL. Plasma lipoproteins
in most epidemiological studies were determined by means of the
"Friedewald Formula",8 a method that does not allow
the differentiation between LDL and lipoprotein(a). The re-evaluation
of all large epidemiological risk factor studies has become necessary.
The results of these evaluations will further confirm lipoprotein(a)
as the primary risk factor for CVD. The evidence that lipoprotein(a),
not LDL, is the primary risk factor for CVD is not limited to
human plasma.
Lipoprotein(a), not LDL, is the Primary
Risk Factor Contributing to Atherosclerotic Plaques
Present concepts of human atherosclerosis assume that LDL
is the main vehicle by which cholesterol and other lipids are
deposited in the vascular wall. More recently it has been proposed
that cellular uptake of oxidized LDL by macrophages and other
scavenger cells and subsequent foam cell formation are the decisive
mechanisms for development of atherosclerotic plaques.4 According
to this concept foam cell formation or the extracellular deposition
of LDL would have to play a decisive role in the progression of
atherosclerotic lesions. A closer histological look on the in
situ situation of human atherosclerotic lesions challenges this
concept. The progression of atherosclerotic deposits is paralleled
by a structural impairment of the vascular wall and by the accumulation
of lipoprotein(a).
Together with my colleagues at Hamburg University
I reported the most comprehensive studies differentiating between
the deposition of LDL and lipoprotein(a) in human atherosclerosis.
??¹¹ Although these studies are frequently quoted, their
significance for the development of human atherosclerosis is still
insufficiently understood. These studies and their correct interpretation
have significant implications for future therapeutic approaches
for CVD. The conclusions of these studies are marshaled here as
follows:
Lipoprotein(a) is the predominant risk factor contributing
to the progression of atherosclerotic lesions in man.
The amount of lipoprotein(a) deposited in atherosclerotic
lesions corresponds with the extent of the lesions.
Lipoprotein(a) is deposited in the extracellular
matrix of the vascular wall in the form of largely intact lipoprotein
particles, which can be isolated from the wall. This finding implies
the reversibility of the lipoprotein(a) deposition in the vascular
wall.
Isolated LDL deposition was rarely found and LDL
alone, without simultaneous lipoprotein(a) deposition, cannot
be considered a primary factor determining the advancement of
human atherosclerotic lesions.
The adhesive protein apo(a) is responsible for
the selective retention of the lipoprotein(a) particle inside
the vascular wall compared to LDL and other lipoproteins.
These results do not exclude the deposition of
other potentially atherogenic lipoproteins (LDL, very low-density
lipoprotein in VLDL) in addition to and in the same areas lipoprotein(a)
accumulated. The discovery of the predominant role of lipoprotein(a)
in human atherosclerosis and the discovery of its potential reversibility
were decisive preconditions directly leading the way to identify
the therapeutic approaches discussed below.
Mechanism Leading to the
Extracellular Accumulation of Lipoprotein(a) in the Vascular Wall
The extracellular accumulation of lipoprotein(a) in the
vascular wall as the predominant pathomechanism of human atherosclerosis
is no coincidence. The frequency of this mechanism today is directly
related to its advantage during the evolution of man. After the
loss of endogenous ascorbate production in our ancestors lipoprotein(a)
became a life-saving feature to counteract fatal blood-loss through
the scorbutic vascular wall. While scurvy is essentially unknown
today, chronic insufficient dietary ascorbate intake is widespread.
The deposition of lipoprotein(a) in the vascular wall stabilizes
the wall of the arteries particularly during ascorbate deficiency.
With insufficient dietary ascorbate intake over decades this defense
mechanism overshoots and CVD develops. 1,2
The lipoprotein(a) particle is an ideal defense
molecule. Apo(a), an adhesive molecule,¹² interacts
with a variety of cellular and extracellular constituents of the
vascular wall including collagen, elastin, fibronectin, and glycosaminoglycanes
as well as fibrin/ fibrinogen. The apo(a) macromolecule itself
as well as the lipoprotein(a) particle confer stability to the
structurally impaired vascular wall.
