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3.
Fibrinogen
Fibrinogen is a key indicator in heart disease risk. In one study of 116
men, it was found that people who have high LDL (bad) cholesterol but low
fibrinogen levels had only 1/6th the heart attack risk of men with high LDL
level and high fibrinogen levels. High fibrinogen levels promote the spontaneous
formation of fibrin clots and increase the risk of heart disease. Reducing
the level of fibrinogen is therefore an important part of a heart disease
prevention program.
A clot is also known as a thrombus. It is formed when platelets and red
blood cells come together. It is formed at the sight of the clot from soluble
circulating protein called fibrinogen. This protein binds the clots together
and is naturally formed in the blood after injury or trauma. The injury
could be severe like when a blood vessel breaks. The injury could also be
very minor from shear forces and stress of the blood flowing in the blood
vessel to free radical attack on the endothelial wall caused by pollutants
and sugar. During the aging process, when the collagen structure of the
blood vessel wall is weakened, clots may also form. Fibrin also impairs blood flow and increases blood viscosity and pressure. Complete blockage
results in heart attack or strokes.
Laboratory testing of fibrinogen is simple
and easy. However, its use has not gained widespread acceptance
because there are no direct drug based treatments for elevated levels available.
The normal range is 180-340 mg/dl for males and 190-420 mg/dl for females.
Plasmin
While there are over 3000 enzymes in the body and there are more than 20
enzymes involved in the coagulation cascade that creates blood clots, there
is only one enzyme that Mother Nature has provided to the human body that
can dissolve the fibrin and break up blood clots. This enzyme is called
plasmin. Unfortunately, the body's production of this declines with age.
In addition to its decreased production with age, fibrinogen levels also
rises 25mg/dl per decade in healthy people. In other words, as we age, our
plasmin level reduces while our fibrinogen level rises. The resulting risk
of cardiac incidents goes up.
Plasmin is called a thrombolytic (clot-dissolving) enzyme and is made from
plasminogens through the action of the enzyme called Tissue Plasminogen
Activator (TPA). Acting on the same principal, a class of drug has been
developed that mimic this activity. For example, Urokinase is a drug that
belongs to a class of medication called Tissue Plasminogen Activities. It
is administered intravenously within a few hours after admission into a hospital after
an acute onset of thrombus formation. It
is also very expensive.
Are there natural compounds that have similar thrombolytic activities? Yes.
Let us take a closer look.
Natto
 In
1980, after studying physiological chemistry at the University of Chicago
Medical School, Japanese researcher Dr. Hiroyuki Humi discovered that a
traditional Japanese food called natto derived from fermented soy had
the ability to dissolve clots. Specifically, he was able to identify and
purify the specific enzyme in the fermented soy cheese that he called nattokinase.
Natto has been widely consumed in Japan as a condiment for over 1000
years.
Extensive studies have been conducted worldwide on this compound. In one
study, 12 volunteers (6 men and 6 women), were fed 200g (7oz.) of natto and
had their thrombinolytic activities measured. Researchers found that the
time needed to completely dissolve a clot was cut in half in those taking
natto as compared to those who did not take it. In 1995, researchers did
a study wherein the corona arteries of rats were injured to induce thrombus
formation. The arteries were then completely blocked and blood flow to the
brain was stopped. Three enzymes (elastase, plasmin, and nattokinase) were then
tested on different rats and the researchers found that nattokinase
was successful in restoring circulation by 62%, while plasmin was only
able to restore it by 16% and elastase produced no reopening. Since natto
is a natural compound, its potency has to be standardized in order to have
relevancy in the studies. In Dr. Sumi's original nattokinase research paper,
it was reported that natto has an average of 40 fibrinolytic units (FU).
In human research, 50-200 gram is the typical daily food dose used to supply
nattokinase. This is equivalent to 2,000-8,000FUs. The nattokinase currently
available in dietary supplementation supplies about 20,000 FU/g. This can
be compared with serrpeptase, an enzyme from the silk worm that has fribrinolytic
properties with an equivalent of 60,000 FU/g.
