Advanced CVD Monitoring:
Total Cholesterol - measurement of cholesterol circulating within your bloodstream.
Can be confusing in that high levels are not always bad and low levels are not always
good. Usually lower cholesterol levels are better in normal circumstance.
LDL-C - this represents the lipid that ultimately leads to plaque formation within blood
vessels. The “C” on LDL-C stands for “cholesterol.” LDL-C was the original way of
evaluating the “bad fat” within a blood vessel in a standard lipid profile. It has become
apparent that measuring LDL-C is flawed in a large part of the U.S. population that is
insulin resistant. When a patient becomes insulin resistant, the LDL-C trades off
“C-Cholesterol” for “triglycerides” making the LDL-C smaller and denser. Since it is the
“C-Cholesterol” within the LDL-C being measured, then the LDL-C measurement tends
to decline as the patient becomes more insulin resistant leading a clinician and the
patient to think everything is fine when it is not! Thus advanced cardiovascular panels
tend to report LDL-P and/or Apo B to more accurately report the level of plaque-forming
bad fat.
HDL-C - this lipid is more confusing to explain, as HDL-C was falsely reported as the
“the good fat” historically and that is not always accurate. We now know that when
HDL-C is “functional” it is then useful at helping with removal of plaque from blood
vessel walls. High levels of HDL-C do not always confer high levels of functional HDL-C
and low levels of HDL-C do not always confer low levels of functional HDL-C. It is useful
to know when the HDL-C is < 50 mg/dl as this usually indicates that insulin resistance is
present.
Triglycerides - Circulating fat that is usually elevated when a person is overeating their
carbohydrate tolerance and/or insulin resistance is present. This test is best evaluated
in a fasting patient to fully understand the severity of the insulin resistance and excess
carbohydrate intake taking place in a patient. When triglycerides are elevated, usually
VLDL, the lipid that ultimately converts to LDL-C, is elevated. The elevated triglyceride
level also correlates with elevated circulating inflammation.
LDL-P - a measurement of the number of “particles” of LDL present within the
circulation. The LDL-P measurement is an advanced cardiovascular measurement of
LDL that is accurately depicting the amount of circulating “bad fat” in a way that is not
made inaccurate by insulin resistance (see LDL-C comments). The LDL-P
measurement helps clinicians make accurate clinical assessments and this means you
get good medical advice based on a more accurate measurement of LDL levels.
Apo B - another advanced cardiovascular measurement of LDL that is a more accurate
method of assessing the amount of LDL within the bloodstream that is not made
inaccurate by insulin resistance. “Apolipoproteins” are a protein tag that sit on a lipid
molecule that allows another way of measuring the lipid that the apolipoprotein is
attached to. Apolipoprotein B is the apolipoprotein that sits on LDL. Since there is 1
apolipoprotein B on each 1 LDL molecule, measuring the Apo B is simply another way
of counting LDL particles. Some clinicians prefer Apo B measurements and some
clinicians prefer LDL-P measurements to accurately assess LDL within the bloodstream.
At True Health Diagnostics Laboratory, we supply your clinician both Apo B and LDL-P
results to maximize the chance that you get the best possible clinical outcome!
sdLDL-C - the “sd” stands for “small dense” and this measures the amount of LDL-C
that is produced by the liver in a smaller, denser form of LDL in response to overeating
carbohydrates. This smaller, more dense form of LDL, is usually considered more likely
to cause plaque than the larger, more fluffy LDL-C. sdLDL-C also associates with an
inflammatory response from the liver, pancreas, and intraabdominal fat cells that lasts
for approximately 4 days after each episode of excessive carbohydrate intake.
Clinicians can use this number to assess how well you are doing with carbohydrate
intake, which is vital to your good clinical outcome. Overeating carbohydrates is one of
the most common reasons people have cardiovascular disease!
Apo A1 - this is the apolipoprotein that is found on HDL-P in a 1:1 ratio. Thus
measuring the amount of Apo A1 is another way of measuring the amount of circulating
HDL in the bloodstream. Having an accurate means of assessing when you are insulin
resistant is vital to your good medical outcome. Low levels of Apo A1 confer that you
have lipid changes that correlate with insulin resistance, and this is rather dangerous if
left untreated.
HDL Size - measuring the size of HDL is another way of assessing if a patient is insulin
resistant. The smaller the HDL-C size is, the more insulin resistance is present. The
HDL-C tends to exchange cholesterol for triglycerides as a person is becoming more
insulin resistance, making the HDL-C size become smaller as the insulin resistance is
worsening. When HDL size gets small enough, it will be filtered out through the kidneys
making the HDL leave the bloodstream through the urine. The HDL-P levels decline with
prolonged insulin resistance due to the HDL size shrinking significantly.
HDL-P - the measurement of the “particles” of HDL within the bloodstream. When
HDL-P counts are low, this confers another lipid change that correlates with insulin
resistance. The earlier your clinician can detect insulin resistance within your body, the
earlier you can get help addressing the insulin resistance. The longer insulin resistance
persists within your body, the more likely chance of you developing cardiovascular
disease state problems.
Patient Lab Information
Apo B:Apo A1 Ratio - this ratio looks at the amount of Apo B (apolipoprotein found on
bad fat) that is present compared to the amount of Apo A1 (apolipoprotein found on
good fat) present in your blood. You are more likely to be insulin resistant as the Apo
B:Apo A1 Ratio increases to high levels.