Moreover, the deposition of lipoprotein(a) in the
vascular wall can favor the additional retention of other lipoprotein
particles such as LDL and VLDL. Lipoprotein(a) has been shown
to bind to lipoproteins containing apoB¹³ and the accumulation
of LDL and VLDL in addition to elevated lipoprotein(a) levels
but not alone.5
With the extracellular deposition of lipoprotein(a)
nature developed a sophisticated and reversible mechanism to render
compensatory stability to the vascular wall during times when
these walls ware weakened by a deficiency of essential nutrients.
The reversible deposition of lipoproteins in the vascular wall
is a key to new therapeutic approaches. To optimally exert this
defense function the lipoprotein(a) particle would inevitably
lead to a loss of its function to confer stability.
In contrast to this mechanism, present hypotheses
on human atherogenesis presuppose the degradation of the lipoprotein
particles into lipids and amino acids by scavenging cells in the
vascular wall.4 The importance of these mechanisms in the development
of human atherosclerosis needs to be further evaluated. It is,
however, evident that these mechanisms are inferior to the extracellular
deposition of lipoprotein(a) with respect to two important features:
stability and reversibility. This may explain why neither foam
cell formation nor the extracellular deposition of LDL are found
to parallel the progression of atherosclerotic lesions.
Irrespective of the pathomechanisms of human atherogenesis
they can largely be prevented by maintaining the structural integrity,
stability, and elasticity of the vascular wall. On the basis of
an improved understanding of human CVD presented in the first
part of this paper I will now summarize the most important preventive
and therapeutic aims for this disease.
Therapeutic Aim #1:
Preserving and Restoring
the Integrity and Stability of the Vascular Wall
The impairment of the vascular connective tissue and loss of the
endothelial barrier functions are the underlying morphologic changes
of any form of CVD. The instability of the vascular wall is a
prominent risk factor for human CVD explaining the predominantly
localized clinical manifestation of this disease in form of heart
attack and stroke.¹'² Preserving and restoring the integrity
and stability of the vascular wall is the most important therapeutic
aim for prevention and treatment of human CVD. Integrity and stability
of connective tissue are critically dependent on an optimum amount
and function of collagen and elastin. Ascorbate stimulates the
production of collagen and elastin and thereby directly contributes
to preserving and restoring the stability and integrity of the
vascular wall.14
It therefore comes as no surprise that CVD is essentially
unknown in animals producing their own vitamin C at a daily rate
of several thousand milligrams. Nor is it a surprise that lipoprotein(a)
is primarily found in species that had lost the ability of ascorbate
synthesis, a discovery I made in 1987. In humans a growing amount
of clinical and epidemiological data support the value of ascorbate
in the prevention of CVD. A recent epidemiological study in 11,000
Americans showed that dietary ascorbate intake between 200 mg
and 500 mg correlated with a reduction in CVD up to 50% and an
increase in life expectancy for up to 6 years.15 Beside providing
structural stability to the human body, ascorbate is also involved
in a variety of enzymatic and other metabolic functions, some
of which will be discussed below.
Therapeutic Aim #2:
Lowering Lipoprotein(a)
Levels in Plasma
Lowering the plasma levels of lipoprotein(a) is the second most
important therapeutic aim. Lipoprotein(a) is produced in the liver
and the production rate of apo(a) largely determines the plasma
levels of this lipoprotein. None of the currently available cholesterol-lowering
drugs is known to significantly affect plasma lipoprotein(a) levels.
In contrast, optimum dosages of two vitamins, niacin (vitamin
B3) and ascorbate have been reported to lower lipoprotein(a) plasma
levels.16-18 Their therapeutic mechanism, however, has not yet
been explained. I have obtained preliminary in vitro evidence
that lipoprotein(a) production can be lowered by increasing the
concentration of NADPH. NADPH is involved in a multitude of metabolic
regulatory processes. Niacin is a constituent of the NADP molecule
and ascorbate can reduce or "re-charge" the NADP molecule
to NADPH. Thus ascorbate and niacin could decrease lipoprotein
plasma levels – at least in part – by increasing NADPH
concentrations (Figure 2).
