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Advanced Lipoprotein
Testing using the NMR LipoProfile
Dr. Varveris is currently publishing 'The HAPI Heart
Diet: A Common Sense Approach to a Happy &
Heart-Healthy Way of Life' which contains almost 90 colored
images regarding: 1) lipoprotein physiology &
pathophysiology; 2) insulin resistance & metabolic syndrome; 3)
type 2 diabetes mellitus & atherosclerotic
cardiovascular disease; 4) how different dietary unsaturated fats
affected lipoprotein particle size dynamics; 5) benefit of
NMR-derived direct lipoprotein testing versus all forms of 'lipid'
testing; & 6) mechanisms of action of all major drug classes
(statins, CAI, BAS, Niacin, fibrates, TZDs, fish oils). If you would
like to order a copy of this book, please click
here.
Atherosclerosis
('hardening of the arteries') leads to the most common cause of
premature death (heart attack) and the most common cause of
permanent disability (stroke) in the
United
States as well as the rest
of the industrialized world. Atherosclerosis is caused by the
inappropriate deposition of cholesterol within arterial walls.
Cholesterol is
deposited within arterial walls due to abnormal concentrations of
blood lipoproteins (LDL, HDL, VLDL and IDL which are made
by the liver & chylomicron/chylomicron-remnants
[CM-R] which are produced in the gut) - complex particles
containing cholesterol and triglyceride which exist within the
bloodstream. Since cholesterol is a type of fat, it can
not exist in solution within the water-based bloodstream as
such and must be transported throughout the body by these
lipoprotein particles. LDL, VLDL, IDL and
chylomicron/CM-R particles are 'bad' since, when in excess,
they lead to cholesterol deposition within arterial walls while HDL particles are 'good' since, when in
excess, they lead to cholesterol removal from arterial walls. HDL
particles have potent anti-inflammatory properties, are the most
powerful natural anti-oxidants found within the body
(far surpassing beta-carotene, vitamin C, vitamin E and/or
Selenium) & also have distinct anti-thrombotic as well as
vasodilatory properties (via nitric oxide and
prostacyclin).
Cholesterol is either
produced by the body in the liver or absorbed from the gut in the
small intestine. Some individuals may be natural
'hyper-producers' of cholesterol while others may be natural
'hyper-absorbers.' Many people are obviously both. When the liver is
making a lot of cholesterol and/or the small intestine is absorbing
a lot of cholesterol, there will be high levels of LDL, VLDL,
IDL and chylomicron/CM-R particles in the blood. On the other
hand, when the production of cholesterol in the liver and/or the
absorption of cholesterol in the small intestine is limited, there
will be much lower levels of LDL, VLDL, IDL and
chylomicron/CM-R particles in the blood.
LDL particles
are much more important than VLDL and IDL particles in leading to
cholesterol deposition within arterial walls primarily because
the former are much more numerous within the bloodstream (due
to a half-life of 2-3 days in LDL particles versus 6-8 hours in
VLDL particles) - approximately 10 to 100 LDL particles
exist for every single VLDL/IDL particle. Small
LDL particles seem to be more aggressive than large LDL
particles since they are more likely to interact with the
endothelium, penetrate it and become
entrapped within the intima & less likely to be
cleared from the bloodstream by the liver and various endocrine
organs (adrenal glands, gonads). The increased cardiovascular risk
of small LDL particles (up to 3 times that of large LDL particles)
only seems to matter when the total concentration of LDL particles
is elevated.
