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Part I. Cardiovascular Disease and
Lipoproteins
Lipoprotein particles
normally serve as transport vehicles within the human bloodstream
for: 1) cholesterol (needed by all cells for membrane synthesis as
well as by the various endocrine tissues for hormone production); 2)
TG (used by the body for energy production as well as energy
storage); 3) phospholipid (also needed by cells for membrane
synthesis); 4) vitamin E (a powerful antioxidant) and; 5) coenzyme
Q10 (CoQ10 – also a powerful antioxidant and used by the tissues of
the body for energy production). The surface proteins allow
lipoprotein particles to interact with various receptors, proteins
and enzymes within our body.
Beta-lipoproteins can
further be broken down into exogenous particles (made by the gut –
chylomicron particles and chylomicron remnant [CM-R] particles) and
endogenous particles (made by the liver – VLDL or very low density
lipoprotein particles, IDL or intermediate density lipoprotein
particles and LDL or low density lipoprotein particles). HDL
particles are made by both the gut and the liver.
In the physiologic state
(when whole body cholesterol levels are relatively low and
appropriate), HDL particles primarily serve to provide cholesterol
to the hormone-producing tissues of the body that require it while
the various β-lipoproteins primarily serve to transport TG for
energy production and vitamin E/CoQ10 for their antioxidant potency.
By the way, the typical, healthy, low-risk 150-pound man would have
about 3000 QUADRILLION or three quintillion LDL particles
circulating in his bloodstream.
However, in the
pathologic state (when whole body cholesterol levels are relatively
high), increased levels of β-lipoproteins (those smaller than 70 nm
in diameter) are ‘"bad" since they may lead to cholesterol
deposition within arterial walls while sufficient levels of
functional HDL particles are "good" since they may lead to
cholesterol removal from arterial walls by transporting that excess
peripheral cholesterol back to the liver for excretion from the
body.
Under physiologic
conditions (as above), the liver produces a relatively low number of
small VLDL particles. 1) These small VLDL particles are secreted by
the liver into the bloodstream. 2) They are first converted into IDL
particles. 3) The resultant IDL particles are then converted into
large LDL particles. 4) The relatively low number of large LDL
particles can be recognized by certain receptors on liver cells and
removed from the bloodstream to complete a "benign" cholesterol
circuit. It is termed benign since the low numbers of large LDL
particles are unlikely to deposit cholesterol within arterial
walls.
Under pathologic
conditions (as above), the liver produces a relatively increased
number of large VLDL particles. 1) These large VLDL particles have
much more triglyceride in their cores than normal. 2) The large VLDL
particles can interact with large LDL particles to convert the
latter into small LDL particles. 3) The large VLDL particles are
also themselves converted into small LDL particles. 4) As mentioned
above, these small LDL particles seem very likely (if in increased
number) to penetrate and become entrapped within arterial walls. 5)
The small LDL particles are very poorly recognized by hepatic
receptors. 6) The entrapped small LDL particles are modified by an
oxidative process (the best marker for this being elevated blood
levels of lipoprotein-associated phospholipase A2
[Lp-PLA2 – see below]). 7) This oxidative modification
leads to the synthesis and release of various inflammatory
substances into the bloodstream. 8) Lp-PLA2 can
(theoretically) itself lead to small LDL particles. 9) Certain white
blood cells (called monocytes) are attracted to the localized
inflammation, penetrate the arterial wall, are converted into
activated macrophages and engulf the modified small LDL particles to
complete a "malignant" cholesterol circuit. It is termed malignant
since the activated macrophages (induced by high numbers of
entrapped small LDL particles) lead to cholesterol build-up within
arterial walls (which becomes toxic to those macrophages) and
eventually CV disease.
When the concentration
of "fat" (cholesterol and/or triglyceride) within the liver is
increased (due to genetic as well as lifestyle factors), the liver
responds by increasing its production of β-lipoproteins as well as
decreasing its removal of β-lipoproteins from the bloodstream. If
that fat is primarily cholesterol (from genetics more so than
lifestyle), the resultant increased β-lipoproteins are mainly large
LDL particles. On the other hand, if the fat is primarily
triglyceride (from lifestyle more so than genetics), the resultant
increased β-lipoproteins are mainly small LDL particles.
