6/4/2018 Heart Disease Part Two by Jeffrey Dach MD

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Heart Disease Part Two by Jeffrey Dach MD
Curriculum Vita

Articles
Heart Disease Part Two - Atherosclerosis: How
NewsLetter Subscribe Does it Happen?
Dr Dach's Books by Jeffrey Dach MD
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A Brief Review of Part I
Disclaimer
The previous report discussed the Coronary Calcium Score, which
is useful because it provides an estimate of total plaque burden.
We also made the shocking statement that the conventional lipid
panel is now obsolete. It has been replaced by the more
sophisticated lipoprotein panel called the NMR or the VAP, which
gives truly useful information of risk markers such as the LDL
particle size and Lipoprotein (a). We also discussed treatment
strategies with dietary modification and various nutritional
supplements such as niacin, fish oil, L-arginine etc which can slow
or reverse plaque formation. My two previous reports have
discussed the role of statin drugs and their adverse side effects.
(7)(8)

In Part I, we explained how plaque

formation is the cause of heart disease, and also discussed how
enlarging plaques eventually cause heart attack by either
occlusion, or plaque rupture with thrombosis. Although there is
usually some warning such as chest pain or shortness of breath,
sudden plaque rupture with thrombosis may cause a heart attack
without warning.

(Image at Left Courtesy of Wikipedia the Cholesterol Molecule)

Part Two - A Closer Look at Plaque Formation

In Part II of this report we take a closer look at the individual

steps leading to plaque formation in the artery wall. Based on this
knowledge, we will then suggest additional strategies for
preventing and reversing plaque formation in the arteries.

An Excellent Review Article on Atherosclerosis

An excellent review article on the detailed mechanism of

atherosclerotic plaque formation can be found here by Navab from
UCLA. (2)

Understanding the Events Leading to Atherosclerosis -The

Fatty Streak

Atherosclerotic plaque formation is a series events. The very first

event is the deposition of lipoproteins in called the Fatty Streak
(yellow in the above diagram) which eventually becomes the lipid
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core of the plaque. We know the fatty streak is the first step
because it has been observed in the human fetus. (18) Now,
that’s really early. The fatty streak is composed of LDL (low
density cholesterol). Formation of the Fatty Streak precedes the
next step in plaque formation which is infiltration with cells called
Monocytes.

The Linus Pauling Theory - Vitamin C Deficiency -

Cholesterol Patches

Linus Pauling and others, suspected that the LDL deposition in the
wall serves as patching material to repair small cracks in the
arterial wall at sites of mechanical stress from pulsations and
flow turbulence. Pauling theorized that, because of a subclinical
vitamin C deficiency, the normal repair mechanisms are
ineffective, so that an alternate repair mechanism with LDL
cholesterol evolved. The LDL cholesterol serves as a sort of
rubber cement to patch up the cracks in arteries, just like patching
the inner tube of our tires.

Since the appearance of the fatty streak appears so early (in the
fetus), it is highly likely that there is a constant ebb and flow of
lipoprotein material in and out of the arterial wall. We now know
there is a transport mechanism for cholesterol to travel in the
blood stream to the arterial wall in the form of LDL particles. And,
there is a reverse cholesterol transport mechanism which
transports cholesterol back from the artery wall to the liver in the
form of HDL particles using the LCAT enzyme (Lecithin-Cholesterol
Acetyl Transferase).

Cholesterol Transport -Good (HDL) and Bad (LDL)

Cholesterol

At left is a blow up of a microscopic

LDL particle with the APO-B protein
colored in yellow, attached at the
top. Cholesterol (orange) is
contained in the center, and is
encapsulated by an outer bi-layer of
phospholipid (purple).

(Image at Left Copyright 2008 Jeffrey Dach

MD, LDL particle)

The HDL particle has a similar

configuration except that the Yellow
protein at the top is replaced with the AP0-A1 protein.

The LDL particles are transported from the liver out to the body
tissues in the blood stream and delivers cholesterol to the Fatty
Streak in the artery wall. The HDL particles carry cholesterol from
the Fatty Streak in the artery wall back to the liver where it is
metabolized and excreted as bile.

Calling LDL "bad", and HDL "good" is like calling the ambulance
that comes from the hospital to your home the "bad" one, and the
ambulance that takes you back to the hospital , the "good" one.
Perhaps this is a useful analogy for children, but is overly
simplistic for adults.(4)

Oxidized Cholesterol

The reality is that LDL cholesterol itself is not the culprit, rather it
is oxidized LDL that is the "bad" guy. Lowering plain LDL
cholesterol will also lower the oxidized fraction of LDL cholesterol,

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but this is a rather crude way to do it. Cholesterol is a building

block for membranes and sex steroids, is important for over-all
health, and lower cholesterol is associated with increased mortality
from cancer, liver disease and mental disease. (5)(6)

Perhaps this is the reason why lowering cholesterol with statin

drugs can reduce "cardiac events", but sadly, statin drugs have
little or no benefit in terms of all-cause mortality. (7)(8) It would
be much more beneficial to selectively reduce only the
OXIDIZED LDL cholesterol.

Researchers have tests to measure oxidized LDL cholesterol, but

this is not yet available to clinicians, and should be.

The Role of Anti-Oxidants

Selectively reducing Oxidized LDL is exactly what is done with

anti-oxidants like vitamin C, E, Carotenoids, and Red wine
polyphenols. These dietary supplements as well as a healthy diet
and lifestyle are clearly beneficial.(9) However, many people are
confused by the opposition views in the medical literature and the
media. These views oppose the use of dietary supplements to
prevent heart disease. Some have even proposed the bizarre
notion that vitamins increase mortality. Of course, these
views represent the interests of the pharmaceutical industry which
stands to lose billions from reduction in heart disease and reduced
demand for drugs.(10)(11)(12)(13)(14) It is clear that dietary
antioxidants like carotinoids in fresh vegetables as well as red
wine polyphenols inhibit LDL oxidation and reduce heart disease.
(15) We will later look at novel anti-oxidants such as liposomal
glutathione (16) and Boswellia.

Infiltration by Monocytes- Macrophages and Inflammation

The next step in plaque formation is the infiltration of cells into the
wall of the artery. Current thinking is that oxidized LDL attracts
the influx of monocytes. These are cells in the blood stream which
have the ability to transform themselves into large scavenger cells
called macrophages which serve as the garbage trucks for pick up
and disposal. They engulf, digest and dispose of the old or toxic
stuff the body needs to get rid of. These macrophages engulf
the LDL cholesterol, and try to dispose of it. During the disposal
process more of the LDL is oxidized . Something goes wrong at
this step , and the macrophages continue to accumulate more and
more oxidized LDL until the poor cell looks like an over inflated
balloon ready to burst. This becomes the Foam Cell.

The Foam Cell- The Culprit is Oxidized LDL

This new over-stuffed macrophage is now called a “Foam Cell”

because it looks foamy under the microscope. It is clear that the
culprit is the oxidized or rancid form of LDL cholesterol. If the LDL
is not oxidized, there seems to be no problem and the LDL can be
transported out of the artery back to the liver in the form of HDL
using the LCAT enzyme for reverse cholesterol transport. The
Foam Cells accumulate, and send out more chemical messages
which invokes an inflammatory cascade that attracts more
macrophages and other cells in an inflammatory reaction.
This inflammation in the wall of the artery causes the thickening in
the wall called plaque formation.