Natto is a fermented cheese-like food and it use as a folk remedy for
heart and cardio vascular disease has been well established. It is produced
using a fermentation process by adding a beneficial bacterium known as bacillus-natto
to boiled soybeans. The resulting nattokinase enzyme is then produced when
the bacillus natto acts on the soybean.
While soy foods do contain a variety of enzymes, it is only in the natto
preparation that contains the specific nattokinase enzyme. Unfermented
soy products such as tofu or soymilk do not contain nattokinase.
Nattokinase produces a prolonged action in two ways: it prevents the coagulation
of blood, and it dissolves existing thrombus. Both the efficacy and the prolonged
action of nattokinase can be determined by measuring the levels of EFA (euglobulin
fibrinolytic activity) and FDP(fibrin degradation product) which become
elevated as fibrin is dissolved. It has been shown that by measuring EFA
and FDP levels that nattokinase activity can last from 8-12 hours.
Nattokinase has been subjected to 17 studies including 2 small human trials.
Nattokinase has also been used to lower blood pressure in Japan. In 1995,
researchers from Miyazaki Medical College and Kurashiki University of Science
and Arts in Japan studied the effects of nattokinase on blood pressure in
both human and animal subjects. With a single administration of 400-450g
of nattokinase infused into the peritoneal, there was a 12.7% drop in systolic
blood pressure within 2 hours of administration. When the same natto extract
was tested on human volunteers, it was shown that when 30g of lyophilized
extract, equivalent to 200g of natto food, was given, 4 out of 5 volunteers
had their systolic blood pressure reduced by 10.9% and their diastolic blood
pressure also reduced by 7%.
To guard against thrombus formation and to dissolve existing clots,
take 25 mg to 100 mg of nattokinase in the
form of nutritional supplements if you do not like to consume natto bean.
Make sure the FU value is more than 20,000 Fu/g .
4.
Arterial Stiffness
One of the hallmarks of aging is the loss of collagen supporting structure
throughout the body. Collagen reduction is visible and presents itself in
the form of wrinkles on our face and skin surfaces during the aging process.
Our blood vessels are also structurally supported by collagen. As
this collagen structure deteriorates, stiffening of the arteries occurs.
Indeed, the fact that arteries stiffen with age, and that such
changes are associated with an increased incidence of major cardiovascular
events and increases in blood pressure, is now established beyond doubt.
Measuring the stiffness of arteries would logically provide a better insight
into blood vessel health, in addition to the traditional blood pressure
measurement. Scientists have machines, with a reproducible parameter termed
'stiffness index' by measuring the time delay between direct and reflected
waves in the digital volume pulse. There are several apparatuses commercially
available to physicians. Unfortunately, its use is not widespread because
there is no drug based treatment program to reduce the stiffness once discovered.
As collagen is lost and elasticity reduced,
stiffening of the arterial wall leads to an increase in systolic and diastolic
pressure. In particular, the systolic pressure will be disproportionately
higher, registering a reading of 140-160mmHg or higher. There is often
a wide systolic to diastolic gap often up to 60-70mmHg (normal is 40 mmHg), with a typical blood pressure reading of 160/100mmHg without medication,
and 140/90mmHg at best with medication.
Postural hypotension is also common. With reduced elasticity to normalize
blood pressure, it can drop quickly as a one goes from sitting to standing. Anyone over age 45 can practically assume that arterial stiffening
is already in a progressive state. Unless active steps are taken, the stiffening
will continue. Those who have elevated blood pressure should be especially
concerned as it may indicate arterial stiffening. Unfortunately, there are
no medications that can reduce the arterial stiffness at this time.
Nitric Oxide (NO)
In 1998, a trio of scientist’s was awarded the Nobel Prize for discovering
the enormous role that Nitric Oxide (NO) plays in our body. NO is the first
gas discovered to have signaling properties. It is produced by one cell
and is able to penetrate through the membrane and regulate the function
of another cell. The discovery of this pathway opens up an entirely new
principle of signaling and communications in the biological system.
Mention nitric oxide and most will think of the toxic gas produced and
given off by car engines. It is a poison that up until now is thought to
exist outside the body and does nothing more than cause trouble. NO was
not expected to be important in higher animals such as humans. This has been
proven wrong. In fact, NO is produced inside most if not all tissues by the
body and plays a very important role in the cardio vascular, immune, and
nervous systems.
