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Cellular
Medicine in Heart Disease
Why Cholesterol Is Not the Cause of Heart Disease
As a result of Dr. Rath’s discovery of the vitamin
C-scurvy-heart disease connection, we now understand the
role of cholesterol in heart disease. High blood cholesterol can
lead to cardiovascular deposits only when combined with the loss
of the integrity and functional weakness of the blood vessel wall,
which triggers the need for its biological repair. This is why
some animals, such as bears, do not massively die of heart attacks
despite the fact that every 100 ml of their blood contains about
600 mg/dl of cholesterol. They produce vitamin C in their bodies,
which ensures optimum collagen production and the stability of
their arteries, so they do not worry about cholesterol. Dr. Rath’s
groundbreaking discovery is detailed in his book Why Animals
Don’t Get Heart Attacks, But People Do!
Cardiovascular Research at the Dr. Rath Research Institute
Our research in the area of cardiovascular disease focuses on
health-beneficial effects of vitamins and essential nutrients
in various aspects of cardiovascular disease, its initiation,
and stepwise progression.
Among various projects, we have been investigating the role of
nutrients in controlling abnormal migration and the growth of
smooth muscle cells in the arterial wall, a hallmark of atheroma
development and growth. We are also studying how nutrient synergy
can be applied to curb inflammation leading to arterial wall cell
damage and blood leukocyte recruitment. We have shown that nutrient
synergy is more effective than individual antioxidants in decreasing
oxidative stress associated with endothelial and smooth muscle
cell damage, lipid and lipoprotein oxidation and their intra-arterial
wall accumulation.
A significant part of our efforts has been concentrated on applying
nutrient synergy in controlling pathological aspects of the remodeling
of the extracellular matrix in the arterial wall. Such pathology
leads to lost integrity and weakening of arterial wall structure,
impaired arterial contractility, lipoprotein retention and oxidation,
pathological behavior of arterial wall resident cells, increased
plaque instability and the risk of its rupture.
Our other research areas include the aspects of sex hormone imbalance
in the development of cardiovascular disease, as well as the cardiovascular
aspects of impaired glucose metabolism (diabetes mellitus). Our
research findings have contributed to a better understanding of
nutrient synergy in controlling uterine smooth muscle tissue contractility
(important in preventing miscarriage) and in autoimmune mechanism-mediated
impairment of bronchial smooth muscle tissue contractility (asthma).
Please select a title
below to read the respective research study.
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| Arrhythmia |
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Reduction
In The Frequency Of Arrhythmic Epidsodes In Patients With
Paroxysmal Atrial Arrhythmia With A Vitamin/Essential Nutrient
Program - NEW -
A. Niedzwiecki, T. Kalinovsky, M. Rath
JANA 2005, 8(3), 21-25. |
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Chronic
deficiency of vitamins and other essential nutrients impairs
cellular bio-energy production and can lead to disturbances
in the generation and conduction of electrical impulses in
the myocardium. We investigated the effect of long-term supplementation
with a combination of vitamins and other essential nutrients
on the number of clinically apparent episodes in patients
with paroxysmal atrial arrhythmia. A randomized, double-blind,
placebo-controlled multi-center study in Germany was undertaken
on 131 patients (ITT), aged 18 to 70 years, who were diagnosed
with paroxysmal atrial arrhythmia, receiving anti-arrhythmic
medication for at least three months, and reporting at least
one paroxysmal cardiac episode per month. Study participants
were advised to continue their prescribed medication and were
treated with either an essential nutrient formulation or placebo
during the 24-week study. Analysis of data demonstrated a
significant decrease in the frequency of clinically apparent
arrhythmic episodes with vitamin/essential nutrient supplementation
(ITT analysis: p=0.0221; PP analysis: p=0.0160) that improved
with time (45.5% of the supplemented group experienced frequent
arrhythmic episodes at three months, in contrast to only 27.3%
at six months). By addressing the underlying cause of arrhythmia,
a deficiency in nutrients that generate bio-energy in the
heart muscle cells, a vitamin/essential nutrient supplementation
program provides a safe and effective reduction of arrhythmic
episodes. |
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| Atherosclerosis |
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Nutrient
Synergy - A Mixture of Ascorbic Acid, Lysine, Proline, Arginine,
Cysteine and Green Tea Extract Suppresses Autocrine Inflammatory
Response in Cultured Human Aortic Smooth Muscle Cells (2003)