The Fibrous Cap

The last step in plaque formation is the fibrous cap which creates
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a seal between the puddle of oxidized LDL and its inflammatory

cells and the flowing blood at the interior of the artery. Rupture of
the fibrous cap is the final event which exposes the thrombogenic
plaque to the blood stream causing clot formation and a heart
attack.

How to Prevent Oxidation of LDL cholesterol

Now that we know the events leading to plaque formation and

rupture, we can create a logical plan to prevent and reverse this
process. Much of this information was covered in Part One of this
article.

Even after LDL becomes oxidized, it can be converted back to its

original form with the use of anti-oxidants in a process called
reduction. There are a number of anti-oxidants which have been
shown effective. The most important and most powerful
intracellular antioxidant is glutathione, a simple structure
composed of three amino acids and sulfur.

What is Glutathione?

Glutathione is the most powerful naturally occurring antioxidant

in all human cells. It is a small simple compound composed of
three amino acids, glutamic acid, cysteine and glycine. Cysteine
contains sulfer accounting for its sulfer taste and smell.

Glutathione is found in all cells in the body, and the highest

concentration in the liver, important for detoxification and
elimination of toxins and products of oxidation called free radicals.

For the past 10 years, Glutathione has been available only as an

intravenous agent. David Perlmutter MD in Naples Florida has
been pioneering the use of IV glutathione in Parkinson’s Disease
patients for the past 10 years with dramatic results. These
Parkinson’s patients have immediate improvement in their
symptoms after Glutathione IV infusion. In addition, inhaled
glutathione in the form of a nebulizer has been beneficial for
chronic obstructive lung disease patients.

Liposomal Glutathione Reduces Plaque by 30%

A recent 2007 publication from the Technion in Haifa showed that

Liposomal Glutathione reduced plaque formation by 30% in
genetically modified Apo-E mice. (16) These are mice that have
accelerated atherosclerosis, the mouse equivalent of familial
hypercholesterolemia in humans. They also found glutathione
peroxidase in the LDL particle itself, an enzyme that allows the
glutathione to refresh the oxidized LDL back to its original reduced
form. How convenient this enzyme is already in place on the LDL
particle. It must be part of some plan.

At the recent ACAM meeting in Orlando (April 2008), Tim Guilford

MD presented the data on Liposomal Glutathione reversing plaque
in Apo-E mice. Technion researchers in this 2007 study used Dr.
Guilford's liposomal glutathione product called Readisorb, which is
available at his web site.

What is Boswellia ?

Oxidation of the LDL cholesterol involves the Lipoxygenase

pathway which can be inhibited by Boswellia.

Boswellia works by suppressing inflammation by inhibiting an

enzyme called 5-lipoxygenase (5 L-OX) and its by products called
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leukotrienes. This pathway is important in chronic inflammatory

diseases such as arthritis, colitis, asthma, allergies, osteoporosis,
eczema and psoriasis. Boswellia is also useful in preventing the
inflammation inside the arterial tree associated with
atherosclerotic plaque formation. In mice where the 5-
lipoxygenase is absent there is a 26 fold reduction in
atherosclerotic plaque compared to controls. (17)

Currently mainstream medicine has no drug to control the 5-L-OX

enzyme, because up to now the pharmaceutical industry has not
been able to make such a drug without major adverse side effects.

However, Boswellia is a safe, natural gum resin of the

frankincense tree, which powerfully suppresses the 5-lipoxygenase
enzyme like no other substance known. Ancient traditional uses
and more recent studies have shown significant improvements in
asthma, arthritis, colitis, allergies, and heart disease.

The most active of Frankincense component is called AKBA

(acetyl-11-keto-beta-boswellic acid ). Unfortunately, currently
available Boswellia extracts contain only a small amount of AKBA
in the range of 1-3%. This small amount makes it virtually
impossible to attain plasma levels needed for any real clinical
benefit. Fortunately, a new Boswellia extract contains the more
active 90% AKBA and is available from True Botanica (Ross
Rentea MD).

Jeffrey Dach MD
7450 Griffin Rd Suite 180/190
Davie, FL 33314

Phone: 954-792-4663
Email: drdach@drdach.com
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References
(1) http://www.lipid.org/clinical/patients/1000005.php
ATHEROSCLEROSIS - A STORY OF CELLS, CHOLESTEROL, AND
CLOTS John R. Guyton, M.D.
Nice Review Article

(2) http://www.jlr.org/cgi/content/full/45/6/993
Journal of Lipid Research, Vol. 45, 993-1007, June 2004

Thematic review series: The Pathogenesis of Atherosclerosis The

oxidation hypothesis of atherogenesis: the role of oxidized
phospholipids and HDL

Mohamad Navab1,*, G. M. Ananthramaiah, Srinivasa T. Reddy*,,

Brian J. Van Lenten*, Benjamin J. Ansell*, Gregg C. Fonarow*,
Kambiz Vahabzadeh*, Susan Hama*, Greg Hough*, Naeimeh
Kamranpour*, Judith A. Berliner*,**, Aldons J. Lusis*,, and Alan
M. Fogelman*

For more than two decades, there has been continuing evidence of
lipid oxidation playing a central role in atherogenesis. The
oxidation hypothesis of atherogenesis has evolved to focus on
specific proinflammatory oxidized phospholipids that result from
the oxidation of LDL phospholipids containing arachidonic acid and
that are recognized by the innate immune system in animals and
humans. These oxidized phospholipids are largely generated by

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potent oxidants produced by the lipoxygenase and

myeloperoxidase pathways.

The failure of antioxidant vitamins to influence clinical outcomes

may have many explanations, including the inability of vitamin E
to prevent the formation of these oxidized phospholipids and other
lipid oxidation products of the myeloperoxidase pathway.
Preliminary data suggest that the oxidation hypothesis of
atherogenesis and the reverse cholesterol transport hypothesis of
atherogenesis may have a common biological basis.

The levels of specific oxidized lipids in plasma and lipoproteins, the

levels of antibodies to these lipids, and the inflammatory/anti-
inflammatory properties of HDL may be useful markers of
susceptibility to atherogenesis. Apolipoprotein A-I (apoA-I) and
apoA-I mimetic peptides (HDL) may both promote a reduction in
oxidized lipids and enhance reverse cholesterol transport and
therefore may have therapeutic potential.

(3) http://physrev.physiology.org/cgi/content/full/84/4/1381
Physiol. Rev. 84: 1381-1478, 2004;
doi:10.1152/physrev.00047.2003

Role of Oxidative Modifications in Atherosclerosis

Roland Stocker and John F. Keaney, Jr.

Centre for Vascular Research, University of New South Wales, and

Department of Haematology, Prince of Wales Hospital, Sydney,
New South Wales, Australia; and Whitaker Cardiovascular
Institute, Evans Memorial Department of Medicine, Boston
University Medical Center, Boston, Massachusetts

Emerging evidence has heightened the interest in the contribution

of lipoxygenase to atherosclerosis. Analysis of atherosclerosis-
prone and atherosclerosis-resistant mice identified a region on
chormosome 6 that conferred resistance to atherosclerosis despite
elevated levels of lipids (614). Further analysis of this locus
determined that 5-lipoxygenase was one putative gene on
chromasome 6 that conferred susceptibility to atherosclerosis
(613).