There are eight major disease states that create inflammation responses entering
the bloodstream. The insulin resistance of Diabetes Type 2 and Pre-Diabetes Type
2, is felt to be one of the most common inflammatory disease states occurring in
patients developing cardiovascular disease. By studying more advanced lipid
analysis like LDL-P and Apo B, we are helping your physician see what your lipid
status is regardless of how insulin resistant you are. With the sdLDL-C we are
helping you see how often you are overeating carbohydrates, as carbohydrates
are “poison” to the patient who is insulin resistant. The Apo A1, HDL-P, HDL Size,
and Apo B:Apo A1 ratio are all lipid measurements that help you assess early on
when you are becoming insulin resistant. This is one of the many reasons you
benefit greatly from having advanced cardiovascular biomarker testing done!
Stress and Inflammation:
hs-CRP - a measurement of generalized inflammation buildup within the circulation.
There are disease states that release inflammation into the bloodstream and there are
things you can do with proper diet, exercise, and medication that will remove
inflammation. The hs-CRP reflects the summation of how much disease state
inflammation is released into the bloodstream against how much inflammation is
removed by your medical plan of care. When your hs-CRP is < 1.0 mg/L you have good
control of your present generalized state of inflammation. The weakness in the hs-CRP
testing is that the measurement can be artificially elevated by recent infection and/or
injury. If you have not had a recent infection or injury though, the hs-CRP level
represents the true generalized inflammation level within your bloodstream.
Fibrinogen - an acute-phase protein made active quickly with any form of inflammation.
Exercise can lower fibrinogen levels quickly while lack of exercise will allow
inflammation entering the bloodstream to elevate fibrinogen quickly and exponentially.
Fibrinogen is another advanced cardiovascular biomarker measuring the generalized
inflammation within the bloodstream.
Lp-PLA2 - a measure of chronic inflammation that correlates with chronic disease
states that place longterm inflammatory changes within the bloodstream. When
Lp-PLA2 is elevated > 235 ng/ml, there is a real risk of imminent plaque rupture that
could lead to a heart attack or stroke. The chronic inflammation that causes Lp-PLA2
Patient Lab Information
elevation furthermore causes increased plaque formation. In many cases it is
impossible to eliminate chronic inflammation, but your goal with Lp-PLA2 is to get as
close to 80 ng/ml as possible.
NT-proBNP - an advanced cardiovascular biomarker that helps you monitor if chronic
inflammation is causing heart stiffening. If your NT-proBNP is elevated, the chronic
inflammation is causing heart stiffening that eventually leads to the development of
congestive heart failure (CHF). When the NT-proBNP is elevated, you want to be careful
to avoid salt in your diet and try to exercise > 50 minutes per day nonstop to improve
your situation. Your clinician will likely monitor your BP and fluid balance closely when
your NT-proBNP elevates, often using medication that blocks aldosterone, a hormone
that begins to rise to dangerous levels with this form of heart stiffening.
Galectin-3 - another advanced cardiovascular biomarker that correlates with heart
stiffening from fibrosis (scar tissue development). Chronic inflammation leads to the
fibrosis related heart stiffening so efforts need to take place that will decrease your
inflammatory medical conditions. An aggressive exercise program that last > 50 minutes
nonstop daily would help your condition regardless of which inflammatory states are
causing the heart stiffening. When your Galectin-3 level gets to ≤ 10 ng/ml, you have
successfully stopped your heart fibrosis problem.
Homocysteine - Elevated homocysteine levels correlate with elevated inflammation
within the bloodstream. There is a definite correlation between elevated homocysteine
levels and elevated rates of cardiovascular disease. Despite the definite correlation
between elevated homocysteine levels and the occurrence of cardiovascular disease,
there is inconsistent evidence whether treating the homocysteine level lessens
cardiovascular disease development. There are numerous factors that play into
homocysteine elevation concerns, as we know that some homocysteine elevations
relate to the MTHFR genetic abnormality that definitely benefits from treatment. There is
recent interest in patients being able to methylate properly, as proper methylation
capability correlates with cancer risks. It is methionine that becomes homocysteine by
losing a “methyl group.” Thus it takes a methyl group for homocysteine to convert back
to methionine, which is a safe amino acid within the circulation. Thus watching
homocysteine levels helps you understand when too much inflammation is circulating
that can cause cardiovascular disease while it may play a role in helping to reduce
cancer occurrence. Watching homocysteine levels thus makes sense as a major health
benefit!
Stress and Inflammation: It is inflammation that is at the root of CV disease,
causing your clinician to want to follow markers of inflammation closely. This
inflammation get’s into your blood vessel walls setting the stage for plaque
development and plaque rupture. Some of the inflammatory factors attack other
places like your heart and kidneys. The best way to get rid of inflammation is to
prevent the disease states from producing inflammation, thus cutting off the
inflammation from it’s origin. It takes time to eliminate some disease state
inflammation and this makes exercise your next best option. You can remove the
overwhelming majority of circulating inflammation with exercise, especially if you
add a low carbohydrate, reduced saturated fat diet to your efforts. Your lab will
help you gauge how well your medical regimen is working to improve your
internal inflammatory condition giving you the best possible chances of
improving your health!
Diabetes/Prediabetes:
Glucose - measurement of circulating blood sugar in the bloodstream. Glucose is a
friend to your cells, but the inflammation related to developing insulin resistance is the
real hardship to your body. When your blood sugar is elevated, that usually indicates
that your insulin resistance is substantial as is the inflammation related to that insulin
resistance. Usually normal fasting blood sugar levels are reported to be between 65 -
100 mg/dl. There was a study called WOSCOPS that found when the fasting blood
sugar is > 84 mg/dl that you have problems with developing insulin resistance. Your
clinician will be using this biomarker information to help to identify when you are insulin
resistant as the earlier you identify and treat insulin resistance, the better your outcome
should be!