V. Ivanov, S. Ivanova, M.W. Roomi, S.P.
Netke, A. Niedzwiecki, M. Rath
Presented at: 3rd World Congress on Heart
Disease
Washington, DC, July 12-15, 2003 |
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It
is recognized that inflammatory processes are involved in
the initiation, development and pathological consequences
of atherosclerotic lesions. This study demonstrated that Nutrient
Synergy, a mixture of ascorbic acid, tea phenolics, and selected
amino acids, has a strong inhibitory potential against vascular
cell inflammatory responses to pathogenic stimuli in human
aortic smooth muscle cell culture. These results suggest that
such a nutrient mixture has therapeutic potential in suppressing
atherogenic inflammatory responses. |
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A
Nutrient Mixture Containing Ascorbic Acid, Lysine, Proline,
Arginine, Cysteine, and Green Tea Extract Suppresses Autocrine
Inflammatory Response in Cultured Human Aortic Smooth Muscle
Cells
V. Ivanov, S. Ivanova, M.W. Roomi, T.
Kalinovsky, A. Niedzwiecki, M. Rath
Research Communications in Pharmacology
Toxicology, 2004,9:3-16. |
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Recognition
of the involvement of inflammatory processes in atherosclerotic
lesion initiation and development of pathological consequences
initiated a search for an effective inhibitor. Naturally occurring
compounds demonstrate a wider spectrum of biological activity
and fewer side effects than synthetic drugs. Mixtures of natural
compounds often produce synergistically enhanced therapeutic
action. This prompted us to investigate whether a unique nutrient
mixture (NS), containing ascorbic acid, lysine, proline, arginine,
N-acetyl cysteine and tea phenolics, could reduce an autocrine
response of human aortic smooth muscle cell (SMC) to inflammatory
stimuli. Cultured SMC were challenged with tumor necrosis
factor-alpha (TNFa) or lipopolysaccharide (LPS) in the presence
or absence of NS. Expression of leading mediators of inflammatory
reaction was assayed with ELISA (R&D Systems). 2.5-fold
induction of interleukin-1alpha (IL-1a) content in cellular
media was completely reversed in the presence of 20 µg/ml
NS (containing 20 µM ascorbic acid). Secretion of pro-interleukin–1
beta (pro-IL-1ß) and of its activator, caspase-1, was
inhibited by 46% and 67%, respectively. This resulted in significant
reduction of IL-1ß formation. Secretion of interleukin-6
(IL-6) and interleukin-8 (IL-8) was also dramatically reduced.
Moreover, addition of NS significantly inhibited expression
of cell adhesion molecules: sP-selectin and monocyte chemoattractant
protein-1 (42% and 65% inhibition, respectively). Anti-inflammatory
effects of NS exceeded the sum of actions of its individual
components. From these data we conclude that the mixture of
ascorbic acid, tea phenolics, and selected amino acids tested
has a strong potential against involvement of vascular cells
into inflammatory response to pathogens. |
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Anti-Atherogenic
Effects of a Mixture of Ascorbic Acid, Lysine, Proline, Arginine,
Cysteine and Green Tea Phenolics in Human Aortic Smooth Muscle
Cells (2003)