This suspicion was confirmed through the use of mice lacking one
copy of the 5-lipoxygenase gene that, when bred with LDL
receptor –/– mice, demonstrated a dramatic decrease in
atherosclerosis (613). This observation has now been extended to
humans as variant 5-lipoxygenase alleles segregate with evidence
of atherosclerosis by carotid imtimal-to-medial thickness
measurements on ultrasound (218). Thus 5-lipoxygenase
appears to be one lipoxygenase isoform that is particularly
germane to the development of atherosclerosis in both
experimental animals and humans.

LDL OXIDATION: CAUSE OR CONSEQUENCE OF

ATHEROSCLEROSIS. It is important to recognize that a large body
of the support referred to in this review to substantiate the
oxidative modification hypothesis of atherosclerosis provides
indirect rather than direct evidence for a causative link between
the two processes. This is perhaps not surprising given the
difficulties in experimental attempts to distinguish LDL oxidation
as a cause rather than consequence of atherosclerosis. For
example, associations such as the relative extent of LDL oxidation
in the vessel wall and disease burden at best only strengthen the
oxidative modification hypothesis; they do not prove the
hypothesis.

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(4) http://www.jpands.org/vol10no3/colpo.pdf
LDL Cholesterol:Bad Cholesterol, or Bad Science? Anthony Colpo,
Journal of American Physicians and Surgeons Volume 10 Number
3 Fall 2005. p 83.

Low Serum LDL is not Healthy

(5) http://www.annclinlabsci.org/cgi/content/abstract/37/4/343

Annals of Clinical & Laboratory Science 37:343-348 (2007)

Low Serum LDL Cholesterol Levels and the Risk of Fever, Sepsis,
and Malignancy

Renana Shor1, Julio Wainstein2, David Oz1, Mona Boaz3, Zipora

Matas4, Asora Fux4 and Aaron Halabe1
1 Departments of Internal Medicine, 2 Diabetes, 3 Statistics, and 4
Biochemistry, The Edith Wolfson Medical Centre, Sackler School of
Medicine, Tel Aviv University, Holon, Israel

In summary, low serum LDL cholesterol level was associated with

increased risks of hematological cancer, fever, and sepsis.

(6) http://www.ncbi.nlm.nih.gov/pubmed/15006277

In men, across the entire age range, although of borderline

significance under the age of 50, and in women from the age of 50
onward only, low cholesterol was significantly associated
with all-cause mortality, showing significant associations
with death through cancer, liver diseases, and mental
diseases.

Why Eve Is Not Adam: Prospective Follow-Up in 149,650 Women

and Men of Cholesterol and Other Risk Factors Related to
Cardiovascular and All-Cause Mortality. Hanno Ulmer, Cecily
Kelleher, Gunter Diem, Hans Concin. Journal of Women's Health.
January 1, 2004, 13(1): 41-53.
doi:10.1089/154099904322836447.

Jeffrey Dach MD Previous Statin Drug Articles

(7)
http://jeffreydach.com/2008/01/27/cholesterol-lowering-statin-drugs-for-women-just-
say-no-by-jeffrey-dach-md.aspx

Cholesterol Lowering Drugs for Women, Just say No, by Jeffrey

Dach MD

(8) http://jeffreydach.com/2007/05/14/lipitor-and-the-dracula-of-modern-
technology-by-jeffrey-dach-md.aspx
Lipitor and the Dracula of Medical Technology by Jeffrey Dach MD

Dietary Anti-Oxidants- Pro

(9) http://circ.ahajournals.org/cgi/content/abstract/107/7/947

(Circulation. 2003;107:947.)Clinical Investigation and Reports

Six-Year Effect of Combined Vitamin C and E Supplementation on

Atherosclerotic Progression - The Antioxidant Supplementation in
Atherosclerosis Prevention (ASAP) Study Conclusions— These
data replicate our 3-year findings confirming that the
supplementation with combination of vitamin E and slow-
release vitamin C slows down atherosclerotic progression
in hypercholesterolemic persons

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Opposition to Anti-Oxidants in Heart Disease Prevention

(10) http://www.ajcn.org/cgi/content/full/84/4/680
American Journal of Clinical Nutrition, Vol. 84, No. 4, 680-681,
October 2006 EDITORIAL

The dubious use of vitamin-mineral supplements in relation to

cardiovascular disease
Donald B McCormick

Slamming Vitamins with Bad Science

(11) http://www.healthfreedom.net/index.php?
option=com_content&task=view&id=425

The Truth Behind the Cochrane Slam on Dietary Supplements. By

now, you have probably read the headlines such as “Vitamins May
Shorten Users' Lives,” “Vitamins may increase risk of death”, or
“Vitamins A, C and E are 'a waste of time and may even shorten
your life.”

These biased articles are based on the latest Cochrane review

which more or less copies the JAMA paper from February 2007.
Unfortunately, bad science and misleading media stories are
confusing consumers. As dietary supplements become more
popular and threaten the bottom line of traditional medicine and
Big Pharma, we see more and more studies and articles that try to
convince the public that dietary supplements are useless,
unregulated, or even deadly.

(12) http://www.alliance-natural-
health.org/_docs/ANHwebsiteDoc_270.pdf

Poor methodology in meta-analysis of vitamins. Dr Steve

Hickeyi,ii, Dr Len Noriegai and Dr Hilary Roberts
iFaculty of Computing, Engineering and Technology, Staffordshire
University; iiSchool of Biology, Chemistry and Health Science,
Manchester Metropolitan University.

A recent review of clinical trials by Bjelakovic et al. (JAMA Feb

2007) claimed to show that certain antioxidant
vitamins increased the risk of death.1 Superficially, this study
appears to have a degree of scientific rigour because of a detailed
and extensive use of statistics. However, the statistics were
inappropriately applied to poorly selected data, thus the
conclusions are invalid.

(13) http://www.ajcn.org/cgi/content/full/85/1/293S

What is the Efficacy of Single Vitamin and Mineral Supplement Use

in Chronic Disease Prevention? Heart disease and single-vitamin
supplementation1,2,3,4 Maret G Traber American Journal of
Clinical Nutrition, Vol. 85, No. 1, 293S-299S, January 2007

(14) http://www.ajcn.org/cgi/content/full/81/4/736

REVIEW ARTICLE : Vitamins E and C are safe across a broad range

of intakes.

American Journal of Clinical Nutrition, Vol. 81, No. 4, 736-745,

April 2005 John N Hathcock, Angelo Azzi, Jeffrey Blumberg,
Tammy Bray, Annette Dickinson, Balz Frei, Ishwarlal Jialal, Carol S
Johnston, Frank J Kelly, Klaus Kraemer, Lester Packer, Sampath
Parthasarathy, Helmut Sies and Maret G Traber

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(15) http://www.ncbi.nlm.nih.gov/pubmed/16596803

Handb Exp Pharmacol. 2005;(170):263-300

Dietary antioxidants and paraoxonases against LDL oxidation and

atherosclerosis development. Aviram M, Kaplan M, Rosenblat M,
Fuhrman B.The Lipid Research Laboratory, Technion Faculty of
Medicin and Rambam Medical Center, Haifa, Israel.

Oxidative modification of low-density lipoprotein (LDL) in the

arterial wall plays a key role in the pathogenesis of
atherosclerosis. Under oxidative stress LDL is exposed to oxidative
modifications by arterial wall cells including macrophages.
Oxidative stress also induces cellular-lipid peroxidation, resulting
in the formation of 'oxidized macrophages', which demonstrate
increased capacity to oxidize LDL and increased uptake of oxidized
LDL.