* Nitrous oxide is known as the laughing gas, the anesthetic that is commonly used
by dentists. This should not to be confused with Nitric Oxide. *
NO and the Cardiovascular System
NO is produced by the inner most layer of the arteries called the endothelium.
Once produced, it rapidly spreads through the cell membrane to the underlying
muscle cells, causing them to relax from their default-constricted state.
This results in the dilation and widening of the artery lumen. Blood pressure
drops as a result. Because NO is short lived, a constant supply of it is
generated by the endothelial cells in response to the sheer stress of the
blood flow on the artery walls. In arthrosclerosis, the endothelium has
been damaged by free radical attacks as well as plaque formation and inflammatory
response. The capacity to produce NO is reduced, and the vascular musculature
constricts and blood pressure can be elevated.
It is now known that the normal cardio vascular contraction state is biased
in one direction towards vessel constriction. This is the
body’s way of maintaining the blood pressure at a slightly constricted state
in order to channel adequate blood supply and oxygen delivery to the brain
continuously. With the constant NO production by the endothelium, vessel
dilation is sustained, and blood pressure is maintained at a normal systolic
rate of around 120mmHg and a diastolic rate of around 80mmHg. Too
much NO can lead to excessive vasodilatation and a fall in the blood pressure,
while too little NO can lead to a rise in blood pressure.
The vasodilatation effect of NO applies to all blood vessels. It can initiate
erection of the penis by dilating the blood vessels to the erectile bodies.
This knowledge has already led to the development of new drugs to treat
impotency such as Viagra.
Any interruption the production of NO interferes with the tone of the arterial
muscles and the blood vessels will return to its constricted state. From
this point of view, a rise in blood pressure may be due to the constriction
caused by other factors such as the hormone epinephrine produced by the
adrenal glands.
In the case of heart disease the tension
is focused on NO deficiency. Healthy blood vessels are pliable
and elastic by nature. They can alter their diameter instantly in response
to a greater or lesser out flow of blood from the heart. This continuous
change happens during exercise as well as when we are excited. This spontaneous
regulation of blood pressure goes on uninterrupted 24 hours a day. As we
age, the elasticity of our blood vessels declines due to collagen loss,
free radical damage, and plaque accumulation. Poor diet, lack of
exercise, cigarette smoking, and genetic predisposition all contribute to
a breakdown of collagen fibers that support the blood vessels. This results
in the lack of elasticity. Blood vessels then become passive and stiff pipe-like
structures which raise blood pressure, forcing the heart to work harder.
In addition to helping the blood vessels relax, NO also helps to prevent
the clogging of arteries in several ways. First, it prevents the white blood
cells from sticking to the arterial wall. It also helps to prevent damage
to the arterial wall by reducing the production of free radicals. In other
words, it acts like an antioxidant. NO also helps to prevent the thickening
of the middle (muscular) wall of the artery that can narrow the opening
where the blood flows.
Other Functions of NO
NO gas, when inhaled by patients with pulmonary hypertension has been shown
to relieve lung congestion. In a treatment for newborn babies, breathing
problems can be helped by inhaling NO that relaxes constricted blood vessels
and dilates the lung’s blood vessels. NO is also produced in the brain in
neuronal form that acts as a chemical messenger at the synapses. This has
opened up a new approach to the studies of Alzheimer’s disease, Parkinson’s
disease, and other neurological disorders. NO also inhibits the loss of
bone, and the release of growth hormones may augment bone density.
Exercise and NO
Exercise alone has also been shown
to increase the production of NO in the body. This may
explain why exercises can reduce blood pressure.
The effect of adding the amino acid arginine and vitamins C and E to an exercise
program have been shown to synergistically increase NO production. In a
study conducted at UCLA, researcher Louis Ignarro studied 6 groups of 8-week-old
receptor deficient male mice with high cholesterol over an 18 week period. The mice
were randomly divided into 3 dietary groups called: fat with high cholesterol
diet alone, fat with high cholesterol diet with antioxidant vitamin E and
C, and a fat with high cholesterol with the antioxidants arginine. It was
shown that the mice from all 3 groups were able to lose weight and had lower
cholesterol when they exercised. The atherosclerotic legions were significantly
reduced in the mice group that had arginine.