HgbA1C - a measurement of how your overall blood sugar control has been over a 12
week period. A person with absolutely no insulin resistance and no excess carbohydrate
intake would have a HgbA1C of 4.7. According to the American Academy of Clinical
Endocrinology (AACE) a HgbA1C of 5.5 is consistent with Impaired Glucose Tolerance
(IGT - the second stage of Pre-Diabetes) and a HgbA1C of 6.5 is consistent with
Diabetes. Your goal HgbA1C is to stay as close to normal as safely possible with the
help of a low carbohydrate/reduced saturated fat diet, exercise, and medication
recommended by your clinician. Ideally, you would benefit from keeping your
carbohydrate intake to ≤ 25 grams of carbohydrates every 4 hours.
Fructosamine - a measurement of how your overall blood sugar control has been over
a 6 week period.
Glycomark - a measurement of how your overall blood sugar control has been over a 2
week period.
Blood sugar accountability is important to you as a patient as we all tend to try
harder when we know someone is carefully looking into our diet excursions. With
the combination of Glycomark level, Fructosamine level, and HgbA1C, a clinician
can assess a pattern for your glucose control and by doing so know when you
were successful and unsuccessful with your diet.
Insulin - Measuring the fasting insulin level explains a great deal about how hard the
pancreas is working. When you are eating a meal, the pancreas gets the message to
secrete insulin responding to the glucose challenge. In ordinary circumstances the
pancreas would secrete the necessary insulin and within 3 hours the insulin level would
be normal again. When insulin resistance is present, even after 8+ hours fasting you will
often see an elevated insulin level > 10 µU/ml and that suggests that there is pancreatic
work overload and a pancreatic inflammatory response comes from this work overload.
When this fasting response is > 20 μU/ml and you have already been on two oral
medications for more than 3 months, your clinician may need to start you on insulin
injections. You need to cooperate with whatever your clinician decides, as this blood test
is rather accurate about assessing when a patient needs insulin and your fear of insulin
may delay you getting the needed treatment!
C-Peptide - the attachment to insulin that is cut off before insulin is packaged in
vesicles and made ready for use. C-Peptide has been used as a biomarker to better
assess insulin secretion for years as insulin is metabolized within the liver’s portal
system while C-Peptide is not effected through the liver’s portal system. When fasting
C-Peptide levels are high, there is a likelihood of significant insulin resistance and the
pancreas is still able to secrete significant levels of insulin. The C-Peptide level is
another means of analyzing pancreatic function and work capacity. When the fasting
C-Peptide is elevated and it has been > 8 hours since your last food intake, that means
that your pancreas is in work overload. This work overload correlates with a pancreatic
inflammatory response and inflammation is what you want to avoid! A low C-Peptide
level might correlate with a pancreas that has diminished work capacity. A pancreas with
diminished work capacity generally means that you will be needing to take insulin
therapy, usually through injections to help the cells within your body get the blood
glucose that they need.
Adiponectin - a hormone secreted from your fat cells within your abdomen. Adiponectin
usually confers blood vessel protection to you with inflammatory lowering properties.
When the levels of adiponectin get low you lack the cardiovascular protection provided
by adiponectin. Overeating carbohydrates causes a chain reaction with your liver,
pancreas, and intraabdominal fat cells that ends up lessening the quantity of
adiponectin being released by the intraabdominal fat cells. When the adiponectin level
gets ≤ 16 µg/ml, this represents a bad inflammatory response coming from the fat cells
inside the abdomen. When the adiponectin gets ≤ 8 µg/ml, there is a really bad fat cell
inflammatory response from within the abdomen. Fat cells are one of the least forgiving
of the 3 organs noticeably effected by overeating carbohydrates, namely the liver,
pancreas, and fat cells. The liver and pancreas inflammatory response to excess
carbohydrate intake is short-lived as the liver and pancreas recover quickly (i.e. within
7-10 days of the excess carbohydrate ingestion). Fat cell’s don’t forgive your excess
carbohydrate intake as well, taking 30+ days for fat cells to recover before they will
allow increased adiponectin release. When a person begins to show signs of consistent,
low intake of carbohydrates over weeks and months, the adiponectin level will gradually
increase to ≥ 45 µg/ml. Aim for getting your adiponectin level ≥ 45 µg/ml as that will take
you a long way toward great health!
Leptin - a hormone secreted from fat cells in your abdomen. These fat cell detect free
fatty acids levels that are elevating in response to excessive carbohydrate intake. Leptin
is released from the intraabdominal fat cells and sent to the brain instructing the brain to
eat less. This leptin to brain feedback mechanism is sometimes defective leading to
“leptin resistance.” The intraabdominal cells sense the leptin resistance and then send
increasing amounts of leptin to the brain in hopes to overcome the leptin resistance.
Recently Diabetes Type 3 was discovered which relates to insulin resistance of the
brain, which ultimately causes the development of Alzheimer’s Syndrome. The patients
that have brain insulin resistance are also leptin resistant, making elevation of leptin
levels likely to correlate with the patient who has developed Diabetes Type 3. Thus
when your Leptin or Leptin:BMI ratio is elevated, you are likely to be a Type 3 Diabetic.
Elevated leptin levels or leptin:BMI levels is then an important way to detect who has
Diabetes Type 3 and who is at risk of developing Alzheimer’s Syndrome. Reducing
carbohydrate intake in your diet, exercising > 50 minutes nonstop daily, and taking a
pioglitazone/GLP-1 analogue combination medication therapy will often help you
overcome your leptin resistance, making Alzheimer’s Syndrome much less likely to ever
occur.
Alpha Hydroxybutyrate - one of the earliest biomarkers to identify insulin resistance.
When alpha hydroxybutyrate is elevated above 4.8 훍g/ml, insulin resistance is
significant. When alpha hydroxybutyrate levels are below 3.1 훍g/ml, you are insulin
sensitive. Alpha hydroxybutyrate levels between 3.1 - 4.8 suggest modest insulin
resistance. Alphahydroxybutyrate may be the first biomarker known to elevate when you
become insulin resistant but this biomarker is also the first biomarker to decline when
the insulin resistance is reversed. Thus the alpha hydroxybutyrate level is a very
important biomarker to assess your insulin resistance status as it is the most sensitive
biomarker known to date related to insulin resistance!