Macrophage-mediated oxidation of LDL depends on the balance

between pro-oxidants and antioxidants in the lipoprotein and in
the cells. LDL is protected from oxidation by antioxidants, as well
as by a second line of defense--paraoxonase 1 (PON1), which is a
high-density lipoprotein-associated esterase that can hydrolyze
and reduce lipid peroxides in lipoproteins and in arterial cells.
Cellular paraoxonases (PON2 and PON3) may also play an
important protective role against oxidative stress at the cellular
level.

Many epidemiological studies have indicated a protective role for a

diet rich in fruits and vegetables against the development and
progression of cardiovascular disease. A large number of studies
provide data suggesting that consumption of dietary
antioxidants is associated with reduced risk for
cardiovascular diseases. Basic research provides plausible
mechanisms by which dietary antioxidants might reduce the
development of atherosclerosis. These mechanisms include
inhibition of LDL oxidation, inhibition of cellular lipid peroxidation
and consequently attenuation of cell-mediated oxidation of LDL.
An additional possible mechanism is preservation/increment of
paraoxonases activity by dietary antioxidants.

This review chapter presents recent data on the anti-

atherosclerotic effects and mechanism of action of three major
groups of dietary antioxidants-vitamin E, carotenoids and
polyphenolic flavonoids.

Liposomal Glutathione

(16) http://www.ncbi.nlm.nih.gov/pubmed/17588583
Atherosclerosis. 2007 Dec;195(2):e61-8. Epub 2007 Jun 22

Anti-oxidant and anti-atherogenic properties of liposomal

glutathione: studies in vitro, and in the atherosclerotic
apolipoprotein E-deficient mice.Rosenblat M, Volkova N, Coleman
R, Aviram M.

The Lipid Research Laboratory, Technion Faculty of Medicine, The

Rappaport Family Institute for Research in the Medical Sciences,
Rambam Medical Center, Haifa 31096, Israel.

Liposomal glutathione, but not the control liposomes (with no

glutathione), dose-dependently inhibited copper ion-induced low
density lipoprotein (LDL) and HDL oxidation. As peroxidase activity
was found to be present in both LDL and HDL, it has contributed
to the anti-oxidative effects of liposomal glutathione. In-vitro, no
significant effect of liposomal glutathione on J774 A.1 macrophage
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cell-line oxidative stress and on cellular cholesterol metabolism

was observed. In contrast, in the atherosclerotic apolipoprotein E-
deficient (E(0)) mice, consumption of liposomal glutathione (12.5
or 50mg/kg/day, for 2 months), but not control liposomes,
resulted in a significant reduction in the serum susceptibility to
AAPH-induced oxidation by 33%. Liposomal glutathione
(50mg/kg/day) consumption also resulted in an increment (by
12%) in the mice peritoneal macrophages (MPM) glutathione
content, paralleled by a significant reduction in total cellular lipid
peroxides content (by 40%), compared to placebo-treated mice
MPM. MPM paraoxonase 2 activity was significantly increased by
27% and by 121%, after liposomal glutathione consumption (12.5
or 50mg/kg/day, respectively).

Analyses of cellular cholesterol fluxes revealed that, liposomal

glutathione (12.5mg/kg/day) consumption, decreased the extent
of oxidized-LDL (Ox-LDL) uptake by 17% and the cellular
cholesterol biosynthesis rate, by 34%, and stimulated HDL-
induced macrophage cholesterol efflux, by 19%.

Most important, a significant reduction in macrophage

cholesterol mass (by 24%), and in the atherosclerotic
lesion area (by 30%) was noted.

We thus conclude that liposomal glutathione possesses anti-

oxidative and anti-atherogenic properties towards lipoproteins and
macrophages, leading to attenuation of atherosclerosis
development.

Inhibition of 5-LOX Reduces Aorta Plaque 26 fold

(17) http://circres.ahajournals.org/cgi/content/full/91/2/120
(Circulation Research. 2002;91:120.)

Molecular Medicine Identification of 5-Lipoxygenase as a Major

Gene Contributing to Atherosclerosis Susceptibility in Mice

Margarete Mehrabian, Hooman Allayee, Jack Wong, Weibin Shih,

Xu-Ping Wang, Zory Shaposhnik, Colin D. Funk, Aldons J. Lusis

We previously reported the identification of a locus on mouse

chromosome 6 that confers almost total resistance to
atherogenesis, even on a hypercholesterolemic (LDL
receptor–null) background.

5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene

synthesis and was among the chromosome 6 locus candidate
genes that we examined. The levels of 5-LO mRNA were reduced
about 5-fold in a congenic strain, designated CON6, containing the
resistant chromosome 6 region derived from the CAST/Ei strain
(CAST), as compared with the background C57BL/6J (B6) strain.

5-LO protein levels were similarly reduced in the CON6 mice.

Sequencing of the 5-LO cDNA revealed several differences
between CON6 and the B6 strain. To test the whether 5-LO is
responsible for the resistant phenotype, we bred a 5-LO knockout
allele onto an LDL receptor–null (LDLR-/-) background. On this
background, the mice bred poorly and only heterozygous 5-LO
knockout mice were obtained.

These mice showed a dramatic decrease (>26-fold;

P<0.0005) in aortic lesion development, similar to the CON6
mice. Immunohistochemistry revealed that 5-LO was abundantly
expressed in atherosclerotic lesions of apoE- /- and LDLR-/-
deficient mice, appearing to colocalize with a subset of

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macrophages but not with all macrophage-staining regions. When

bone marrow from 5-LO+/- mice was transplanted into LDLR-/-,
there was a significant reduction in atherogenesis, suggesting that
macrophage 5-LO is responsible, at least in part, for the
effect on atherosclerosis.

These results indicate that 5-LO contributes importantly to the

atherogenic process and they provide strong presumptive
evidence that reduced 5-LO expression is partly responsible for
the resistance to atherosclerosis in CON6 mice.

Fatty Streak in Fetal Aortas

(18) http://www.pubmedcentral.nih.gov/articlerender.fcgi?
tool=pubmed&pubmedid=9389731
J Clin Invest. 1997 December 1; 100(11): 2680–2690.

Fatty streak formation occurs in human fetal aortas and is greatly

enhanced by maternal hypercholesterolemia. Intimal accumulation
of low density lipoprotein and its oxidation precede monocyte
recruitment into early atherosclerotic lesions.

C Napoli, F P D'Armiento, F P Mancini, A Postiglione, J L Witztum,

G Palumbo, and W Palinski, Department of Clinical and
Experimental Medicine, Federico II University of Naples, 80131
Naples, Italy.

Oxidized LDL Cholesterol, Not LDL Cholesterol

http://atvb.ahajournals.org/cgi/content/abstract/20/3/708
Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:708.)

Oxidized Cholesterol in the Diet Accelerates the Development of

Atherosclerosis in LDL Receptor– and Apolipoprotein E–Deficient
Mice, Ilona Staprans; Xian-Mang Pan; Joseph H. Rapp; Carl
Grunfeld; Kenneth R. Feingold

We found that in LDLR-deficient mice, feeding of an oxidized-

cholesterol diet resulted in a 32% increase in fatty streak
lesions (15.93±1.59% versus 21.00±1.38%, P<0.03). Similarly,
in apo E–deficient mice, feeding of an oxidized-cholesterol diet
increased fatty streak lesions by 38% (15.01±0.92% versus
20.70±0.86%, P<0.001).