The explanation is that exercise will increase both the amount of endothelial
nitric oxide synthetase (NOS) and the enzymes that will then convert the arginine
into NO, which in turn lowers abnormally elevated blood pressure, prevent
unwanted blood clots and early inflammation associated with coronary artery
disease. Nitric oxide production is stabilized when vitamins C and E are
added as these remove destructive oxidants from the blood stream.
Even without exercise, these supplements will work on their own to increase
NO. Studies have shown that mice that were sedentary and fed supplements
alone showed a 40% reduction in atherosclerotic legions compared to mice
that were on a regular, high cholesterol diet but did not exercise or take
supplements.
Exercise alone without supplementation also showed a 35% reduction in legions.
Therefore, it can be concluded that amino acid supplementation has an atherosclerotic
reduction effect similar to exercise. Doing both exercise and supplementing
with antioxidants concurrently will produce the best results.
Formation of NO
NO is formed in various places in the body. In the endothelium, NO is formed
by the enzymatic action of nitric oxide synthetase (NOS) on the amino acid
arginine and citrulline. This process is enhanced when antioxidants are
present, especially vitamin C. NO also forms in nerve cells, where it spreads
rapidly in all directions and affects all cells in the vicinity. NO is also
produced in white blood cells such as macrophages and NO is toxic to
invading bacteria and parasites.
There are 3 forms of NOS enzymes. There is one in the endothelium, one in the
immune system, and one in the brain. Genes responsible for encoding the
NOS are located in chromosomes 12, 7, and 17 respectively. The discovery
of NOS opens up another new class of drugs based on n-monomethyl-arginine
(l-nmma), an inhibitor of the NOS enzyme. Drugs are being used to explore
the possibility of blocking NO production in order to raise blood pressure.
Experiments have been performed where volunteers were injected with l-nmma.
Blood flow was then compared from one arm to the other arm. As l-nmma was
infused, blood flow is observed to gradually decrease to half compared
to that in the control arm. This has important ramifications, and drugs
are being developed to raise blood pressure. Clinical application of this
pathway is particularly useful for those who have acute low blood pressure
as frequently experienced when in shock or trauma.
L-Arginine and NO
L-arginine is an essential amino acid
that is present in many foods and it is also a precursor of NO production.
Studies have shown that arginine, when
taken in proper amounts, can stimulate NO production. In a 1999
study, 30 impotent men were given 1500 mg of arginine each per day. It was
shown that it worked no better than the placebo in terms of vasodilatation
and sexual performance. However, when 21 men with mild to moderate impotence
were given 3,000mg of arginine a day, significant improvement in erections
as well as sexual satisfaction were reported. This study was published in
the December 1998 issue of Hawaii Medical Journal. It is obvious that the
use of arginine as a nitric oxide precursor is dose dependant, and a low
dose regiment will not be effective.
L-arginine supplementation has also been shown to significantly reduce systolic
and diastolic blood pressure. Reductions were evident in subjects when they
were rested as well as when they were not stressed. The reduction in blood
pressure was associated with increased cardiac output. These findings were
reported in the in the American Heart Association meeting in November 2003
where 16 hypercholestrolemic men with normal blood pressure were given 12
grams of oral arginine a day over a period of 3 weeks.
L-arginine has long been used in the enhancement of sports performance and
cardiac function. A double blind placebo controlled study of 22 subjects with
stable angina and supplementation with l-arginine at 1 gram twice a day
has been shown to significantly improve their exercise capacity. Arginine
supplementation has also been reported to result in a 70% reduction in angina
attacks in another study.
L-arginine works by stimulating the production and release of NO. However,
L-arginine may have separate anti-atherogenic independent in of its role
in the enzymatic formation of NO. For example, l-arginine itself may have
antioxidant activity. It has been shown to inhibit the oxidation of unoxidized
low density lipoprotein (LDL) to oxidized LDL (ox-LDL). The oxidation of
LDL to ox-LDL is believed to be a critical early step in the formation
of arthrosclerosis.