Oleic Acid - the most abundant fatty acid in human adipose tissue. Oleic acid levels
elevate with insulin resistance and contribute to the Quantose IR test score detecting
insulin resistance early. This test is probably the second most sensitive biomarker test
known to date related to detecting insulin resistance early.
Linoleoyl-glycerophosphocholine (L-GPC) - another biomarker that is an
independent predictor of insulin resistance. L-GPC is a biomarker that contributes to the
Quantose IR test developed to help identify patients who have insulin resistance.
Quantose IR - a test that combines the information received from alpha
hydroxybutyrate, oleic acid, linoleoyl-glycerophosphocholine, and insulin to provide a
conglomerate test result predictive of insulin resistance.
Quantose IGT - a convenient surrogate test designed to detect Impaired Glucose
Tolerance (IGT) without the inconvenience of doing a 2 hour Glucose Tolerance Test.
The test should be drawn fasting, meaning at least 8 hours after stopping all food and
drink intake.
Cortisol - a biomarker that works against insulin resistance. The levels of cortisol are
often elevated with Diabetes Type 2, especially when the disease is progressive and
numerous complications are present. Elevated cortisol levels cause: 1) increased fat
circulating, 2) increased liver production of glucose, 3) increased insulin resistance, and
4) increase in appetite. From a diabetes perspective, you want to have normal levels of
circulating cortisol. Normal levels of circulating cortisol are more likely to occur when
your diet is low in carbohydrates (ideally < 25 grams of carbohydrates every 4 hours)
and you exercise aerobically > 50 minutes nonstop daily.
Detecting insulin resistance early is vital as the earlier you detect the insulin
resistance, the earlier you can do something about the insulin resistance
problem. Earlier detection of insulin resistance should help you avoid the bad
consequences that come from insulin resistance as you can then work with your
physician to treat the disorder. Ignoring the insulin resistance problem makes it
more likely that you will have cardiovascular disease. Be thankful that your
clinician is aware of methods to detect insulin resistance early through the use of
biomarkers provided on your Advanced Cardiovascular Laboratory Report.
Anti-GAD antibodies - antibodies in your bloodstream that help you identify an
autoimmune response aimed at your pancreatic beta cells, the cells that make insulin in
your pancreas. Identifying this antibody showing up helps you identify Diabetes Type 1
and Diabetes Type 1.5. When anti-GAD antibodies are present on your lab test and you
don’t require insulin injections within 6 months, this means you have Diabetes Type 1.5
(AKA Latent Autoimmune Diabetes of Adults). Patients with Diabetes Type 1.5 have a
rather slow autoimmune demise of the pancreatic beta cell function over a 5-12 year
period after the anti-GAD antibody shows up. There is growing evidence emerging that
shows that a Rx of basal analogue insulin (i.e. Levemir or Lantus) in a Diabetes Type
1.5 patient might assist with turning off the autoimmune response and putting Diabetes
Type 1.5 into remission. In addition to the insulin used in Diabetes Type 1.5 patients,
there may be an additional benefit from using medications such as GLP-1 agonist or a
DPP-4 blocking medication, as both GLP-1 agonists and DPP-4 blocking medications
have been shown to stimulate pancreatic beta cells regeneration (i.e. helps the
pancreas make more insulin again).
The Four Types of Diabetes:
Diabetes Type 1 - a rapid acting autoimmune attack on the pancreas causes this type
of diabetes that usually occurs in childhood. This autoimmune attack on the pancreas
usually causes the requirement of insulin injections within 3-6 months of the
autoimmune onset.
Diabetes Type 1.5 - a slow acting autoimmune attack on the pancreas that usually
takes 5-12 years before insulin is required due to severe loss of pancreatic function.
Diabetes Type 2 - a form of diabetes related to insulin resistance below the neck, that
will gradually wear out the pancreas due to pancreatic work overload. Diabetes Type 2
is genetically derived and is aggravated by obesity and excess carbohydrate intake.
Diabetes Type 3 - a form of diabetes related to insulin resistance in the brain. This form
of diabetes is also genetic in origin and made worse by excess carbohydrate intake.
Patients with the Apo E4 genotype may have a higher propensity to develop Diabetes
Type 3. Patients that develop Diabetes Type 3 are believed to make up 80% of the
developing cases of Alzheimer’s Syndrome. Diabetes Type 3 is the most recently
discovered form of Diabetes and thus there is much information needed to better
understand how to diagnose this condition early and ward off the possibility of
developing Alzheimer’s which is related to Diabetes Type 3. Early reports suggests that
pioglitazone, GLP-1 agonists, and basal analogue insulin may help in the treatment of
Diabetes Type 3.
Your clinician’s use of advanced diabetic testing will help your clinician detect
exactly what types of diabetes you have so that your ultimate plan of care will be
very effective. The diabetic test panel will also help your clinician better evaluate
the effectiveness of your diet, exercise, and medication. Since diabetes and pre-
diabetes is seen in approximately 84% of patients entering the emergency room
with a heart attack, this area of testing is very important to you and your
cardiovascular health!
Metabolic
25-OH, Vitamin D - an emerging prominent biomarker related to cardiovascular health
and mental health. There are various ways to measure Vitamin D but this is considered
one of the best choices to accurately assess Vitamin D levels as it measures the
Vitamin D produced through the skin as well as the Vitamin D absorbed through the
intestines. Cardiovascular health occurs when the 25-OH level is between 30 - 100
ng/ml but neurovascular health occurs when the 25-OH level is between 50 - 100 ng/ml.