The results of the current study thus demonstrate that

oxidized cholesterol in the diet accelerates fatty streak
lesion formation in both LDLR- and apo E–deficient mice.

http://atvb.ahajournals.org/cgi/content/abstract/18/6/977
Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:977-
983.)

Oxidized Cholesterol in the Diet Accelerates the Development of

Aortic Atherosclerosis in Cholesterol-Fed Rabbits Ilona Staprans;
Xian-Mang Pan; Joseph H. Rapp; ; Kenneth R. Feingold

Abstract—Oxidized lipoproteins may play a role in atherosclerosis.

Recently, we have demonstrated that the levels of oxidized fatty
acids in the circulation correlate directly with the quantity of
oxidized fatty acids in the diet and that dietary oxidized fatty acids
accelerate atherosclerosis in rabbits. The present study tests the
hypothesis that oxidized cholesterol in the diet accelerates the
development of atherosclerosis. Rabbits were fed a diet containing
0.33% nonoxidized cholesterol (control diet) or the same diet
containing 0.33% cholesterol of which 5% was oxidized (oxidized
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diet). Serum cholesterol levels increased to a similar extent in

both groups, with the majority of cholesterol in the ß-VLDL
fraction. Moreover, in the serum ß-VLDL fraction and liver, there
was a significant increase in the oxidized cholesterol levels. Most
importantly, feeding a diet enriched in oxidized cholesterol
resulted in a 100% increase in fatty streak lesions in the aorta.
Western diets contain high concentrations of oxidized cholesterol
products, and our results suggest that these foods may be a risk
factor for atherosclerosis.

http://www.specialtylabs.com/books/display.asp?id=1095

Oxidized Low Density Lipoproteins and their Autoantibodies

James B. Peter, M.D., Ph.D. & Ruihua Wu, M.D.*, Ph.D. & Janet
Cook, MT (ASCP), M.S.

Modified forms of low density lipoprotein (LDL), the major

cholesterol carrying lipoprotein, are associated with accelerated
atherosclerosis. Macrophages take up oxidized LDL (ox-LDL) and
acetylated LDL (acetyl-LDL) to form foam cells, the earliest step in
atherogenesis.1 Probably reflecting their rapid binding to the
scavenger receptor on the macrophage immediately after its
formation ox-LDL are undetectable in circulating blood, but are
detected in atheromatous plaques.

Other risk factors for myocardial infarction may have a final

common pathway through ox-LDL. For example, homocyst(e)ine
and cysteine can induce oxidative modification of LDL.2 Cigarette
smoking and hypercholesterolemia synergistically impair
endothelial cell function and enhance oxidation of LDL and their
combined presence is associated with autoantibodies to ox-LDL.3
Iron catalyzes the formation of reactive oxygen species, which, in
turn, leads to the modification of LDL at the molecular level,
facilitating its deposition and leading to the formation of
artherosclerotic plaque.4

Monoclonal antibodies specific for MDA-modified LDL and ox-LDL

are detectable by EIA. Autoantibodies to ox-LDL (ox-LDL-Ab) are
considered a good surrogate marker of LDL oxidation. Ox-LDL is
more immunogenic than native LDL, and elevated antibodies to
ox-LDL are associated with carotid atherosclerosis. Patients with
abnormal coronary angiograms have significantly elevated
concentrations of ox-LDL-Ab compared to patients with normal
coronary angiograms or normal subjects.6 High LDL cholesterol
(>3 mmol/L) is associated with poor coronary flow reserve only in
patients with elevated ox-LDL-Ab.7

http://www.fasebj.org/cgi/content/full/15/12/2073
The FASEB Journal. 2001;15:2073-2084.)

Oxidized LDL and HDL: antagonists in atherothrombosis, ANN

MERTENS and PAUL HOLVOET1 Center for Experimental Surgery
and Anesthesiology, Katholieke Universiteit Leuven, Belgium

Increased LDL oxidation is associated with coronary artery

disease.

The predictive value of circulating oxidized LDL is additive to the

Global Risk Assessment Score for cardiovascular risk prediction
based on age, gender, total and HDL cholesterol, diabetes,
hypertension, and smoking. Circulating oxidized LDL does not
originate from extensive metal ion-induced oxidation in the blood
but from mild oxidation in the arterial wall by cell-associated
lipoxygenase and/or myeloperoxidase.

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Oxidized LDL induces atherosclerosis by stimulating

monocyte infiltration and smooth muscle cell migration and
proliferation. It contributes to atherothrombosis by inducing
endothelial cell apoptosis, and thus plaque erosion, by impairing
the anticoagulant balance in endothelium, stimulating tissue factor
production by smooth muscle cells, and inducing apoptosis in
macrophages.

HDL cholesterol levels are inversely related to risk of coronary

artery disease. HDL prevents atherosclerosis by reverting the
stimulatory effect of oxidized LDL on monocyte infiltration. The
HDL-associated enzyme paraoxonase inhibits the oxidation of LDL.
PAF-acetyl hydrolase, which circulates in association with HDL and
is produced in the arterial wall by macrophages, degrades
bioactive oxidized phospholipids. Both enzymes actively protect
hypercholesterolemic mice against atherosclerosis. Oxidized LDL
inhibits these enzymes. Thus, oxidized LDL and HDL are indeed
antagonists in the development of cardiovascular disease.

Foam Cells and Oxidized LDL

http://bme.virginia.edu/ley/lab/publications/Shashkin.pdf
Current Pharmaceutical Design, 2005, 11, 3061-3072 3061

Macrophage Differentiation to Foam Cells

Pavel Shashkin1,#, Bojan Dragulev2 and Klaus Ley1,*University

of Virginia, 1Cardiovascular Research Center and Department of
Biomedical Engineering and 2Dept. of Microbiology, Charlottesville
VA 22908

Foam cell formation from macrophages with subsequent fatty

streak formation plays a key role in early
atherogenesis. Foam cell formation is thought to be induced by
Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or
minimally modified LDL (mmLDL). Understanding the molecular
mechanisms involved in OxLDL- and mmLDL-induced foam cell
formation is of fundamental importance for atherosclerosis and
cardiovascular disease.

Recent observations indicate a role 5-lipoxygenase, 15-

lipoxygenase and the leukotriene receptors in foam cell formation.
Selective inhibitors of lipoxygenases and leukotriene
receptors could be useful in the treatment of
atherosclerosis by preventing or reducing foam cell
formation.

5-Lipoxygenase implicated in Heart Disease

http://circres.ahajournals.org/cgi/content/full/91/2/120
Identification of 5-Lipoxygenase as a Major Gene
Contributing to Atherosclerosis Susceptibility in Mice

Circulation Research. 2002;91:120.Molecular Medicine, Margarete

Mehrabian, Hooman Allayee, Jack Wong, Weibin Shih, Xu-Ping
Wang, Zory Shaposhnik, Colin D. Funk, Aldons J. Lusis

We previously reported the identification of a locus on mouse

chromosome 6 that confers almost total resistance to
atherogenesis, even on a hypercholesterolemic (LDL
receptor–null) background.

5-Lipoxygenase (5-LO) is the rate-limiting enzyme in leukotriene

synthesis and was among the chromosome 6 locus candidate
genes that we examined.