1) Sugar and starch
enter the upper small intestine from ingested carbohydrate-rich
foods. 2) Free cholesterol (FC) also enters the upper small
intestine (25% from ingested animal products and 75% from secretions
of the bile duct system). 3) Various free fatty acids (FFA) enter
the upper small intestine from ingested fatty foods. 4) FC is incorporated into
particles know as micelles. 5) Unabsorbed bile acids can be found in
the last portion of the small intestine. 6) Sugar and starch are
easily absorbed in the upper small intestine. 7) FFA can be absorbed
in the upper small intestine. 8) FC within the micelles is also
absorbed in the upper small intestine. 9) Bile acids are reabsorbed
in the last portion of the small intestine. 10) FFA can eventually
be transferred to the hepatocyte (liver cell). 11) FFA as well as sugar and
starch are converted into TG. 12) In the setting of elevated hepatic
TG levels, large VLDL particles are created and secreted into the
bloodstream. 13) As described above, these large VLDL particles are
stepwise converted into small LDL particles. 14) FC absorbed via
micelles in the upper small intestine and bile acids reabsorbed in
the last portion of the small intestine are eventually transferred
to the hepatocyte. 15) This FC can be converted into cholesteryl
ester (CE). 16) In the setting of elevated hepatic CE levels, small
VLDL particles are created and secreted into the bloodstream. 17) As
mentioned above, these small VLDL particles are stepwise converted
into large LDL particles. 18) Hepatic LDL receptors (LDLr) recognize
large but not small LDL particles to remove the former from the
bloodstream. 19) Mechanisms exist to convert large VLDL particles
into small VLDL particles. 20) Different mechanisms exist to convert
large LDL particles into small LDL
particles.
Part II.
Pre-Diabetes
The current medical
classification of MS/IR includes five clinical parameters: 1)
hypertension (HTN); 2) abdominal obesity; 3) elevated serum TG
levels; 4) low serum HDL-C levels; and 5) high serum FBG levels. The
diagnosis of MS/IR necessitates three or more of these five clinical
parameters. The abnormal lipid "shadow" values suggest elevated
levels of large VLDL particles, low levels of large HDL particles
and elevated levels of small LDL particles.
Abnormal serum
lipoprotein concentrations of the type described above can be
detected in the bloodstream of those individuals destined to become
type 2 diabetics up to 20-25 years before the serum FBG begins to
rise. Dyslipoproteinemia is the precursor to CV disease with heart
attacks and/or strokes occurring perhaps years prior to any
elevation of FBG and diagnosis of type II DM.
Part
III. Advanced
Testing
The NMR LipoProfile
directly measures lipoprotein particle number in all major
lipoprotein subclasses but focuses primarily on total LDL particle
number (LDL-P) and small LDL-P. NMR-derived total LDL-P and small
LDL-P are the ONLY lipid-related parameters of CV risk that
have consistently been shown to remain significant and
independent in predicting such risk when modified for other
associated clinical parameters (family history, smoking, obesity,
blood pressure, FBG, lipids, ApoB, C-reactive protein
[CRP]).
If you have no access to
NMR-derived lipoprotein testing, you could guess the likelihood of
large versus small LDL particles based upon HDL-C and TG levels. In
the "average" person, when HDL-C levels are < 60 mg/dL and/or
when TG are > 100 mg/dL, the presence of small LDL particles is
likely (when HDL-C < 40 mg/dL and/or TG > 150 mg/dL, the
predominance of small LDL particles is likely). On the contrary,
when HDL-C levels are ≥
60 mg/dL AND when TG levels are ≤ 100 mg/dL in the "average"
person, the absence of small LDL particles with predominance of
large LDL particles is likely. The problem is, no one is an average
person – we are all individuals.
I
have seen many individual patients with HDL-C levels in the 30s who
DID NOT have small LDL particles whereas I have seen many
other individuals with HDL-C levels in the 70s who did not have
large LDL particles. TG levels represent a force driving the
conversion of large into small LDL particles and HDL-C levels
represent a separate force blocking this conversion. These lipid
values are static measurements and thus can not give reliable
information about the "functionality" of the related processes in
any given individual (i.e. one person can have TG levels much less
than 100 mg/dL which are ‘"hyper"-functional and driving the
formation of small LDL particles while another can have HDL-C levels
much greater than 60 mg/dL that are "hypo"-functional and not
blocking the formation of small LDL particles).