V. Ivanov, S. Ivanova, M.W. Roomi, S.P.
Netke, A. Niedzwiecki, M. Rath
Presented at:
12th International Congress on Cardiovascular Pharmacotherapy
Barcelona, Spain, May 7-10, 2003
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In
this study, the synergistic anti-atherogenic effects of nutrients
such as ascorbic acid, lysine, proline, arginine, cysteine,
and epigallocatechin gallate (from green tea extract) were
investigated in cultured human aortic smooth muscle cell (SMC)
by measuring SMC growth rate, invasiveness, matrix metalloproteinase-2
(MMP-2) expression, and secretion of monocyte chemoattractant
protein-1 (MCP-1) and interleukin-6 (IL-6). By inhibiting
the atherogenic response of vascular smooth muscle cells to
pathological stimuli, Nutrient Synergy blocks the development
of atherosclerotic lesions. |
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Plasmin-Induced
Proteolysis and the Role of Apoprotein(a), Lysine, and Synthetic
Lysine Analogs (1992)
M. Rath, L. Pauling
Journal of Orthomolecular Medicine, 7:17-23.
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Proteolytic degradation of extracellular matrix (ECM) by the
protease plasmin is a universal mechanism, determining human
health and disease. Under physiological conditions, this leads
to cell migration and organ remodeling; under pathological
conditions, to sustained degradation of the ECM, as associated
with cancer and viral spread, as well as cardiovascular disease.
In this paper, apoprotein(a), lysine and synthetic lysine
analogs are discussed as inhibitors of plasmin-induced proteolysis
and proposed as natural therapeutic options. |
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Reducing
the Risk for Cardiovascular Disease With Nutritional Supplements
(1992)
M. Rath
Journal of Orthomolecular Medicine, 7:153-162.
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This
paper discusses the pathomechanisms for development of CVD
and proposes the therapeutic use of ascorbate, niacin, L-proline,
L-lysine and natural antioxidants for cardiovascular disease,
based on their anti-atherosclerotic therapeutic actions such
as releasing lipoprotein-a from the vascular wall. |
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Solution
to the Puzzle of Human Cardiovascular Disease: Its Primary
Cause Is Ascorbate Deficiency, Leading to the Deposition of
Lipoprotein(a) and Fibrinogen/Fibrin in the Vascular Wall
(1991)
M. Rath, L. Pauling
Journal of Orthomolecular Medicine, 6:125-134.
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This
article proposes that human cardiovascular disease is primarily
a degenerative disease, resulting from the accumulation of
lipoprotein(a), which is increased by low ascorbate concentrations.
Ascorbate deficiency results from the inability of humans
to synthesize endogenous ascorbate combined with an insufficient
dietary ascorbate intake. Chronic ascorbate deficiency leads
to extracellular accumulation of lipoprotein(a) and fibrinogen/fibrin,
the hallmarks of the atherosclerotic lesion. |
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Apoprotein(a)
Is an Adhesive Protein (1991)
M. Rath
Journal of Orthomolecular Medicine, 6:139-143. |
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Apoprotein(a)
plays important physiological roles as an adhesive protein
in organizing the interaction between cellular systems and
the extracellular matrix in tissue formation, remodeling,
and repair. The importance of these roles is enhanced under
pathological conditions, such as ascorbate deficiency, as
it mediates the cellular-extracellular interaction during
chronic repair processes. |
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Anti-Atherosclerotic
Effect of Probucol in WHHL Rabbits: Are There Plasma Parameters
to Evaluate This Effect? (1991)
B. Finckh, A. Niendorf, M. Rath, U. Biesiegel
Arteriosclerosis, 9: 579-592.
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To
study the antioxidative activity of probucol (a lipid-lowering
agent) and its influence on plaque development, the animal
model of the LDL-receptor-defective Watanabe heritable hyperlipidemic
(WHHL) rabbit was used. In addition to assessment of biochemical
levels (lipid, probucol, alpha and beta tocopherol, and thiobarbituric
reactive substances), the plaque areas were macroscopically
and microscopically evaluated. Probucol decreased the progression
of atherosclerotic plaques by way of a combined lipid-lowering
and antioxidative effect. |
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Lipoprotein
(a) Is a Surrogate for Ascorbate (1990)
M. Rath
Proceedings of the National Academy of Sciences,
87: 6204-6207.