Vitamin D levels correlate with your potential to make serotonin in your brain, and
ultimately serotonin is both a quality of life issue and a quantity of life issue. Serotonin
helps you with sleep quality, memory, concentration, mood, and energy. When you lack
serotonin, you have to circulate high levels of adrenaline to compensate for the lack of
serotonin, and that raises cardiovascular risk substantially. The high levels of adrenaline
circulating 24 hours per day, 7 days per week, causes the serotonin deficient nerves in
the brain to “jumpstart” after 10-15 nerve signals instead of just one signal if the nerve
contained serotonin. Obviously it is very inefficient to send 15 signals through a neuron
to activate the nerve when one signal should do the trick if the neuron contained
adequate serotonin. The excess adrenaline circulating because of the low Vitamin D
induced serotonin deficiency causes inflammation to be present throughout the
circulatory system. Chronic inflammation from Vitamin D deficiency even irritates the
heart in such ways that heart stiffening can take place. Please note that Vitamin D is a
fat soluble vitamin and elevated levels > 100 ng/ml can cause high levels of calcium to
build up (hypercalcemia) leading to signs of toxicity which include fatigue, loss of
appetite, excessive thirst and urination, and dehydration.
Vitamin B-12 - a water soluble vitamin important to blood cell efficiency, balance, nerve
function, and energy. Low Vitamin B-12 levels are best replaced by injectable or
sublingual routes because stomach acid destroys 98% of Vitamin B-12 taken through
the oral route! When you are deficient of Vitamin B-12 or folate, your red blood cells
enlarge and this red blood cell enlargement is called macrocytosis. When macrocytosis
is present, problems with low energy, poor concentration, and shortness of breath may
be present. The macrocytosis represents the presence of enlarged, inefficient cells that
don’t transfer oxygen like the normal sized cells transfer oxygen. Thus the lack of
Vitamin B-12 or folate that is leading to the macrocytosis causes increased workload on
the heart because red blood cells must be circulated more frequently to distribute the
needed oxygen to all tissues. If you treat the Vitamin B-12, and not the folate related to
the macrocytosis, you risk nerve damage. See comments under the MTHFR genetic
test to understand better how the folate replacement should take place.
Folate - (AKA Folic Acid or Vitamin B-9) a very busy B vitamin that helps your
cardiovascular system from many different directions. The active form of folate is the
fifth breakdown product called methylfolate (AKA methyltetrahydrofolate). Recently we
discovered the MTHFR genetic defect that is present in approximately 60% of the U.S.
population causing patients to have a gradually declining ability to convert folate into
methylfolate. Thus the MTHFR patient could have perfectly normal folate levels within
their bloodstream and not be able to use very much of the folate because of their
inability to make the folate:methylfolate conversion. Thus when you evaluate your folate
level you have to consider your MTHFR 677 and 1298 genetic status.
Folate converted to methylfolate is responsible for: 1) the production of 4 important
brain chemicals (serotonin, melatonin, dopamine, norepinephrine), 2) nitric oxide
production (dilator of arteries, decreases blood vessel inflammation), 3) contribution to
production of red blood cells, 4) helping to produce DNA, 5) helping break down, use,
and create new proteins, 6) neural tube formation of fetal development, 7) converting
homocysteine back to methionine (a benign amino acid). When patients are
methylfolate deficient they will have: A) low energy, B) poor memory and concentration
capability, C) moodiness, D) problems with blood vessel inflammation and blood vessel
constriction caused by increased circulating adrenaline, E) problems lessening blood
vessel inflammation and problems dilating constricted blood vessels due to nitric oxide
deficiency, F) anemia leading to increased heart workload, G) genetic issues including
problems leading to arousal of dormant cancer cells (methylation problems), H) birth
defects including Down’s Syndrome, Spina Bifida, and Autism.
Iron - a mineral that is an essential component of hemoglobin (a blood protein that
transfers oxygen to tissues) and myoglobin (a protein that provides oxygen to muscles).
Iron is necessary for normal growth and development. Iron is involved in the production
of certain hormones and connective tissue. Low levels of iron leads to health problems
such as anemia which makes the heart work harder to circulate adequate amounts of
oxygen to meet body demands. High levels of iron leads to hemochromatosis, a
condition that cause cirrhosis of the liver and heart disease.
Ferritin - a protein that stores iron, used as an early indicator of iron deficiency. When
you are iron deficient, circulating levels of ferritin will be low, leading to iron deficiency
anemia. When extremely high levels of ferritin are present, this would correlate with iron
overload, and concern for hemochromatosis would be high.
Cystatin C - an advanced biomarker that is used to measure kidney function. Cystatin
C appears to be a much better lab tool to detect early stages of chronic kidney disease
(CKD) than the traditional measurement of creatinine. There are five stages of CKD with
the 5th stage leading to need for dialysis. The various stages of CKD are dependent on
estimated glomerular filtration rate (eGFR) calculations, with Cystatin C being able to
help you to detect CKD as you enter stage 2 CKD (eGFR of 60-89). When the older
creatinine biomarker is used to measure eGFR, your clinician cannot reliably tell what
the eGFR truly is until you enter stage 3 CKD (eGFR of 30-59). Once you enter stage 3
CKD, serious complications develop including problems with erythropoietin deficiency
anemia as your kidneys lose their ability to produce adequate erythropoietin in stage 3
CKD. When you lack erythropoietin needed to make red blood cells, you require
erythropoietin injections near monthly and these injections are rather expensive. Thus
using the Cystatin C regularly as an advanced biomarker to detect CKD earlier, may
cause you to get the best medical help early helping you avoid the complications that
occur with Stages 3-5 CKD. Testing for Cystatin C regularly makes sense when you
consider that the Cystatin C test itself is a relatively inexpensive lab test capable of
helping you to avoid costly erythropoietin injections and dialysis.When reasonably good
kidney function is maintained you have more medication options available as well
adding even more value to the Cystatin C test.