Another
big problem with guessing based upon HDL-C and TG levels is, even if
you’re right about the presence or absence of large versus small LDL
particles, you won’t know how many of them actually exist. And you
must have this specific kind of information in order to make (from
the physician’s perspective) or follow (from the patient’s
perspective) any specific lifestyle and/or pharmacologic
recommendations. So there’s really no way around it – you need the
kind of detailed information that is ONLY provided by
NMR-derived lipoprotein testing.
Medicare (nationally),
Medicaid (in certain states) and many private medical insurers now
cover the NMR LipoProfile. Several private insurers still refuse to
do so, obviously as a method to enhance their "bottom line’" but at
the expense of their enrollees’ health. On the bottom of this page
is a copy of the form letter I use at my own medical practice to
hopefully convince such uninformed, unwise and basically unethical
medical insurers to cover such testing.
Part
IV. More About the NMR LipoProfile by
LipoScience
Since excessive
cholesterol deposition is the main pathologic process leading to the
formation and destabilization of plaques (focal accumulations of
cholesterol) within arterial walls and it is the rupture of these
plaques that causes almost ALL causes of heart attack and
stroke, knowing the amount and type of lipoprotein particles
transporting cholesterol in the bloodstream is
crucial.
What the VAST
majority of physicians (even those who specialize in metabolic
disorders [endocrinologists] as well as cardiovascular disorders
[cardiologists]) currently measure is NOT lipoprotein
concentrations but rather "lipids" (cholesterol and TG measurements)
which are nothing more than "shadow" or surrogate markers for
lipoproteins. This concept has been well understood in laboratory
science since the 1960s but, due to the fact that lipoprotein
testing has been impossible to perform (until recently – see below),
lipid measurement has been utilized for the purpose of estimating
lipoprotein concentrations.
Imagine there was
patient who "really needed to know’" whether or not they had a brain
tumor OR they knew they had a brain tumor but they really
needed to know if it was responding appropriately to treatment. An
x-ray of the skull ("shadows") could be ordered or an MRI of the
brain. Which would be the correct choice? The answer is obvious: the
MRI of the brain (if someone actually cared about the patient). This
is what we’re talking about, but it’s an MRI of the blood – the NMR
LipoProfile (www.liposcience.com).
Why does NMR/MRI blood
testing work so well? It just happens to be a fact (like gravity
causing a pen to fall when released or a prism breaking sunlight
into ‘ROYGBIV’) that lipoproteins of different sizes have naturally
distinguishable signals in a magnetic field. Since different
lipoproteins can be separated by their size, these different signals
represent different lipoprotein subclasses. The signal amplitudes
represent the concentrations of those particular subclasses. Since
NMR is a lipoprotein rather than lipid test, differences in core
lipid composition will not "fool" it – LDL particles of a specific
concentration with cholesterol-enriched cores will have the
EXACT same signal as those with cholesterol-depleted
cores.
NMR-derived total LDL
particle concentration (LDL-P) has been demonstrated to be FAR
SUPERIOR to any other lipid-related parameter (LDL particle
size, TC:HDL-C, direct LDL-C, ApoB) in terms of predicting future CV
risk. Respected clinical authorities have recognized that
NMR-derived lipoprotein data is CLEARLY superior to lipids in
predicting future related CV
risk.
Let’s say there was this
doctor who used TC levels and nothing more than that to diagnose and
treat "cholesterol" problems in the current day. What do you think
his peers would think of him? They’d think he’s an idiot, that’s
what they’d think. Why? Because something better has come along
(LDL-C, HDL-C, TG) that better predicts CV risk and makes more
sense. Well, guess what? Something WAY better has come along
(NMR-derived total LDL-P) that DRAMATICALLY predicts CV risk
better and makes WAY more sense. Lipid testing is now an
anachronism.
Again, imagine there
were two different patients with similar shoulder pain complaints.
X-rays of their shoulders were similar, showing mild arthritis.