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The
concept that lipoprotein(a) is a surrogate for ascorbate is
suggested by the fact that this lipoprotein is found generally
in the blood of primates and the guinea pig, which have lost
the ability to synthesize ascorbate, but only rarely in other
animals. Properties shared with ascorbate, in accordance with
this hypothesis, are the acceleration of wound healing and
of cell repair mechanisms, strengthening of extracellular
matrix (as in blood vessels), and prevention of lipid peroxidation.
Evidence supporting this hypothesis is discussed. |
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Immunological
Evidence for the Accumulation of Lipoprotein(a) in the Atherosclerotic
Lesion of the Hypoascorbemic Guinea Pig (1990)
M. Rath
Proceedings of the National Academy of Sciences,
87: 9388-9390.
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Atherosclerosis
was induced in three guinea pigs by dietary ascorbate depletion.
Using SDS/PAGE and subsequent immunoblotting, Lp(a) was identified
as accumulating in the atherosclerotic plaque. Furthermore,
adequate amounts of ascorbate (40 mg/kg body weight/day) prevented
development of atherosclerotic plaques and accumulation of
Lp(a). Guinea pigs were chosen for this study as, similar
to humans, they lack endogenous ascorbate production. |
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| Heart Disease
- General |
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The
progression of atherosclerotic lesions in patients with cardiovascular
disease can be controlled naturally, but not with statins
V. Ivanov, MD PhD, A.Niedzwiecki PhD,
M. Rath MD
Research Institute BV, Santa Clara, CA. |
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Despite
questionable evidence that high cholesterol in the bloodstream
causes heart disease, manufacturers of cholesterol-lowering
drugs have poured huge funds into scientific and clinical
research. This has been coupled with the manipulation of
public opinion by lobbying and aggressive marketing of this
“cholesterol dogma.” The introduction of a new
class of drugs called statins in the early 1990s accelerated
these marketing efforts. These drugs inhibit the activity
of HMG-coenzyme A reductase, a key enzyme in the cellular
biosynthesis of cholesterol molecules. The introduction
of these drugs has raised many concerns by physicians and
researchers regarding potential side effects of this new
class of medication. It is a scientific fact that inhibition
of HMGCoA reductase has other metabolic consequences, including
the depletion of coenzyme Q10, a critical nutrient for cellular
energy production, resulting in muscle and liver damage.
It can also impair the synthesis of hormones and vitamin
D. Moreover, various research data indicated earlier that
statins could cause cancer. Despite these warnings, new
prescription guidelines for cholesterol drugs introduced
in 2001 immediately made millions of people “cholesterol
–sick” and requiring prescriptions.
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A
Nutrient Approach to Inhibition of Cardiovascular Disease
V. Ivanov, S. Ivanova, M.W. Roomi, A.
Niedzwiecki, M. Rath
Oral Presentation at: American Chemical
Society National Meeting, San Diego, CA, March 13-17, 2005
Published in: Book of Abstracts,
229th ACS National Meeting, Abstract # 60
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Every
year over 12 million people worldwide die of the results of
atherosclerosis, heart infarctions, and strokes. Conventional
treatment focuses on symptoms, but does not address the cellular
cause of cardiovascular disease – chronic deficiency
of essential nutrients. The nutrient mixture of ascorbic acid,
lysine, proline and green tea extract inhibited the key steps
in atherosclerotic plaque progression:
• Inflammation
- Inhibits secretion of inflammatory mediators and Inhibits
attraction of monocytes
• Oxidation - Protects LDL
from free radicals
• SMC growth and invasion - Direct
and ECM-mediated inhibitory effects
• ECM production
- Promotes anti-atherogenic changes in ECM composition and
quantity |
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A
New Era in Medicine (1993)
M. Rath
Journal of Orthomolecular Medicine, 8:134-135.
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This
article proposes that, in contrast to the past, the 21st century
will see the eradication of major diseases, such as CVD, and
the establishment of nutritional medicine as an essential
part of the healthcare system. Skepticism and bias against
nutritional supplements will be replaced by acceptance of
vitamins and essential nutrients as safe and affordable preventative
and therapeutic agents, based on an objective scientific attitude
towards nutrient medical research. |
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Unified
Theory of Human Cardiovascular Disease Leading the Way to
the Abolition of This Disease as a Cause for Human Mortality
(1992)
M. Rath, L. Pauling
Journal of Orthomolecular Medicine, 7: 5-15.