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The levels of 5-LO mRNA were reduced about 5-fold in a congenic

strain, designated CON6, containing the resistant chromosome 6
region derived from the CAST/Ei strain (CAST), as compared with
the background C57BL/6J (B6) strain. 5-LO protein levels were
similarly reduced in the CON6 mice. Sequencing of the 5-LO cDNA
revealed several differences between CON6 and the B6 strain. To
test the whether 5-LO is responsible for the resistant phenotype,
we bred a 5-LO knockout allele onto an LDL receptor–null
(LDLR-/-) background. On this background, the mice bred poorly
and only heterozygous 5-LO knockout mice were obtained. These
mice showed a dramatic decrease (>26-fold; P<0.0005) in aortic
lesion development, similar to the CON6 mice.

Immunohistochemistry revealed that 5-LO was abundantly

expressed in atherosclerotic lesions of apoE- /- and LDLR-/-
deficient mice, appearing to colocalize with a subset of
macrophages but not with all macrophage-staining regions. When
bone marrow from 5-LO+/- mice was transplanted into LDLR-/-,
there was a significant reduction in atherogenesis, suggesting that
macrophage 5-LO is responsible, at least in part, for the effect on
atherosclerosis.

These results indicate that 5-LO contributes importantly to the

atherogenic process and they provide strong presumptive
evidence that reduced 5-LO expression is partly responsible
for the resistance to atherosclerosis in CON6 mice.

http://www.jlr.org/cgi/content/full/43/1/26
Journal of Lipid Research, Vol. 43, 26-35, January 2002
Copyright © 2002 by Lipid Research, Inc.

Induction of monocyte differentiation and foam cell formation in

vitro by 7-ketocholesterol

John M. Hayden1,a, Libuse Brachova1,a, Karen Higginsa, Lewis

Obermillera, Alex Sevanianb, Srikrishna Khandrika2,a, and Peter
D. Reavena

Oxidized Cholesterol in Plasma Strong Predictor of Heart

Attack

http://circ.ahajournals.org/cgi/content/full/112/5/651
(Circulation. 2005;112:651-657.)

Plasma Oxidized Low-Density Lipoprotein, a Strong Predictor for

Acute Coronary Heart Disease Events in Apparently Healthy,
Middle-Aged Men From the General Population

Christa Meisinger, MD, MPH; Jens Baumert, MS; Natalie

Khuseyinova, MD; Hannelore Loewel, MD; Wolfgang Koenig, MD

Plasma oxLDL was the strongest predictor of CHD events

compared with a conventional lipoprotein profile and other
traditional risk factors for CHD. When both oxLDL and C-reactive
protein were simultaneously assessed in the same model, they still
predicted future CHD events even after multivariable adjustment.

Conclusions— Elevated concentrations of oxLDL are predictive of

future CHD events in apparently healthy men. Thus, oxLDL may
represent a promising risk marker for clinical CHD complications
and should be evaluated in further studies.

http://www.blackwell-synergy.com/doi/full/10.1111/j.1365-
2796.2004.01402.x
Oxidized low-density lipoprotein in plasma is a prognostic marker
of subclinical atherosclerosis development in clinically healthy men

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Journal of Internal Medicine 256 (5) , 413–420 K. Wallenfeldt, B.

Fagerberg, J. Wikstrand, J. Hulthe (2004)

Using this antibody (mAb-4E6) it is possible to measure very

small amounts OxLDL containing a conformational epitope in the
apoB-100 moiety of LDL that is generated as a consequence of
substitution of lysine residues of apoB-100 with aldehydes [7].

OxLDL at entry, but not LDL cholesterol, was associated with

the number and size of plaques at follow-up (P = 0.008), also
after adjustment for plaque status at entry (P = 0.033). The
plasma OxLDL concentration at entry was associated with change
in carotid artery IMT (r = 0.17; P = 0.002) and in a stepwise
multiple regression analysis this association remained after
adjustment for other cardiovascular risk factors (P = 0.005).

Conclusions. These results provide new information, supporting

the concept that circulating OxLDL was associated with the silent
phase of atherosclerosis progression in clinically healthy men
independently of conventional risk factors

Measuring Oxidized LDL in Blood

http://diabetes.diabetesjournals.org/cgi/content/full/53/4/1068
Diabetes 53:1068-1073, 2004

The Metabolic Syndrome, Circulating Oxidized LDL, and Risk of

Myocardial Infarction in Well-Functioning Elderly People in the
Health, Aging, and Body Composition Cohort

Paul Holvoet1, Stephen B. Kritchevsky2, Russell P. Tracy3,4, Ann

Mertens1, Susan M. Rubin5, Javed Butler6, Bret Goodpaster7, and
Tamara B. Harris8

We concluded that the metabolic syndrome, a risk factor for CHD,

is associated with higher levels of circulating oxLDL that are
associated with a greater disposition to atherothrombotic coronary
disease.

Levels of oxLDL were measured (2000–2001) blindly at the Center

for Experimental Surgery and Anesthesiology. An mAb-4E6-
based competition enzyme-linked immunosorbent assay
(ELISA) was used for measuring plasma oxLDL levels
(5,16,17). The monoclonal antibody mAb-4E6 is directed against a
conformational epitope in the apoB-100 moiety of LDL that is
generated by substituting aldehydes for at least 60 lysine residues
of apolipoprotein B-100.

APO A1 and APO B Proteins

http://en.wikipedia.org/wiki/Apolipoprotein_A1
Apolipoprotein A1

Apolipoprotein A-I (ApoA-I) is an apolipoprotein. It is the major

protein component of high density lipoprotein (HDL) in plasma.
The protein promotes cholesterol efflux from tissues to the liver
for excretion. It is a cofactor for lecithin cholesterol-acyl-
transferase (LCAT) which is responsible for the formation of most
plasma cholesteryl esters.

http://en.wikipedia.org/wiki/Apolipoprotein_B

Apolipoprotein B (APO-B is the primary apolipoprotein of low

density lipoproteins (LDL or "bad cholesterol"), which is
responsible for carrying cholesterol to tissues. While it is unclear
exactly what functional role APOB plays in LDL, it is the primary
apolipoprotein component and is absolutely required for its
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formation. What is clear is that the APOB on the LDL particle acts
as a ligand for LDL receptors in various cells throughout the body
(i.e. less formally, APOB "unlocks" the doors to cells and thereby
delivers cholesterol to them). Through a mechanism that is not
fully understood, high levels of APOB can lead to plaques that
cause heart disease (atherosclerosis). There is considerable
evidence that levels of APOB are a better indicator of heart disease
risk than total cholesterol or LDL. However, primarily for practical
reasons, cholesterol, and more specifically, LDL-cholesterol,
remains the primary lipid target and risk factor for atherosclerosis.

APOB100 is found in lipoproteins originating from the liver (VLDL,

IDL, LDL). Importantly, there is one APOB100 molecule per
hepatic-derived lipoprotein. Hence, using that fact, one can
quantify the number of lipoprotein particles by noting the
total APOB100 concentration in the circulation. Since there is
one and only one APOB100 per particle, the number of particles is
reflected by the APOB100 concentration. The same technique can
be applied to individual lipoprotein classes (e.g. LDL) and thereby
enable one to count them as well.

It is well established that APOB100 levels are associated

with coronary heart disease, and are even a better
predictor of it than is LDL level. A naive way of explaining
this observation is to use the idea that APOB100 reflects
lipoprotein particle number (independent of their
cholesterol content). In this way, one can infer that the
number of APOB100-containing lipoprotein particles is a
determinant of atherosclerosis and heart disease.

