Millions of Cracks – Atherosclerosis Begins Simply

Millions of Cracks –
Atherosclerosis Begins Simply
Copyright Dr. Rath Health Foundation
2013
80’s Cholesterol Clogs Arteries Myth
• FALSE: Cholesterol gums up arteries like debris
in plumbing and is a 1-way, no return process.
• TRUE: Cholesterol is insoluble in water (blood)
and is made soluble by being wrapped with
ApoB and delivered as LDL by the liver. This
does not deposit the way “junk” would in
plumbing and does not “clog” an artery. HDL
is the return vehicle for cholesterol from the
artery back to the liver.
Cholesterol Causes
Heart Disease Myth
• FALSE: All heart patients have abnormally high
LDL cholesterol and elevated LDL is solely
responsible for coronary heart disease.
• TRUE: 50% of heart patients have completely
“normal” LDL levels. Dr. Matthias Rath’s
statement concurs with contemporary clinical
data compiled from 2000-2006.
2000-2006 Clinical Census – 50% of 136,905
Patients Hospitalized with Acute Coronary Syndrome
Had Normal LDL Levels
•
Suggests decreasing threshold of normal LDL even lower than 70mg/dL (cause hypocholesterolemia for
everybody) and raising HDL requirements as a clinical response .
Arterial Size Myth
• FALSE: The smallest arteries (capillaries) “clog”
with cholesterol and atherosclerotic deposits first
and the largest ones “clog” last.
• TRUE: The smallest (nose, ear) are some of the
last to clog, even with capillary leakage. The
largest arteries are the first to suffer
atherosclerosis, and most likely those in the
heart. Lipoproteins do not behave like silt, and
do not clog the smallest conduits first and the
largest last.
Lesion Location Myth
• FALSE: Atherosclerosis occurs randomly across
the entire circulatory system simultaneously.
• TRUE: It occurs primarily in regions of
hemodynamic and mechanical stresses such
as coronary arteries, bifurcations (branching
points), and inside curvatures. Smoking and
diabetes extends atherosclerosis to areas
where it does not occur.
Dietary Cholesterol Myth
• FALSE: Dietary Cholesterol greatly increases
serum cholesterol.
• TRUE: For most people, large increases in
consumption elevate serum cholesterol only
mildly or not at all, all other things being the
same. Some people are hyper absorbers, and
a few others always have high cholesterol
even on a strict vegetarian diet.
“Eating cholesterol has very little impact on the cholesterol
levels in your body.” Is This True??
“This is a fact, not my opinion. Anyone who tells you different is, at best, ignorant of this topic. At
worst, they are a deliberate charlatan. Years ago the Canadian Guidelines removed the limitation of
dietary cholesterol. The rest of the world, especially the United States, needs to catch up.”
– Peter Attia, MD, http://eatingacademy.com/nutrition/the-straight-dope-on-cholesterol-part-vii
•
Increased consumption of cholesterol via eggs in hypercholesterolemic
individuals from 2 eggs per week to 7 eggs did not have increased LDL with a
low fat diet and PUFAs over SFAs. [1] (No increase)
•
Consumption by normolipidemic individuals of 2 eggs/day did not impact LDL
levels. HDL2 actually increased beneficially. [1] (No increase)
•
Consumption of 3 eggs/day by obese men on a carb restricted diet actually
increased HDL while LDL did not change. [1] (No increase)
•
Obesity, acute phase reaction, genetics, and dietary factors OTHER THAN
cholesterol influence large fluctuations in serum cholesterol. [1]
1) Br J Nutr. 2011 Jul;106(1):6-14. doi: 10.1017/S0007114511000237. Epub 2011 Mar 9.
Dietary cholesterol: from physiology to cardiovascular risk.
Before Reaching For the Statins (Again) to Lower
LDL-Particles After Reading That, Remember:
• There is no such thing as a statin deficiency.
• Statins may cause unpleasant side effects, some have
been severe such as muscle damage. (The heart is a
muscle.)
• Statins also cut CoQ10 which is important to prevent
LDL oxidation and important for heart function.
• Statins negatively affect cognitive function, sometimes
having caused transient global amnesia.
• Lowering cholesterol is not the primary mechanism by
which statins benefit the arteries.
Biochemistry Myth
• FALSE: High Dietary Vitamin C is useless and has
nothing to do with arteries or cholesterol.
• TRUE: Vitamin C is essential for arterial integrity
both at the structural and biochemical level.