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In
contrast to current therapeutic approaches, which target individual
pathomechanisms or specific risk factors for CVD, this paper
proposes a unified pathogenetic and therapeutic approach based
on genetic, metabolic, evolutionary and clinical evidence
- ascorbate deficiency. Chronic ascorbate deficiency leads
to loosening of the connective tissue in the vascular wall
and compensatory deposition of Lp(a) (lipoprotein(a)) and
fibrinogen/fibrin. |
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Solution
to the Puzzle of Human Evolution (1992)
M. Rath
Journal of Orthomolecular Medicine, 7:73-80.
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This
article discusses the rationale for the proposal that the
underlying genetic precondition for the evolution of man was
the loss of endogenous ascorbate production about 40 million
years ago. This genetic mutation became the basis of the dramatic
acceleration of human evolution and a quadruplication of the
brain size in the recent 2.5 million years. Scurvy, the greatest
threat to evolutionary survival of ascorbate-deficient man
during the Ice Age, led to survival genetic features: Lp(a)
for stabilizing the vascular wall and apo(a) to increased
brain size, intelligence and fertility. |
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| HRT and Heart
Disease |
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Enhancement
of Cardio-Protective Effects and Attenuation of Adverse Effects
of Female Sex Hormones on Cultured Human Vascular Smooth Muscle
Cells by a Combination of Ascorbic Acid, Lysine, Proline,
Arginine, Cysteine and Epigallocatechin Gallate (2003)
V. Ivanov, S. Ivanova, M.W. Roomi, S.P.
Netke, A. Niedzwiecki, M. Rath
Presented at: European Congress of Endocrinology
Lyon, France, April 26-30, 2003 |
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Large
numbers of menopausal women are using hormone replacement
therapy (HRT) for counteracting such adverse effects as hot
flashes and loss of bone mass. However, HRT has been recently
shown to have major adverse effects on cardiovascular health.
When tested in an experimental system of cultured human vascular
smooth muscle cells, female sex hormones produced diverse
effects on atherogenic changes in smooth muscle cells properties
such as pathologically increased growth rate and invasiveness
and excessive production of extracellular matrix components
and inflammatory SW. Nutrient Synergy enhanced the cardio-protective
action of female sex hormones and counteracted their adverse
effects in these experimental conditions, suggesting that
it has great potential as an adjunctive therapeutic agent
in inhibiting adverse effects and enhancing the cardio-protective
effects of female sex hormones in HRT. |
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Enhancement
of Cardio-Protective Effects and Attenuation of Adverse
Effects of Female Sex Hormones on Cultured Human Vascular
Smooth Muscle Cells by a Combination of Ascorbic Acid, Lysine,
Proline, Arginine, Cysteine, and Epigallocatechin Gallate
V. Ivanov, S. Ivanova, M.W. Roomi, T.
Kalinovsky, A. Niedzwiecki, M. Rath
JANA January 2005, 7 (3), 17-22. |
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In
this in vitro study, the effects of adjunctive use of a formulation
(NS) containing ascorbic acid, lysine, proline, arginine,
N-acetyl cysteine, and epigallocatechin gallate with female
sex hormones were tested on human aortic smooth muscle cells
(SMC). Estradiol and progesterone stimulated DNA synthesis
in SMC 30% and 24% respectively at 25–150 nmol/L concentrations.
NS (20 _g/ml) inhibited SMC growth by 30% over the control,
and reversed the stimulatory effect of the sex hormones to
a maximum of 25% inhibition. Dehydroepiandrosterone sulfate
(DHEAS) inhibited SMC growth by 50% at 0.1 mmol/L. Addition
of NS enhanced the DHEAS inhibitory effect to 70% as compared
to the control. DHEAS and progesterone significantly increased
SMC capacity to invade Matrigel by 20% and 60%, respectively.