APO -E

http://en.wikipedia.org/wiki/Apolipoprotein_E
Defects in apolipoprotein E result in familial
dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III),
in which increased plasma cholesterol and triglycerides are the
consequence of impaired clearance of chylomicron and VLDL
remnants.[1]

More Glutathione

http://www.ebmonline.org/cgi/content/full/230/1/40

Experimental Biology and Medicine 230:40-48 (2005)

Glutathione Preconditioning Attenuates Ac-LDL–Induced

Macrophage Apoptosis via Protein Kinase C–Dependent Ac-LDL
Trafficking

Rene S. Rosenson-Schloss*, Evangelia Chnari*, Thomas A.

Brieva*, Anh Dang* and Prabhas V. Moghe*,,1

https://content.nejm.org/cgi/content/full/349/17/1605
NEJM Volume 349:1605-1613 October 23, 2003 Number 17

Glutathione Peroxidase 1 Activity and Cardiovascular Events in

Patients with Coronary Artery Disease

Stefan Blankenberg, M.D., Hans J. Rupprecht, M.D., Christoph

Bickel, M.D., Michael Torzewski, M.D., Gerd Hafner, M.D.,
Laurence Tiret, Ph.D., Marek Smieja, M.D., Ph.D., François
Cambien, M.D., Jürgen Meyer, M.D., Karl J. Lackner, M.D., for the
AtheroGene Investigators

Conclusions In patients with coronary artery disease, a low level of

activity of red-cell glutathione peroxidase 1 is independently

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associated with an increased risk of cardiovascular events.

Glutathione peroxidase 1 activity may have prognostic value in
addition to that of traditional risk factors. Furthermore, increasing
glutathione peroxidase 1 activity might lower the risk of
cardiovascular events.

http://content.onlinejacc.org/cgi/content/full/47/5/1005

J Am Coll Cardiol, 2006; 47:1005-1011, CLINICAL RESEARCH:

ATHEROSCLEROSIS

The Relationship Between Plasma Levels of Oxidized and Reduced

Thiols and Early Atherosclerosis in Healthy Adults, Salman Ashfaq,
MD, FACC*, Jerome L. Abramson, PhD, Dean P. Jones, PhD,
Steven D. Rhodes, RN, William S. Weintraub, MD, FACC, W. Craig
Hooper, PhD, Viola Vaccarino, MD, PhD, David G. Harrison, MD,
FACC and Arshed A. Quyyumi, MD, FACC,*

CONCLUSIONS: Glutathione redox state (Eh GSH/GSSG), an in

vivo measure of intracellular oxidative stress, is an
independent predictor for the presence of early
atherosclerosis in an otherwise healthy population. This
finding supports a role for oxidative stress in the pathogenesis of
premature atherosclerosis, and its measurement may help in the
early identification of asymptomatic subjects at risk of
atherosclerotic disease.

http://circ.ahajournals.org/cgi/content/full/100/22/2244

Circulation. 1999;100:2244.

Serum Glutathione in Adolescent Males Predicts Parental Coronary

Heart Disease

John A. Morrison, PhD; Donald W. Jacobsen, PhD; Dennis L.

Sprecher, MD; Killian Robinson, MD; Philip Khoury, MS; Stephen
R. Daniels, MD, PhD

Background—Traditional risk factors account for only half of the

morbidity and mortality from coronary heart disease (CHD). There
is substantial evidence that oxidative injury plays a major role in
the atherosclerotic process. Thus, antioxidants may protect
against development of atherosclerosis. Glutathione, an
intracellular tripeptide with antioxidant properties, may be
protective.

Methods and Results—This case-control study compared total

serum glutathione (tGSH) in 81 adolescent male offspring of
parents with premature CHD (ie, before 56 years of age) and 78
control male offspring of parents without known or suspected
CHD. Case offspring had significantly lower tGSH than control
offspring. In multiple logistic regression with parental CHD status
as the dependent variable, age entered as a covariate, and other
CHD risk factors competing to enter the model as significant
independent predictor variables, LDL cholesterol (odds ratio [OR],
2.15 [units=1.5 SD]; 95% CI, 1.21 to 3.82), tGSH (OR, 0.40;
95% CI, 0.22 to 0.71), HDL cholesterol (OR, 0.42; 95% CI, 0.22
to 0.78), and total serum homocysteine (OR, 2.6; 95% CI, 1.35 to
5.02) entered the model as significant predictors of parental CHD
status.

Conclusions—Low tGSH in adolescent boys is a significant

independent predictor of parental CHD, in addition to elevated LDL
cholesterol, low HDL cholesterol, and elevated total serum
homocysteine concentrations.

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Prasad A, Andrews NP, Padder FA, et al. Glutathione reverses

endothelial dysfunction and improves nitric oxide bioavailability. J
Am Coll Cardiol 1999;34:507-514.

Tim Guilford MD

http://www.cancercontrolsociety.com/bio2005/guilford.html
TIM GUILFORD, M.D., received his Medical Degree from the
University of Texas Medical Branch in Galveston, Texas. He trained
in surgery for 2 years at Johns Hopkins Hospital in Baltimore,
Maryland and completed his training at the University of Michigan,
Ann Arbor. He is Board Certified in Ear, Nose and Throat, Head
and Neck Surgery.

In Clinical Practice since 1981, Dr. Guilford was also Director of

Biological Information System Clinical Laboratory specializing in
Allergy and Immunology testing until 1993. His areas of medical
interest include treatment of allergy, chronic illnesses and he uses
Homeopathy and nutrient support for chronic illnesses.

Over the last 10 years Dr. Guilford has become an expert in the
role that glutathione plays in chronic illnesses. Glutathione
decreases with age and chronic illnesses, and plays a key role in
several systems that are critical for the maintenance of health.
Low glutathione levels are associated with chronic inflammation,
which prevents efficient immune function, and diminishes the
ability to remove toxins.

Dr. Guilford’s interest in glutathione has lead tp the formation of a

liposomal glutathione product called ReadiSorb™ Glutathione.
More information is available at www.Readisorb.com.

http://www.readisorb.com/ Readisorb Liposomal Glutathione Web

Site

Boswellia

http://www.truebotanica.com/boswellia_science.html

Cardio-vascular Diseases

The role of the 5-Lipoxygenase in atherosclerosis is particularly

interesting.

Atherosclerosis, a major cause of morbidity and mortality, is now

seen as an inflammatory fibro-proliferative disease. Leukotriene
receptors are abundantly expressed in atherosclerotic lesions in
the aorta, heart and carotid artery. In fact the presence of high
expression of 5-Lipoxygenase, correlates well with high plaque
instability.

Review of animal and human data suggest that 5-Lipoxygenase

and its metabolites are up regulated in vessel walls, macrophages,
dendritic cells, foam cells, mast cells, and neutrophils. Recent
studies clearly have identified the 5-Lipoxygenase gene as a risk
factor in such cardio vascular diseases as stroke and myocardial
infarction.

A survey of 470 subjects identified to have a gene variant leading

to an increased expression of 5-Lipoxygenase demonstrated a
significant increase in carotid artery intima-media thickness.
Dietary intake of fish oils, which reduce the production of
Leukotrienes, blunted the genotype effect. Another recent survey
of subjects from Britain and Iceland, with higher than normal 5-
Lipoxygenase expression, showed, double the usual rate of heart

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attacks. Mice genetically lacking the 5-Lipoxygenase gene showed

a dramatic 26 fold reduction in aortic lesions.

These studies suggest that 5-Lipoxygenase inhibition would be a

valuable preventative measure in CV disease.

Significantly increased urinary Leukotriene levels were found in

patients following admission for acute myocardial infarction.
Elevated levels of Leukotrienes were also found in patients with
unstable angina.