Arterial cells actively accumulate and store 10x
against what is in the serum. Vitamin C
deficiencies damage arteries and also allow free
radicals to damage lipoprotein cholesterols.
So What Starts Atherosclerosis?
• Millions of microscopic cracks in the artery wall that
are either repaired or compensated for by coagulation
and anti-proteolytic systems over decades. It begins
with “millions of microscopic cracks.”
• If the damage is not repaired or the irritant cleared, the
immune system builds lesions at these sites of chronic
inflammation.
• If the lesion built over decades gets a “crack,”
thrombosis occurs over it and a heart attack or stroke
occurs. It ends with “millions of microscopic cracks.”
Vitamin C Deficiency Causes Millions of Arterial Cracks
From: Maeda et al. “Aortic wall damage in mice unable to synthesize ascorbic acid” PNAS 2000; 97;841846.
Acute scurvy causes endothelial degeneration in humans and mice incapable of synthesizing ascorbic
acid (vitamin C). Long term sub-optimal levels of vitamin C causes subtle cumulative damage through
additional mechanisms including increased free-radical oxidation of LDL and Lp(a) as well as inactivation
of HDL and PON activity.
dfdfdfddf
Vitamin C Deficiency Causes
Lipoprotein Oxidation
From: Retsky et al. “Ascorbic acid oxidation product(s) protect human low density lipoprotein against
atherogenic modification. Anti- rather than prooxidant activity of vitamin C in the presence of transition
metal ions.” J Biol Chem. 1993 Jan 15;268(2):1304-9. (Markings added)
50uM
2013 US Dietary RDA for Vitamin C Is
Below Threshold for LDL Protection
• US RDA is 90mg for males, 75mg for females,
85mg during pregnancy, and 120mg during
lactation.
• For a daily vitamin C intake of 100 mg, the
median plasma concentrations were 54
µmol/L for all participants, 56 µmol/L for
adults, 42 µmol/L for older adults, 53 µmol/L
for non-smokers and 42 µmol/L for smokers. (D
Brubacher et al. Vitamin C concentrations in plasma as a function of intake: a
meta-analysis. Int J Vitam Nutr Research 2000 70: 226-237.)
What Millions of Cracks? Oxidized LDL but not Normal
LDL Causes Gaps Between Arterial Cells.
Extracted From “Oxidized LDL Damages Endothelial Monolayer and Promotes Thrombocyte Adhesion” American Journal of
Hematology 57:341-343 (1998). (Markings added.)
Clot Forms on Arterial Crack
•
Extracted From “Oxidized LDL Damages Endothelial Monolayer and Promotes Thrombocyte Adhesion” American Journal
of Hematology 57:341-343 (1998). Markings added.
Arterial Cracks Cause Arterial Leaks
Evans Blue Albumin Leakage (Orange Color) Occurs Around Dead or Dying Arterial Lining (Endothelial Cells) –
From: Lin et al. “Role of dying endothelial cells in transendothelial macromolecular transport.” Arteriosclerosis.
1990 Sep-Oct;10(5):703-9.
Where Are These Millions of Cracks Most Likely To Form?
What Is So Different Here in the Heart?
(Hemodynamic and Mechanical Stress)
From: Olgac et al.
“Patient-specific threedimensional simulation
of LDL accumulation in a
human left coronary
artery in its healthy and
atherosclerotic states.”
Am J Physiol Heart Circ
Physiol. 2009
Jun;296(6):H1969-82.
How Big Are the Millions of Cracks?
• A leaky junction (crack) is >20nM and
sometimes relatively very large, sometimes
reaching over 1000nM in size.
• A normal pore is ~20nM in diameter.
• A tight junction is ~2nM in diameter.
Albumin,
Water, Small
Molecules
Healthy
EC
Sick
EC
Healthy
EC
Healthy
EC
Healthy
EC
How Big is an LDL or Lp(a) Particle?
20 – 40 nM in Diameter
How big is an HDL Particle?
(From http://eatingacademy.com/nutrition/the-straight-dope-on-cholesterol-part-vii)
Size Entry and Exclusion
• Tight Junction < HDL ~Albumin < Normal Pore <
LDL/Lp(a) < VLDL < Leaky Junction ~Chylomicron
• Lipoprotein(a), LDL, and VLDL simply cannot enter a
healthy artery because of size exclusion by Tight
Junctions and Normal Pores, much like a kitchen sieve.
• Receptor-Vesicular consumption represents 10% of LDL
entry. (Tarbell JM)
• Lipoprotein(a), LDL, and VLDL easily enter a damaged
and/or unhealthy artery with Leaky Junctions.