Similar treatment was prescribed to both patients. One returns a few
weeks later with resolved symptoms but the other returns with
persistent pain. The treating physician concludes this second
patient might have a higher risk problem and orders an MRI. The MRI
shows a completely torn rotator cuff tendon. This is not apparent on
the x-ray. Why not? Is the x-ray wrong? Is the MRI wrong? No, it’s
just that the x-ray COULDN’T SEE the real problem while the
MRI could. Well, lipids commonly can’t see the real problem either
and symptoms might not occur until the time of a catastrophe (heart
attack, stroke, sudden death). So the patient and doctor can’t wait
for symptoms. If someone wants to know what their lipids are, it’s
only because they REALLY (whether they recognize this or not)
want to what their lipoproteins are. So let’s check them – with the
NMR LipoProfile.
At the Heart Attack
Prevention Institute (HAPI) in Naples, I use NMR-derived
lipoprotein testing first to help determine an individual patient’s
future CV risk from the "lipid" perspective. If the results of such
testing demonstrate the total LDL-P to be elevated, the patient and
I will make the appropriate therapeutic choices in order to reduce
this risk. These interventions ALWAYS involve appropriate
lifestyle changes (diet, exercise, attaining/maintaining optimal
body weight, smoking cessation) and may, depending on the individual
patient, also involve various pharmaceuticals.
Part
V. More About CIMT Testing by
CardioRisk
When cholesterol is deposited by excess LDL particles into
arterial walls, the development of plaque may occur as an
inflammatory response by the body against this pathologic
deposition. Two basic patterns of inflammation may ensue: 1)
significant fibrosis (with high numbers of smooth muscle cells
[SMCs]), minimal persistent inflammatory cells in the intima (the
innermost section of the arterial wall) and low numbers of quiescent
foam cells in the plaque’s lipid core; and/or 2) minimal fibrosis
(with low numbers of SMCs), significant intimal inflammatory cells
and high numbers of activated macrophages in the lipid core. The
first pattern is considered "stable" since, if the endothelium (the
inner "skin" of the arterial wall having direct contact with
circulating blood) is "torn" by various stressors, there will be no
interaction between bloodstream and lipid core, no resultant clot
formation (thrombosis) and thus no clinical event (heart attack,
stroke). However, if the second pattern exists and the endothelium
is ruptured, the likelihood of interaction between lipid core and
bloodstream is relatively high with increased chance of resultant
clinical event (thrombosis with/without embolization) and thus this
pattern is considered "unstable."
Think of an arterial plaque as a volcano. A volcano goes
through a lifecycle where magma ascends from the earth’s core
(cholesterol deposition within arterial walls progresses) and the
volcano arises from the surrounding landscape (plaque formation
occurs). The likelihood of an eruption (heart attack, stroke, sudden
death, amputation, ruptured aneurysm) increases during this portion
of the volcano’s lifecycle. However, the volcano also has another
portion of its lifecycle, where magma descends back to the earth’s
core (cholesterol removal from arterial walls [RCT] ensues), the
volcano many times forms a crater relative to the surrounding
landscape (plaque regression occurs) and the likelihood of eruption
is negligible.
Think again of the arterial wall as a bucket and cholesterol
deposition as water within that bucket. If the concentration of LDL
particles is lowered (measuring cup adding water to the bucket is
reduced in size) and/or the concentration of functional HDL
particles is enhanced (measuring cup removing water is increased in
size), the bucket will surely empty. If the physician and patient
team KNEW that the bucket was emptying (the amount of
cholesterol within arterial walls was reducing) and/or that any
detectable volcanoes were going into their quiescent phase (unstable
plaques were becoming stable), that team could pat themselves on the
back – knowing that their joint efforts had "really paid off" since
the likelihood of future CV events was now seemingly nil. How can
such information be garnered?
At HAPI, I use carotid intima-media thickness (CIMT) testing
by a company called CardioRisk headquartered in Salt Lake City, UT
(www.cardiorisk.us] for this purpose. CIMT testing utilizes
specialized carotid ultrasonography probes combined with specialized
computer software to determine the amount of cholesterol deposition
and quantify as well as qualify any visualized plaque(s) within a 30
mm segment of the left and right common carotid arteries (CCAs)
where they split into the external carotid arteries (ECAs –
supplying blood to the tissues of the face and scalp) and internal
carotid arteries (ICAs – supplying blood to the anterior and
superior portions of the brain – see Image 58 below). CardioRisk
employs highly trained and qualified technicians and physicians to
ensure accuracy and reproducibility of their CIMT findings. Thus
CIMT testing by CardioRisk provides quick (taking just 10 minutes),
safe (non-invasive) and reliable information on the state of any
patient’s overall CV system as well as the extent of visualized
atherosclerotic plaques. Various clinical trials have demonstrated
that CIMT progression (bucket fills up and/or magma ascends) is
directly correlated with increased likelihood of future CV
events.