Large HDL particles are overall possibly more
protective than small HDL particles. In the Framingham Offspring
Study, high HDL-cholesterol (HDL-C) levels (where large HDL
particles predominated) were correlated with low CV-disease risk
whereas low HDL-C levels (where small HDL particles predominated)
were correlated with high CV-disease risk. Exceptions to this rule
include individuals with ApoA1-Milano who typically have HDL-C <
20 mg/dL (with 'super-charged' abnormal small HDL particles) but
very low CV-disease risk and individuals with genetic CETP
inhibition disorders who typically have HDL-C > 70 mg/dL (with
'impotent' large HDL particles) but very high CV-disease risk
(another rare genetic example of high HDL-C with high CV-disease
risk is SR-B1 deficiency where the hepatic receptors for HDL are
missing). Large HDL particles usually have more ApoA1 (an
important protein on the particle surface involved with the
benefical physiologic effects of the HDL particle) than
small HDL particles (3-4 ApoA1 per large HDL
particle compared to 1-2 ApoA1 per small HDL particle). Since
ApoA1 levels seem to be directly correlated with the
anti-atherogenic effects of HDL particles (anti-inflammatory,
anti-oxidant, anti-thrombotic, vasodilatory), this may be
one main explanation for why large HDL particles are
possibly more protective than small HDL particles. Small HDL
particles are definitely important, however, as the ApoA1 on small
HDL particles is more easily recognized by liver receptors than the
ApoA1 on large HDL particles (better allowing 'direct' reverse
cholesterol transport of cholesterol from arterial walls back to the
liver for reprocessing). On the contrary, large HDL particles are
also capable of transferring their extra core cholesterol
stores to LDL, VLDL and IDL particles (uniquely allowing 'indirect'
reverse cholesterol transport [CETP-mediated] - a process thought to
be equally as important as 'direct' reverse cholesterol
transport in returning cholesterol from arterial walls back to the
liver for reprocessing). Another possible problem with small HDL
particles is their tendency (due to their extremely small
size and increased density) to be filtered through the
glomerulus and thus excreted from the body by the kidney.
Large VLDL particles are more aggressive than small VLDL
particles mainly because: 1) they lead to the direct formation of
IDL and small LDL particles; & 2) they lead to the indirect
formation of small LDL and small HDL particles. They are
also less likely to be cleared from the bloodstream by the liver and
various endocrine organs. Large VLDL particles are of
the same overall size as highly aggressive exogenous
lipoproteins known as chylomicron-remnants (CM-R as mentioned above)
created in the lining of the small intestine due to dietary intake
of cholesterol, saturated fat, alcohol and refined
carbohydrates (sugars & starches). CM-R
particles are thus not typically measured in 'fasting' blood
specimens. IDL particles may also be quite atherogenic but are
rarely found in the bloostream other than for a few hours in the
postprandial state as well as in certain insulin-resistant patients.
The smaller (< 70 nm in diameter) beta-lipoproteins (LDL, IDL,
small VLDL as well as some CM-R) are capable of penetrating the
arterial wall and leading to cholesterol deposition and thus
atherosclerosis.
It has been understood
since the mid-1960s that direct measurement of the various
lipoprotein concentrations as well as their average sizes was
crucial to recognize the true underlying risk of atherosclerosis as
well as to manage this condition most effectively. However, until
very recently measuring lipoproteins was not technically feasible,
so physicians became accustomed to measuring 'lipids' (cholesterol
and triglyceride) - not because 'lipids' were better than
lipoproteins at predicting risk but because 'lipids' were
'better than nothing.' Think of 'lipids' as 'shadow markers'
of lipoproteins - as such, they can significantly over- and/or
under-estimate the actual concentration of lipoproteins and will
never provide detailed information on the various lipoprotein
subpopulations. LDL-cholesterol (LDL-C, the amount of
total blood cholesterol carried by an entire population of LDL
particles) is the 'shadow marker' of large, CE-enriched LDL
particles. HDL-C is the 'shadow marker' of large, CE-enriched HDL
particles and indirectly suggests LDL particle size. Fasting
TG are the 'shadow marker' of large, TG-enriched VLDL particles
and indirectly suggest LDL particle size. The main
problem with using 'lipids' to predict risk for later
atherosclerotic cardiovascular disease is that they are
not very good at doing it - elevated levels of LDL-C only account for about 25% of premature heart
attacks while abnormalities of total cholesterol, LDL-C, HDL-C
and/or triglycerides (TG) only explain about 40% of premature
heart attacks. In fact, 80% of individuals in the landmark
Framingham Heart Study who later developed coronary heart disease
had the same LDL-C levels as did those individuals who NEVER
developed coronary heart disease.