• Oxidized forms of LDL and Lp(a) variants are harmful to
arterial cells but not native forms. Free radicals
oxidize, antioxidants prevent and reverse oxidation.
Lp(a) is LDL Specific for Injured Tissue
(Such as in Damaged Arteries)
• Lp(a) is LDL with an apo(a) attached to it.
• Lp(a) is masked from LDL receptors by apo(a).
• Apo(a) is specific for lysine residues that
appear with damaged arterial ECM and
collagen.
• LDL does not bind fibrinogen, Lp(a) does.
• Lp(a) is more specific in its targets than LDL.
Lp(a) in the Arterial Lesion
From: Rath M et al. “Detection
and quantification of
lipoprotein(a) in the arterial
wall of 107 coronary bypass
patients.” Arteriosclerosis.
1989 Sep-Oct;9(5):579-92.
Lipoprotein(a) present in healing wounds
around fibrous caps and capillaries
From: Yano et al. “Immunolocalization of lipoprotein(a) in wounded tissues.”
J Histochem Cytochem. 1997 Apr;45(4):559-68.
A = apo(a) in tongue ulcer tissue at first healing stage. (brown)
B = ApoB in same tissue serial section (brown)
Lipoprotein(a) absent in regenerated tissue
after healing
From: Yano et al. “Immunolocalization of lipoprotein(a) in wounded tissues.”
J Histochem Cytochem. 1997 Apr;45(4):559-68.
A = apo(a) staining of colon mucosa in last stage of healing.
B = no apo(a) in normal regenerated area of A.
C = apo(a) in small capillaries of A around which appear inflammatory
immune cells.
Vitamin C Mends Millions of Cracks
• Leaky Junctions are tightened within hours of
Vitamin C administration, not days.
• Not heavy pharmacological doses but orally
achievable doses.
• “Coupled Endothelial NO Synthase” generating
NO (good) and not Superoxide (uncoupled eNOS;
bad) is the mechanism and conjunction between
Vitamin C and endothelial layer health.
• Vitamin C directly activates the critical eNOS
pathway enzymatically as well as indirectly by
antioxidant function for NOS products.
Orally Achievable Levels of Vitamin C Reduce Leaks
Between Arterial Lining Cells Within 2 hours
From: May et al. “Nitric
Oxide mediates tightening
of the endothelial barrier
by ascorbic acid.” Biochem
Biophys Res Commun. 2011
Jan 14;404(2):701-5.
(Markings added in green.)
Arterial Lining
Cells accumulate
Vitamin C to
more than 10
times higher
than what is
present in
blood.
Decreasing Leakiness
Between Cells in “Carpet of
Arterial Lining Cells”
~50uM
Dose Given Arterial Lining Cells
Orally Achievable Levels of Vitamin C Activate Enzyme (eNOS)
Critical for Preventing Cracks Between Arterial Lining Cells
Within Hours
From: Ladurner et al.
“Ascorbate stimulates
endothelial nitric oxide
synthase enzyme
activity by rapid
modulation of its
phosphorylation
status.“ Free Radic Biol
Med. 2012 May
15;52(10):2082-90.
Artificial Drugs Instead of Vitamin C?
Br J Pharmacol. 2011 Sep;164(2):213-23. doi: 10.1111/j.1476-5381.2010.01196.x.
Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling.
Förstermann U, Li H.
(Markings Added in red.)
??
Why is Vitamin C
Absent Here?
Medscape Presentation by NIH Program Concludes – “ A New Dawn of
Treatment of Dyslipidemia”
(Solution = Increase HDL Levels)
(From http://www.medscape.org/viewarticle/467414_3 via Google)
New Dawn = Old News.
• PON1 and antioxidant synergy (good) already
discovered to prevent LDL pathogenicity (bad).
• Vitamin C prevents NO (good) becoming toxic
peroxynitrite (bad) and HDL damage (bad).
• Vitamin C shown to increase HDL functions
(good) and lower LDL damage (good),
complimenting all preexisting ideas of Lp(a)
and/or LDL involvement in cardiovascular
disease.
As of 2013, Antioxidants Known in 1999 to Assist HDL Activity
Antioxid Redox Signal. 1999 Winter;1(4):585-94.
Macrophage foam cell formation during early atherogenesis is determined by the balance between prooxidants and anti-oxidants in arterial cells and blood lipoproteins.
Aviram M.