Beside the lowering of lipoprotein(a) in plasma
the risk for CVD can be further reduced by preventing accumulation
of this risk factor in the vascular wall.
Therapeutic Aim #3:
Preventing the Accumulation
of Lipoprotein(a)
in the Vascular Wall
Prevention of the accumulation of lipoprotein(a) in the vascular
wall is an important therapeutic aim in reducing the risk of CVD.
As discussed above the lipoprotein(a) particle can interact with
a variety of constituents of the vascular wall. The extracellular
deposition of lipoprotein(a) particles in the vascular wall via
the adhesive protein apo(a) immediately suggests novel therapeutic
approaches. Interfering with the binding of lipoprotein(a) to
constituents of the vascular wall will decrease the tendency of
this atherogenic lipoprotein to accumulate in the vascular wall
and thereby reduce the risk for the development of atherosclerotic
lesions.
Figure 2.
The amino acids L-lysine, L-proline, and hydroxyproline can interfere
with the binding of lipoprotein(a) to important constituents of
the vascular wall.13'1? The use of L-lysine and L-proline to prevent
the deposition of atherogenic lipoproteins in the vascular wall
opens novel therapeutic avenues. Supplementation of hydroxyproline
and hydroxylysine can be rendered redundant by co-administration
of ascorbate which can hydroxylate lysine and proline residues.2
L-Lysine
The essential amino acid L-lysine competitively
inhibits the binding of lipoprotein(a) to fibrinogen, fibrin,
and fibrin degradation products which are known to be hallmarks
of the atherosclerotic lesion. My earlier findings about the potential
reversibility of lipoprotein(a) deposition and the isolation of
lipoprotein(a) by use of lysine led to the therapeutic introduction
of L-lysine and lysine analogs in an earlier paper1 (Figure 3a).
L-proline and hydroxyproline
Trieu et al. Reported that lipoprotein(a) also
binds to L-proline and hydroxyproline with an even higher affinity
than to lysine.13 Since collagen and elastin are particularly
rich in proline residues this mechanism is of importance for the
binding and retention of the lipoprotein(a) particle in the vascular
wall. On the basis of these observations I propose here the therapeutic
use of L-proline in the prevention and treatment of CVD. The dietary
supplementation of this amino acid should prevent the binding
of lipoprotein(a) to collagen and other proline-rich constituents
of the vascular wall and thereby prevent the accumulation of lipoprotein(a)
in the vascular wall (Figure 3b).
Therapeutic Aim #4:
Reversal of Existing Atherosclerotic
Lesions
by Releasing Lipoprotein(a) from the Vascular Wall
The improved understanding about human atherosclerosis and in
particular about the role of lipoprotein(a) discussed in this
paper opens the way to a break-through in the treatment of CVD:
the pharmaceutical reversal of existing atherosclerotic lesions.
The key to this breakthrough is the reversibility of the accumulation
of lipoprotein(a) in the vascular wall. Through the same mechanism
by which L-lysine and L-proline can prevent lipoprotein(a) deposition,
optimum concentrations of these amino acids can release accumulated
lipoprotein(a) from the vascular wall. The release of lipoprotein(a)
from the atherosclerotic lesions must lead to a reduction of these
atherosclerotic deposits and thereby to a reversal of existing
CVD.
Dietary supplementation of optimum amounts of L-lysine
and L-proline could contribute to releasing lipoprotein(a) deposited
in the vascular wall. The experimental evidence for these novel
therapeutic options is already available. Comprehensive clinical
confirmation should soon lead to the reduction of existing atherosclerotic
deposits in CVD patients on the basis of selected nutritional
supplements.
Therapeutic Aim #5:
Reducing the Risk for CVD
from Other Lipids and Lipoproteins
LDL
While the CVD risk for elevated LDL levels alone has to be re-evaluated,
elevated LDL levels in addition to elevated lipoprotein(a) levels
are known to increase the risk for CVD exponentially.5 This fact
can be explained by the following mechanism. LDL can bind to lipoprotein(a)
via proline residues (Figure 3c). This binding of LDL to lipoprotein(a)
already deposited in the vascular wall can accelerate the development
of atherosclerotic lesions.