Free Fatty Acids - an important link between obesity, insulin resistance, and diabetes
type 2. Free fatty acids are fatty acids not attached to other lipid entities. When
elevated, free fatty acids cause the development of insulin resistance while
simultaneously causing increased pancreatic insulin secretion. Some patients with
elevated free fatty acids have a mismatch of insulin resistance and pancreatic insulin
secretion, and these patients are unable to make enough insulin to keep up with needs
caused by the FFA stimulated insulin resistance. When the insulin resistance exceeds
the pancreas capability to make insulin, you develop diabetes type 2. The free fatty acid
elevations seen on your blood test are usually caused by your excess carbohydrate
intake during the 5 days before your lab draw. Everyone has a carbohydrate capacity
that they can metabolize, whether you are a diabetic or non-diabetic. Overeating your
carbohydrate capacity will lead to elevations of your free fatty acids, triglycerides, and
sdLDL-C levels while simultaneously stimulating an inflammatory response from the
liver, pancreas, and intraabdominal fat cells. If you see elevations of the free fatty acid
level, consider decreasing your carbohydrate intake. If you have markers of insulin
resistance evident, consider eating < 25 grams of carbohydrates every 4 hours to
prevent further inflammatory insults to your cardiovascular system.
Uric Acid - a biomarker used to assess risk for gout, diabetes, and cardiovascular
disease. When uric acid is elevated you are at increased risk for developing a form of
arthritis, called gouty arthritis. When you see high levels of uric acid present there is
also often insulin resistance present that leads to higher risk of the development of
diabetes type 2 and cardiovascular disease. Causes of elevated uric acid levels include:
1) diets containing high intake of dietary purines (i.e. organ meats, anchovies, mackerel,
and sardines), high fructose corn syrup, and sugar, 2) reduced kidney excretion of uric
acid, and 3) certain medications such as hydrochlorothiazide.
PTH (Parathyroid Hormone) - a hormone produced by the parathyroid that acts to
increase calcium within the bloodstream. Elevated levels of PTH have been thought to
be associated with elevated rates of cardiovascular events, albeit this is controversial.
Elevated levels of PTH are also associated with Vitamin D deficiency, and it is thought
possible that it is the associated Vitamin D deficiency that my be the real reason that
elevated PTH levels were thought to correlate with increased cardiovascular event
rates.
Molecular/DNA
Factor V Leiden - a genetic test indicating increased risk of blood clotting that can lead
to deep vein thrombosis and/or pulmonary embolism. If you are heterozygous (one
parent gave you the normal gene and one parent gave you the abnormal gene defect)
for the Factor V Leiden genetic defect, your risk of blood clots are mainly going to occur
with any event that causes you to be inactive (i.e. general anesthesia for surgery,
wearing a cast or a splint on an injured limb, or transcontinental travel within limited
ability to move about the airplane). The only time most heterozygous Factor V Leiden
patients are thought to need anticoagulation is when they have situations making them
inactive. Homozygous (when both parents give you the abnormal gene defect) patients
with the Factor V Leiden genetic defect are at very high risk of developing blood clots
and often need anticoagulation medication support for the rest of their lives.
Prothrombin Mutation (AKA Factor II Mutation) - a genetic test indicating increased
risk of blood clotting that can lead to deep vein thrombosis and/or pulmonary embolism.
Blood clots are formed by platelets sticking together within a tightly woven set of protein
fibers called fibrin. Prothrombin is a blood clotting protein essential to the formation of
fibrin. Patients with the Prothrombin Mutation genetic defect generally make too much
prothrombin increasing their risk of making blood clots. Patients heterozygous for the
Prothrombin Mutation genetic defect usually do not require anticoagulation medication
as long as they do not become inactive (i.e. general anesthesia for surgery, wearing a
cast or a splint on an injured limb, or transcontinental travel within limited ability to move
about the airplane). Patients that are homozygous for the Prothrombin Mutation genetic
defect are at considerably higher risk for developing blood clots, and these patients will
need to discuss the benefits versus the risks of taking longterm anticoagulation
medication with their clinician.
Note: Patients who are heterozygous for both Factor V Leiden and Prothrombin
Mutation genetic defects simultaneously are at high risk for developing blood
clots forever, and these patients need to discuss the benefits versus the risks of
taking longterm anticoagulation medication with their clinician.
MTHFR - this is one of the most important genetic test findings of the 21st century thus
far! Patients with the MTHFR genetic abnormality lack sufficient quantities of an enzyme
called methylenetetrahydrofolate reductase (MTHFR). Lacking sufficient quantities of
MTHFR leads MTHFR genetic abnormality patients to be unable to break down folic
acid into the 5th breakdown product called methylfolate (AKA methyltetrahydrofolate).
Folate converted to methylfolate is responsible for: 1) the production of 4 important
brain chemicals (serotonin, melatonin, dopamine, norepinephrine), 2) nitric oxide
production (dilator of arteries, decreases blood vessel inflammation) which is a chemical
vital to your cardiovascular health, 3) contribution to production of red blood cells, 4)
helping to produce DNA, 5) helping break down, use, and create new proteins, 6) neural
tube formation of fetal development, 7) converting homocysteine back to methionine (a
benign amino acid) which represents methylation capability (potentially lowers cancer
risk). When patients are methylfolate deficient they will have: A) low energy, B) poor
memory and concentration capability, C) moodiness, D) problems with blood vessel
inflammation and blood vessel constriction caused by increased circulating adrenaline,
E) problems lessening blood vessel inflammation and problems dilating constricted
blood vessels due to nitric oxide deficiency, F) anemia leading to increased heart
workload, G) genetic issues including problems leading to arousal of dormant cancer
cells (methylation problems), H) birth defects including Down’s Syndrome, Spina Bifida,
and Autism.