In the late-1990s,
thanks to MRI technology, it finally became possible to directly
measure lipoprotein concentrations as well as their average sizes
with a diagnostic blood test known as the NMR LipoProfile provided
by a company called LipoScience headquartered in Raleigh,
North Carolina. This test gives the actual number of LDL particles
(LDL-P) and in addition provides the amount of protective HDL
particles as well as harmful VLDL particles. The NMR
LipoProfile is at least 99% accurate. It has been
determined in multiple clinical studies that LDL-P is more
predictive of future CHD risk than any other lipid-based parameter.
The NMR LipoProfile has recently been
updated with all lipoprotein subclass levels now presented in actual
particle concentrations.
The vast majority
of US physicians do not currently measure lipoproteins and continue
to measure 'lipids.' The sad truth is that most doctors do not even
manage 'lipids' effectively. For example, recent studies have shown
that less than 12-18% of individuals with coronary heart disease
managed by US physicians have their LDL-C lowered to less than
100 mg/dL, which is considered the current goal of treatment
per National Cholesterol
Education Panel guidelines
published in 2001 (although an update published in July 2004
mentions an optional target LDL-C less than 70 mg/dL in
certain high-risk patients).
The
reason that no measurement of 'lipids' can reasonably estimate the
actual concentration of lipoproteins is that all lipoproteins come
in different sizes and contain different ratios of cholesterol to
triglyceride (ranging from 2:1 up to 12:1 with 5-6:1 being
considered normal in LDL particles - as a comparison,
VLDL particles typically have a 1:5 CE/TG ratio [when TG levels are
< 70-100 mg/dL but may be 1:10-20 when TG levels are >>
100-130 mg/dL] and IDL particles usually have a 1:1 ratio). These
differences are quite common and not at all predictable. For
example, 30% of low-risk individuals (healthy people in their
20's) have abnormalities of lipoprotein size and/or
cholesterol/triglyceride content that lead to LDL-C significantly
underestimating their actual LDL-P while 20% have
abnormalities that lead to LDL-C significantly overestimating their
LDL-P. 80% of high-risk individuals (diabetics, patients with
metabolic syndrome) have LDL-C levels that significantly
underestimate their actual LDL-P. One individual whose LDL
particles are small can have 70% more particles than another whose
particles are normal-sized (large), even though both individuals
have the exact same LDL-C. And, one individual whose LDL particles
are cholesterol-depleted can have 40% more particles than another
whose particles are normal in their core lipid composition (CE:TG of
5-6:1), even though both individuals have the exact same LDL-C.. In fact, one individual whose LDL
particles are very small and very cholesterol-depleted can actually
have 300% more particles than another whose particles
are very large & very cholesterol-enriched, even though
both individuals have the exact same LDL-C. A clue
for LDL particles being smaller than normal and
thus having less CE per particle than normal is HDL-C <
60-65 mg/dL whereas a clue for LDL particles having more TG
per particle & thus less CE per particle is TG > 70-100
mg/dL. Thus, 'lipids' will commonly
provide false or misleading information to the physician potentially
leading to inappropriate therapeutic decisions.
At the
Heart Attack Prevention Institute, Dr. Varveris routinely employs
advanced lipoprotein testing with the NMR LipoProfile in order to
recognize and thus manage any patient’s potential underlying
lipoprotein disorder in the most optimal manner possible. At this
point, Medicare (in all states), Medicaid (in certain states)
and many private medical insurance plans (but not all) pay for
the NMR LipoProfile. Dr. Varveris has found that
most private insurers will reimburse for the NMR
LipoProfile if the benefits of such testing are explicitly expressed
by the clinician to said insurer (see Image 2
below).
Image 1: Patient instruction form on how to
handle 'flushing'
Image 2:
Form to assist in private insurer NMR
reimbursement
Call (239)
261-3988 today for an appointment at the Heart Attack
Prevention Institute (HAPI) with Dr.
Varveris. |