Figure 3a.
Figure 3b.
In the light of this mechanism, lowering elevated
plasma levels of LDL remains a therapeutic aim. In numerous studies
niacin as well as ascorbate have been shown to reduce elevated
plasma levels of LDL. As with lipoprotein(a) NADPH may play a
regulatory role on the synthesis rate of VLDL the precursor of
LDL. Moreover, dietary supplementation of L-proline could prevent
the binding of LDL to lipoprotein(a) already deposited in the
vascular wall and, by the same mechanism, release already deposited
LDL from the atherosclerotic lesions.
VLDL
VLDL is a potentially atherogenic precursor of LDL particularly
enriched in triglycerides. Niacin and ascorbate have also been
shown to be of particular value in lowering VLDL plasma levels.
Moreover, optimum L-proline concentrations should also interfere
with the binding of VLDL inside the vascular wall.
Thus dietary supplementation of ascorbate and niacin
are of particular value to decrease the plasma levels of atherogenic
lipoproteins. Optimum dietary supplementation with the amino acids
L-lysine and L-proline could release not only lipoprotein(a) but
also other atherogenic lipoproteins from the vascular wall.
VLDL and other triglyceride-rich lipoproteins,
however, can contribute to atherogenesis also by another mechanism.
Their enrichment in fatty acids renders them particularly subjectible
to oxidative modification and thereby enhances their atherogenicity.
Figure 3c.
Therapeutic Aim #6:
Prevention of Damage from
Oxygen Free Radicals
Oxygen free radicals are promoters of atherogenesis. They lead
to structural impairment and to oxidative modification of lipoproteins
as well as other metabolic constituents.²³ Antioxidant
nutrients such as ascorbate, tocopherol (vitamin E) and beta carotene
(provitamin A) can protect against oxidative damage and against
oxidative modification of lipoproteins. Elevated plasma concentrations
of these nutrients have been shown to be associated with a decreased
risk of CVD. 23,24 Nutritional supplements with antioxidative
properties, including coenzyme Q 10 and selenium, contribute to
maintaining optimum cardiovascular health.
Therapeutic Aim #7:
Optimum Cellular Function
Optimum function of endothelial cells, myocardial cells, smooth
muscle cells, macrophages and other cell system critically determine
optimum cardiovascular health. Optimum metabolic function of these
cells depends on the availability of essential cofactors for a
multitude of biochemical reactions. Of particular importance are
pantothenate, a cofactor for acetyl coenzyme A, carnitine for
fatty acid transport, the B vitamins for metabolic energy transfer,
ascorbate for enzymatic hydroxylations, and coenzyme Q10 in the
respiration chain. Optimum availability of these and other essential
nutrients, including certain minerals, not only helps protect
the vascular system but also improves cardiac function.24 The
reduction of the risk for CVD is, of course, also dependent on
other factors, such as exercise, cessation of smoking, and a prudent
diet.
Conclusion
Effective reduction of the risk for CVD is a primary goal of the
health care system in any industrialized country. In this paper
I have presented new therapeutic approaches for this disease.
Several of my earlier discoveries turned out to be of particular
importance for these recommendations: The prominent role of lipoprotein(a)
in human atherosclerotic lesions urged for new therapeutic approaches;
the isolation of lipoprotein(a) particles from the vascular wall
implied the reversibility of human atherosclerosis; the isolation
techniques of lipoprotein(a) via lysine suggested the therapeutic
use of this amino acid to induce this reversal. The report of
the binding of lipoprotein(a) to proline¹³ suggested
the therapeutic use of this amino acid in an analogous way. Most
importantly my earlier discovery that lipoprotein(a) is primarily
found in species which had lost the ability to synthesize ascorbate
triggered a series of publications which may significantly improve
our understanding of human CVD.¹’²’²º’²6
Ascorbate and several other nutritional supplements
are of particular value including niacin, L-proline and L-lysine
as well as natural antioxidants. The therapeutic use of these
nutrients may pave the was towards a new therapeutic goal: the
pharmaceutical, noninvasive reversal of existing CVD with nutritional
supplements.
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