At HAPI, I use CIMT testing first to help individualize any
patient’s future CV risk. Such testing, if it demonstrates that the
patient’s CIMT is much greater than an "average" individual of the
patient’s age, may force the patient and myself to intensify our
therapeutic plan since the patient’s CV system appears much "sicker"
than we previously thought. However, if said testing demonstrates
that the patient’s CIMT is actually much lower than an "average"
individual of the patient’s age, this information may, on the
contrary, allow the patient and myself to "back away" from any
planned aggressive therapeutic choices since the patient’s CV system
appears much healthier than we thought.
I
also use CIMT testing to follow any patient’s response to therapy in
order to document and thus PROVE regression of CV disease
(bucket empties and magma descends). At HAPI, our goal is
ALWAYS regression since, as was mentioned in The
HAPI Heart Diet and Cookbook's introduction, if you’re going to
do something important, DO IT RIGHT! I will repeat CIMT
testing every 12 to 24 months or so and if CIMT regression is not
demonstrated, will recommend intensification of therapy to the
patient in no uncertain
terms .
Part
VI. More About Lp-PLA2Testing
by
diaDexus
As mentioned in the
previous section, one major differentiator between unstable and
stable plaques is the presence of significant inflammation in the
former versus an absence of the same in the latter. Much of this
inflammation is due to the penetration, entrapment and subsequent
oxidation of LDL particles within the arterial wall intima.
When activated
macrophages engulf and "digest" an oxidized LDL particle and
metamorphosize themselves into foam cells (the hallmark of
atherosclerotic plaque), they synthesize and secrete an inflammatory
chemical known as Lp-PLA2 (lipoprotein-associated
phospholipase A2) which is released into the bloodstream. This
substance then attaches primarily to LDL particles, especially the
small ones.
As mentioned above,
elevated concentrations of total LDL-P drive LDL particles into the
arterial wall intima. LDL particles containing Lp-PLA2,
when oxidized in the intima, lead to the release of various
cytokines and adhesion molecules which attract monocytes and assist
them in penetrating the endothelium. These monocytes are themselves
transformed into activated macrophages which become foam cells after
interacting with more oxidized LDL
particles.
The more
Lp-PLA2 found in the bloodstream, the more penetration
and oxidation of LDL particles within arterial walls is occurring
and the more resultant unstable plaques are developing. Thus
bloodstream measurement of Lp-PLA2 can assist in the
clinical determination of the presence and extent of unstable plaque
burden in any given individual.
At HAPI, I use
Lp-PLA2 testing by diaDexus (www.diadexus.com) to assist in the
determination of future CV risk for any given individual patient.
Such testing, if it demonstrates a significantly elevated
Lp-PLA2 level, may encourage the patient and myself to
intensify our therapeutic plan since the likelihood of unstable
plaque at that point in time appears relatively high. However, if
said testing demonstrates the patient’s Lp-PLA2 to be
quite low, this information may, on the contrary, allow the patient
and myself to "back away" from any planned aggressive therapeutic
choices since the likelihood of unstable plaque at that point in
time appears relatively low.
I
also use Lp-PLA2 testing to help individualize any
patient’s response to lipid-modifying therapy. If total LDL-P is
reduced (with pharmacologic and/or non-pharmacologic modalities) to
a level which would appear optimal for an "average" patient in that
clinical circumstance but the Lp-PLA2 level remains
elevated, this suggests that particular total LDL-P goal may not be
"low enough" for that particular patient and I will thus recommend
intensification of therapy to the patient in no uncertain terms. If
Lp-PLA2 thereafter drops, this probably signifies the determination
of the particular total LDL-P goal for that individual patient. I
use the same concept to help determine optimal individual BP
and HgbA1C levels as well as optimal anti-platelet therapeutic
aggressiveness. At HAPI, I repeat Lp-PLA2 testing
somewhere between every three to 12
months .
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