There are presently two MTHFR genetic alleles known to correlate with the above
problems associated with folic acid metabolism, MTHFR 677 and MTHFR 1298 genetic
abnormalities. The numbers, 677 and 1298, simply represent the location of the genetic
defect within the gene of MTHFR genetic abnormality patients.
More is known about the MTHFR 677 abnormality patients since this was the first
MTHFR genetic defect discovered. Homozygous MTHFR 677 abnormality patients tend
to have problems with Attention Deficit Disorder (ADD) as a child. The homozygous
MTHFR 677 abnormality patients have only a 35% capacity of making 4 key brain
chemicals (serotonin, melatonin, dopamine, and norepinephrine) when they are born,
with further decline of brain chemical production as they age. The homozygous MTHFR
677 abnormality patient’s brain function survives on high circulating levels of adrenaline
24 hours per day, seven days per week. The high adrenaline levels circulating in the
homozygous MTHFR 677 abnormality patient leads to the brain’s nerve cells (called
neurons) having an inefficient firing mechanism. This MTHFR genetic abnormality
patient may send 15 signals through the same neuron before it fires due to the
adrenaline “jumpstarting” the nerve by attaching to the postsynaptic membrane (the
backdoor of the nerve). When stimulant medications ( i.e. Ritalin or Adderall) are used
for these homozygous MTHFR 677 abnormality patients that have ADD, they are
increasing circulating adrenaline levels so that the neurons will fire more quickly. Now
that we understand the mechanism behind the ADD patients brain irregularity, it seems
much more reasonable to address the methylfolate deficiency issue so the patients
could begin making adequate brain chemicals to function normally. More studies will
need to be done in this area of methylfolate prescriptions for ADD patients to assess
safety and dosing issues before this treatment regimen could be approved by the FDA.
Patients with heterozygous MTHFR 677 genetic abnormality have similar problems to
the homozygous MTHFR genetic abnormality patients but the heterozygous patient’s
symptoms just don’t show up too badly until they get approximately 30 years of age. At
30 years of age, the heterozygous MTHFR 677 genetic abnormality patient is beginning
to have the same chemical issues that the homozygous MTHFR 677 genetic
abnormality was having at birth.
Other medical problems with MTHFR genetic abnormality patients besides memory and
concentration problems include: 1) problems with getting to sleep as well as problems
staying asleep, 2) decreased energy, 3) moodiness, 4) headaches, 5) fibromyalgia, and
6) clinical depression as these patients age (these patients often become withdrawn
from society, doing only what they have to like go to work, buy groceries, and attend
children’s functions). By age 50, most MTHFR patients prefer to stay at home and avoid
people, essentially because things that people do gets on their nerves. Things that used
to not bother the MTHFR genetic abnormality patient (i.e. kids making noise, traffic
issues, etc) now bother them tremendously as they age.
Recent studies demonstrated significant improvement in MTHFR 677 patients that take
L-methylfolate (Deplin) 15 mg daily. The MTHFR 677 abnormality patients taking Deplin
15 mg daily initially don’t notice much benefit from the prescription until the 8th week of
medication intake. These MTHFR 677 abnormality patients start noticing improved
memory, concentration, sleep, mood, and energy by week 8 of treatment with Deplin 15
mg daily and the improvement seems to continue until 18 months after the medication is
begun. The Deplin 15 mg prescription should be continued forever as this genetic
condition will always be present causing continuous need for the Deplin.
The MTHFR 1298 genetic abnormality patient has most of the same symptoms as the
MTHFR 677 allele patients, but the MTHFR 1298 patients are much more difficult to
treat. Deplin 15 mg daily seems to help the MTHFR 1298 genetic abnormality patients
as well, but improvement is seen much more gradually. The MTHFR 1298 genetic
abnormality patient prescribed Deplin 15 mg daily tends to see the following: 1) sleep
quality begins to improve by the third month of therapy, 2) memory, concentration, and
mood tend to improve by the sixth month of therapy, 3) energy starts to improve by the
12th month, but not so much energy improvement that you would write home about, and
4) by month 18, energy has improved enough to write home about. More study is going
to have to be done on this group as their are possible early indicators that these
patients may need higher doses of Deplin at the onset of their therapy but this has not
been proven yet.
Apo E Genotype - Apo E genotyping has been a bit controversial through the years,
but there are some parts about Apo E genotyping that seem generally accepted.There
are 3 levels of Apo E patient, namely Apo E2, Apo E3, and Apo E4. It’s the Apo E4
patients that seem to be causing the more serious cardiovascular consequences.
Apo E4 patients are prone to have higher levels of circulating inflammation and more
atherosclerosis issues than the average patient. Apo E4 patients also have a higher
tendency to develop Alzheimer’s Syndrome as they age than the other Apo E subgroup
patients. Apo E2 patients tend to have elevated levels of triglycerides and VLDL, lipid
changes often seen in patients that are insulin resistant. Apo E3 patients are patients
that have relatively normal lipid metabolism and inflammation issues. Apo E3 patients
are not without risk though, as even Apo E3 patients have high levels of atherosclerosis
and inflammation if they eat unhealthily or don’t exercise often.
Pharmacogenomics
Pharmacogenomics is a new “hot topic” aimed toward improving healthcare by
identifying genetic abnormalities within the liver metabolic pathways that would
effect the way a prescription medication would react within a patient.