“Antioxidants can protect LDL from oxidation not only by their binding to the lipoprotein, but also following their accumulation in cells of the
arterial wall. Whereas antioxidants can prevent the formation of Ox-LDL, human serum paraoxonase (PON 1), an HDL-associated esterase that
hydrolyzes organophosphates, can eliminate oxidized LDL (by hydrolysis of its lipid peroxides), which is formed when antioxidant protection is
not sufficient. Ox-LDL, in turn, can inactivate paraoxonase activity. Thus, the combination of antioxidants together with active paraoxonase
decreases the formation of Ox-LDL and preserves PON1's ability to hydrolyze this atherogenic lipoprotein and hence, to attenuate
atherosclerosis.”
PMID: 11233155 [PubMed - indexed for MEDLINE]
Clin Chem Lab Med. 1999 Aug;37(8):777-87.
Oxidized low density lipoprotein: atherogenic and proinflammatory characteristics during macrophage foam
cell formation. An inhibitory role for nutritional antioxidants and serum paraoxonase.
Kaplan M, Aviram M.
“Protection of LDL against oxidation by antioxidants that can act directly on the LDL, or indirectly on the cellular oxidative machinery, or
conversion of Ox-LDL to a non-atherogenic particle by HDL-associated paraoxonase (PON-1), can contribute to attenuation of
atherosclerosis.”
PMID: 10536926 [PubMed - indexed for MEDLINE]
Free Radic Biol Med. 1999 Apr;26(7-8):892-904.
Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by
antioxidants.
Aviram M, Rosenblat M, Billecke S, Erogul J, Sorenson R, Bisgaier CL, Newton RS, La Du B.
“The action of antioxidants and PON on LDL during its oxidation can be of special benefit against atherosclerosis since these agents reduce the
accumulation of Ox-LDL by a dual effect: i.e. prevention of its formation, and removal of Ox-LDL associated oxidized lipids which are
generated during LDL oxidation.”
PMID: 10232833 [PubMed - indexed for MEDLINE]
The Body Can Render Oxidized LDL harmless?
PPAR Res. 2012;2012:616371. doi: 10.1155/2012/616371. Epub 2012 Jan 24.
PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways.
Camps J, García-Heredia A, Rull A, Alonso-Villaverde C, Aragonès G, Beltrán-Debón R, Rodríguez-Gallego E, Joven J.
PON and HDL “Good Cholesterol” (Bad Cholesterol?)
Revert Toxic Ox-LDL Inside the Artery to Harmless LDL
PPAR Res. 2012;2012:616371. doi: 10.1155/2012/616371. Epub 2012 Jan 24.
PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways.
Camps J, García-Heredia A, Rull A, Alonso-Villaverde C, Aragonès G, Beltrán-Debón R, Rodríguez-Gallego E, Joven J.
In Summary
Vitamin C Used in Building The Artery and Maintaining Tight Junctions. Minimizes Free
Radicals Which Damage LDL, HDL, PON, and the Arterial Lining.
Vitamin C Deficiency Causes Endothelial Cell Contraction and Loss of Cell-Cell Junctions,
Exposing and Damaging ECM, Allowing Entry of Repair Molecules and Repair Lipoproteins.
Vitamin C Deficiency Causes Oxidation and Inflammation Which Causes Arterial Cells to Emit
Cytokines .
Cytokine Signaling Attracts the Immune System, Causing Engulfment of Macrophages with
Oxidized Lipids.
The Macrophages Become Dysfunctional Foam Cell Lesions, Causing Further Damage.
Newest Dr. Rath Research Results –
Vitamin C Deficiency Increases LDL-C
and Lowers HDL-C In Vivo.
Vitamin C Helps Prevent “Millions of
Microscopic Cracks” in the Arterial Wall
•
Neglecting arterial requirements for metabolic substrates (Vitamin C, Amino Acids,
etc.) causes arteries to develop “Millions of Cracks” in their barrier linings through
which Lp(a) and LDL enter.
•
Sealing up the artery lining and quenching free radicals nutritionally prevents
normal LDL/Lp(a), acute phase reactants, blood coagulation and immune system
factors from initiating atherosclerotic damage.
•
Current recommended daily allowances of supplementary Vitamin C are still too
low to maintain optimal arterial protection. Additional supplementation of
Vitamin C is a very reasonable suggestion as a preventive measure.
•
Prevention is a superior approach to increased incidence, reactive synthetic drugs
of limited efficacy, risky painful surgery, and escalating medical bills. Exploring
what modern medicine has to offer after heart attack or stroke will be an
expensive, painful, time-consuming adventure with statistically random outcomes.