Reducing the Risk for Cardiovascular Disease with Nutritional Supplements
Matthias Rath M.D.
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
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.
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
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
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
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
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
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
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
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.
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.
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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