L-arginine may also independently have a scavenger effect in sweeping up
super oxide anions and hydrogen peroxide as well as reducing the peroxidation
of lipid. Furthermore, it has been shown to have immunomodulatory activities.
Supplementation of this amino acid in breast cancer has been shown to increase
the quantity and cytotoxicity of natural killers (NK) and Lymphokine-activated-killer
(LAK) cells. The exact mechanism is not clear but it has been shown
that l-arginine is a precursor in the synthesis of tetrapeptide
tuftsiin, which itself appears to have immunomodulartory activities.
Arginine is an excellent helper when it comes to wound repair. This may
be due to its precursor role in the formation of l-ornthine, and ultimately
l-proline. L-proline in conjunction with l-lysine and vitamin C are the
key elements in collagen biosynthesis. Collagen is the main ingredient in
tissue healing and scar tissue formation. Arginine participates in the maintenance
of muscle and lean tissue in the body.
Arginine, in high dose, promotes an increase in the body’s production of
insulin like growth factor (a measure of human growth hormone). Its use,
together with lysine, ornithine and glutamine, is one way to stimulate the
body’s release of growth hormones.
Interestingly, l-arginine has also been shown to increase sperm counts.
In one early study, 178 men with oligospermia, of which 93 were diagnosed with severe oligospermia, were all given 4g of l-arginine
daily. A 100%
increase in sperm count was found in 42 cases resulting in 15 pregnancies.
Studies have also shown that l-arginine is beneficial for people with kidney
diseases as well as interstitial cystitis. It also improves kidney function in
diabetic animal models and it helps promote renal vasodilatation.
In summary, arginine is a very versatile amino acid. Many of its functions are just starting to be explored. NO produced
in the body from the intake of arginine can play a major role in anti-atherogenic
activity. NO inhibits mononuclear cell adhesion, platelet aggregation,
proliferation of vascular smooth muscle, and production of some reactive
oxygen species, such as super oxide anions. It is a promoter of endothelium
dependant dilation and is able to normalize high blood pressure. In other
words, it relaxes the blood vessel and reduces the arterial stiffness. It
also increases sperm count, boosts immune function, enhances male sexual disorders,
restores protein balance, and speeds the healing of wounds.
Arginine Dosage
Arginine is a non-toxic compound. Dosage
of up to 15 grams a day has been well tolerated. The most common
adverse reaction to high doses (15-30 grams a day) are nausea, abdominal
cramps, and diarrhea. Scaling back the dosage will eliminate the problem.
Because high dose and long term use of arginine can lead to an increase
in growth hormones, therefore, pregnant and nursing mothers should refrain from high
doses of arginine supplementation. The use of arginine in the cardio vascular
and erectile dysfunction settings has been very promising. While no supplementation
can work 100% of the time, most people do experience some improvement when
dosed properly. For cardio vascular health
doses, 2-15 grams a day should be used in divided doses. To help
sperm count, doses of 10-20 grams a day have been used. For erectile dysfunction,
daily doses of 5 grams a day have been used. For interstitial cystitis,
1 to 4 grams a day is commonly used.
To avoid arginine’s risk of promoting
free radical oxidation, supplementation should always be accompanied by
antioxidants including vitamin C, ascobyl palmitate, lysine, proline, a small
amount of co-enzyme Q10, lipoic acid, and other antioxidants. This
is especially important for those with inflammatory problems such as arthritis
as excess NO can stimulate an inflammatory response. If the immune enhancing
properties of arginine are desired, always add proline and lysine. Because
some infectious pathogens may actually use arginine as a fuel, lysine should
be added to help neutralize any virus attacks. Children under 18 should not
take arginine for any extended period of time.
Anyone concerned with cardiovascular health, and especially with normalization
of blood pressure, should consider nutritional supplementation of arginine
in conjunction with other synergistic and pre-cautionary co-factors mentioned
above. Arginine dosage ranges from 2-5 grams a day. Those who have a
history of low blood pressure should be careful as NO may further lower
the pressure.
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