Addition of NS reversed the stimulatory effects, producing
up to 60% inhibition of SMC invasion. Addition of NS reversed
the effects of DHEAS on total collagen synthesis in SMC from
28% stimulation to 56% inhibition. Estradiol, progesterone,
and DHEAS demonstrated some inhibition of tumor necrosis factor-alpha-stimulated
SMC secretion of interleukin (IL) 1-beta, IL-6, and monocyte
chemo attractant protein-1 in cultured media; NS enhanced
inhibition of these cytokines under most conditions. The results
of this study imply that the specific formula of nutrients
tested enhances the cardioprotective effects of female sex
hormones and counteracts their adverse effects on atherogenic
properties. |
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| Hypertension |
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Bioflavonoids Effectively Inhibit Smooth Muscle Cell-Mediated
Contraction of Collagen Matrix Induced by Angiotensin II
- NEW -
V. Ivanov, M.W. Roomi, T. Kalinovsky,
A. Niedzwiecki, M. Rath
Matthias Rath Research Institute, 1260 Memorex Drive, Santa
Clara, CA 95050
Published in: The Journal of Cardiovascular
Pharmacology,- 2005, 46(5):570-6
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Bioflavonoids participate in the
regulation of SMC-mediated contraction and have a strong potential in counteracting pathophysiological
effects of ATII. Bioflavonoid activity depends on structural characteristics and can be related to
extracellular matrix integrity. |
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Mixture
Of Natural Nutrients Reduces Collagen Matrix Contraction Driven
By Aortic Smooth Muscle Cells
- NEW -
V. Ivanov, S. Ivanova,
M.W. Roomi, A. Niedzwiecki, M. Rath
Matthias Rath Research Institute, 1260 Memorex Drive, Santa
Clara, CA 95050
Presented at: International Academy of Cardiology,
12th World Heart Congress, New Trends in Research, Diagnosis,
and Treatment Vancouver, B.C., Canada, July 16-19, 2005
Published in: The Journal of Heart Disease;
vol 4(1): 99, Abstract #394
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Impaired
arterial smooth muscle contractility plays a leading role
in the development of systemic hypertension. Structural changes,
such as occlusive atherosclerotic plaque formation, and functional
changes, such as hormonal disturbances, play roles in pathophysiological
mechanisms of altered arterial contractility. Accelerated
gel contraction was accompanied by elevated secretion of MMPs
into cell culture media. We found that purified polyphenols
and catechins counteracted SMC-dependent collagen gel contraction;
this gel relaxation effect was further enhanced by addition
of ascorbic acid and amino acids lysine, arginine, cysteine
and proline to green tea extract. A reduction in gel contraction
correlated with decreased MMP expression. These results are
significant as they indicated that nutrients can effectively
counteract angiotensin-mediated excessive stimulation of arterial
tissue contraction and have therapeutic potential in hypertension. |
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Bioflavonoids
Effectively Inhibit Smooth Muscle Cell-Mediated Contraction
of Collagen Matrix Induced by Angiotensin II (2004) -
NEW -
V. Ivanov, S. Ivanova, M.W. Roomi, A.
Niedzwiecki, M. Rath
Presented at: 5th Annual Conference
of Arteriosclerosis, Thrombosis and Vascular Biology
San Francisco, CA, May 6-8, 2004 |
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Plant-derived
bioflavonoids have been recognized to support arterial wall
structural integrity and interfere with a variety of pro-atherosclerotic
stimuli. This study examined the effect of various bioflavonoids
on angiotensin II-stimulated contraction by human aortic smooth
muscle cells (SMC) embedded in a three-dimensional collagen
matrix. Bioflavonoid inhibition of SMC contraction was found
to be dependent upon structural characteristics with EGCG
and quercetin showing the greatest inhibition at 97% and 120%,
respectively. These results are significant since they imply
that plant derived bioflavonoids have a great potential in
controlling hypertension by counteracting pathophysiological
effects of angiotensin. |
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