Leukotrienes are also involved in sickle cell disease and septic

shock. Taken together these studies demonstrate that there is a
significant benefit to treat patients suffering from ischemic injuries
and the resulting organ damage by eliminating inflammatory
events through 5-Lipoxygenase control.

Recently, LT receptors have been shown to be expressed in the

intimal hyperplasia of early atherosclerosis and in restenotic
lesions after angioplasty. These findings emphasize the role that a
5-Lipoxygenase target could play in preventing restenosis after
coronary interventions.

Articles by Ross Rentea MD on Boswelia etc.

http://www.satyacenter.com/health-plant_medicine-gold-
frankincense-myrrh
Gold, Frankincense and Myrrh - Companions for overcoming work-
related stress?
by Ross Rentea, M.D.

http://www.lilipoh.com/articles/2005/summer/sensory_overload.asp
Sensory Overload Author: An Interview with Ross Rentea, M.D.
Issue: LILIPOH #40 - Summer 2005: HEALTH & THE SENSES
http://www.lilipoh.com/articles/2006/winter/anthroposophical_aspects_of_diabetes_treat
Aspects of Diabetes Treatment Author: Ross Rentea, M.D..Issue:
LILIPOH #46 - Issue 11 Winter 2006

http://www.truebotanica.com/
True Botanica Web Site

http://www.frankincensegifts.com/

http://www.threekingsgifts.com/

http://www.wfu.edu/wfunews/2000/120400g.htm

Boswellia References
Am. J. Respir. Crit. Care Med., Volume 161, Number 2, February
2000, S120-S124
5-Lipoxygenase and Leukotrienes Transgenic Mouse and Nuclear Targeting
Studies COLIN D. FUNK and XIN-SHENG CHEN

Department of Pharmacology and Center for Experimental

Therapeutics, University of Pennsylvania, Philadelphia,
Pennsylvania

Anon. Treatment of Crohn's disease with incense (Boswellia

serrata extract). Arztezeitschrift fur Naturheilverfahren
2001;42:636.

Ammon HPT. Boswellic acids in chronic inflammatory diseases.

Planta Medica 2006;72:1100-16.

Ba¨ck M, Hansson GK. Leukotriene receptors in atherosclerosis.

Annals of Medicine 2006;38:493-502.

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Badria FA, El-Farahaty T, Shabana AA, Hawas SA, El-Batoty MF.

Boswellia-curcumin preparation for treating knee osteoarthritis: A
clinical evaluation. Alternative and Complementary Therapies
2002;8:341-8.

Badria FA, Mohammed EA, El-Badrawy MK, El-Desouky M. Natural

leukotriene inhibitor from Boswellia: A potential new alternative
for treating bronchial asthma. Alternative and Complementary
Therapies 2004;10:257-65.

Bertsche T, Schulz M. Therapy with Boswellia extracts.

Pharmazeutische Zeitung 2002;147:34-6.

Bishnoi M, Patil CS, Kumar A, Kulkarni SK. Analgesic activity of

acetyl-11-keto-beta-boswellic acid, a 5-lipoxygenase-enzyme
inhibitor. Indian Journal of Pharmacology 2005;37:255-6.

Catalano A, Procopio A. Targeting 5-lipoxygenase signaling

pathways to reverse drug resistance in cancer. Letters in Drug
Design and Discovery 2006;3:459-61.

Huang M-, Badmaev V, Ding Y, Liu Y, Xie J-, Ho C-. Anti-tumor

and anti-carcinogenic activities of triterpenoid, ß-boswellic acid.
BioFactors 2000;13:225-30.

Poeckel D, Werz O. Boswellic acids: Biological actions and

molecular targets. Current Medicinal Chemistry 2006;13:3359-69.

Werz O, Steinhilber D. Pharmacological intervention with 5-

lipoxygenase: New insights and novel compounds. Expert Opinion
on Therapeutic Patents 2005;15:505-19.

Poeckel D, Tausch L, Altmann A, et al. Induction of central

signalling pathways and select functional effects in human
platelets by ß-boswellic acid. British Journal of Pharmacology
2005;146:514-24.

Rubin P, Mollison KW. Pharmacotherapy of diseases mediated by

5-lipoxygenase pathway eicosanoids. Prostaglandins and Other
Lipid Mediators 2007;83:188-97.

C-Reactive Protein (CRP)

http://health.ucsd.edu/news/2002/09_09_Chang.html
Sept. 9, 2002 by Proceedings of the National Academy of Sciences
UCSD Team Identifies Potential Role of CRP In Development of
Atherosclerosis

UCSD researchers pinpoints how CRP attaches itself to oxidized

LDL, the so-called "bad cholesterol" that accumulates in the artery
wall and generates atherosclerotic plaques. LDL is the major
cholesterol carrying particles. When they enter the artery wall
from the circulation, they are believed to be modified by oxidation.
It is this "oxidized LDL" that is thought to be the culprit leading to
inflammation and cholesterol accumulation.

Mi-Kyung Chang, M.D., first author "Our study points out that CRP
is not merely a marker of future cardiovascular events, as most
people believe, but it actually binds to oxidized LDL and apoptotic
or dying cells, giving it a potential role in development or
modulation of atherosclerosis, as well as in other inflammatory
disease,"

http://www.emedicine.com/med/TOPIC446.HTM
Coronary Artery Atherosclerosis Vibhuti N Singh, MD

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http://www.thirdage.com/ebsco/files/21509.html#ref40
L- Arginine

IV Glutathione in Parkinson's Video

http://www.glutathioneexperts.com/benefits-glutathione.html
Benefits of Glutathione, The information in the following video
describes the use of intravenous glutathione in Parkinson's disease
at the Perlmutter Health Center, Naples, Florida with Dr. David
Perlmutter. We see videos of Parkinson's patients before and after
glutathione is administered. You can noticeably see the
improvement in each patient after IV glutathione. The video
should not be used in and of itself to diagnose or treat any specific
medical condition.

http://www.glutathioneexperts.com/parkinsons.html
IV Glutathione Articles - Parkinson's Disease

http://www.glutathioneexperts.com/index.html
Reduced L-glutathione, most commonly called glutathione or GSH,
is the most powerful naturally occurring antioxidant in all human
cells. We have developed this site to deliver information about
this powerful antioxidant to consumers that are considering
Glutathione.

It is a tripeptide composed of the amino acids glutamic acid,

cysteine and glycine. Glutathione is found in all cells in the body,
including the bile, the epithelial lining fluid of the lungs, and—at
much smaller concentrations—in the blood.

The highest concentration of glutathione is found in the liver,

making it critically important in the detoxification and elimination
of free radicals. Accumulation of these dangerous compounds can
result in oxidative stress, which occurs when the generation of
free radicals in the body exceeds the body’s ability to neutralize
and eliminate them. Free radicals are highly reactive compounds
created in the body during normal metabolic functions; they can
also enter the body through the environment.

http://www.drperlmutter.com/
Pioneered use of IV Glutathione for PArkinson's. David Perlmutter,
MD, FACN is a Board-Certified Neurologist and Fellow of the
American College of Nutrition who received his M.D. degree from
the University of Miami School of Medicine where he was awarded
the Leonard G. Rowntree Research Award. After completing
residency training in Neurology, also at the University of Miami,
Dr. Perlmutter entered private practice in Naples, Florida where he
serves as Medical Director of the Perlmutter Health

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