Pharmacogenomics studies the Cytochrome p450 information within a patient,
which are the “metabolic highways” that medications breakdown in as they travel
through your body. Most of the Cytochrome p450 activity takes place within the
liver. These Cytochrome p450 highways can involve slow breakdown of a
medication (i.e. poor and intermediate metabolizers) or rapid breakdown of a
medication (i.e. rapid and ultra-rapid metabolizers). If you are a slow metabolizer
of a medication, you tend to sustain larger quantities of that medication than
normal metabolizers of the medication. The slow metabolizer is then exposed to
more risk of adverse drug reactions due to the higher than usual circulating drug
levels of the medication they metabolize slowly. If you are a slow metabolizer of a
medication, your clinician can choose to use a different medication in a metabolic
highway that works better for you or the clinician can use a lower dose of the
needed medication to avoid large medication levels building up in you. If you are
a rapid metabolizer of a medication, your clinician will usually use a different
medication that travels through a metabolic highway that works better for you or
occasionally the clinician will possibly dose the medication higher than usual and
dose it more frequently when the medication is going to break down rapidly or
ultra-rapidly. For lifesaving medications or complicated medication regimens,
pharmacogenomics can help make your medical experience tremendously better
by ensuring that you are getting the best medication for you at the correct dosage
needed to get the job done. Pharmacogenomics has the potential to help you get
the maximum benefit from medication while substantially lessening adverse drug
reactions!
Cardiovascular Pharmacogenomics
CYP2C19 - the highway within the liver that metabolizes key medications used in
cardiovascular patients such as clopidogrel (Plavix), citalopram (Celexa), escitalopram
(Lexapro), and omeprazole (Prilosec). Cardiovascular patients often have sudden
developments that lead to them getting a stent placed within an artery suddenly without
warning, and knowing your CYP2C19 status can help your clinician quickly make the
correct decision about your needed antiplatelet therapy. Clopidogrel (Plavix), a
CYP2C19 medication, was the first prescription antiplatelet medication on the market,
and thus it is often the most commonly prescribed medication after a stent. If you have
problems in the CYP2C19 pathway, your physician will benefit from knowing your
CYP2C19 status as there are two other antiplatelet medications on the market that are
not CYP2C19 medications, prasugrel (Effient, CYP3A4 substrate + CYP2B6 activity)
and ticagrelor (Brilinta, CYP3A4). Choosing the correct antiplatelet medication makes it
less likely that your recently placed stent will get clogged up with a blood clot.
CYP2C9 - the primary highway within the liver that metabolizes warfarin (Coumadin).
Knowing your CYP2C9 metabolic status helps you better understand the longterm
strategy for dosing warfarin, a complex blood thinner commonly used in cardiovascular
patients. The CYP2C9 pathway is the third most commonly used liver metabolic
pathway responsible for breaking down 15-20% of known medications. Other common
medications use this as their primary metabolic pathway including ibuprophen (Motrin),
naproxen (Naprosyn), meloxicam (Mobic), celecoxib (Celebrex), phenytoin (Dilantin),
rosuvastatin (Crestor), fluvastatin (Lescol), glipizide (Glucotrol), glyburide (Micronase),
glimepiride (Amaryl), irbesartan (Avapro), valsartan (Diovan), and losartan (Cozaar).
Being familiar with all of these medications using this metabolic pathway helps your
clinician know how to avoid getting too many medications in the same liver highway,
thus avoiding a medication traffic jam.
VKORC1 - the product of this gene activates Vitamin K so that blood clotting takes
place. Warfarin (Coumadin) antagonizes the product of the VKORC1 gene, allowing for
blood thinning. Knowing the patient’s level of sensitivity to warfarin helps your clinician
properly dose warfarin.
CYP3A4 - the busiest metabolic highway in the liver responsible for breaking down
multiple common medications including ticagrelor (Brilinta), prasugrel (Effient),
amlodipine (Norvasc), diltiazem (Cardizem), verapamil (Calan), nifedipine (Procardia),
atorvastatin (Lipitor), simvistatin (Zocor), lovastatin (Mevacor), ranolazine (Ranexa),
alprazolam (Xanax), buspirone (Buspar), erythromycin (PCE), fentanyl (Duragesic),
methadone (Dolophine), and quinine sulfate (Qualaquin)
CYP2D6 - a rather busy metabolic highway in the liver that breaks down 25% of the
most commonly used medications in the United States. The CYP2D6 pathway is also
highly expressed in areas of the brain including the substantia nigra, the area of the
midbrain associated with Parkinson’s Syndrome but also plays a role in reward,
addiction, and movement. The CYP2D6 pathway is responsible for breaking down
numerous medications including most antidepressants, most opiates, and most beta
blockers. The medications broken down in the CYP2D6 category include amitriptylline
(Elavil), fluoxetine (Prozac), paroxetine (Paxil), venlafaxine (Effexor), duloxetine
(Cymbalta), codeine (Tylenol #3), tramadol (Ultram), hydrocodone (Norco), oxycodone
(Percocet), aripiprazole (Abilify), risperidone (Risperdal), haloperidol (Haldol),
metoprolol (Toprol), carvedilol (Coreg), propranolol (Inderal), metoclopramide (Reglan),
promethazine (Phenergan)
CYP2B6 - another metabolic highway in the liver with several common medications
broken down in this pathway which include prasugrel (Effient) and bupropion
(Wellbutrin).
CYP2A6 - this is the primary metabolic pathway for nicotine and cotinine (a metabolite
of nicotine) clearance.
CYP1A2 - the primary metabolic pathway for caffeine to be broken down and
deactivated.
Coronary Ischemia
HS cTnI - an extremely important advanced cardiovascular biomarker that can detect
when your heart has clogged blood vessels leading to lack of oxygen getting to parts of
your heart muscle. Highly Sensitive (HS) Cardiac Troponin I (cTnI) is an extremely
sensitive measurement of protein molecules that are highly specific to heart muscle.
There is a normal turnover in heart muscle cells making a certain level of HS cTnI in
your bloodstream normal. Recent studies have shown that when a patient’s HS cTnI
level exceeds 4.7 pg/ml, there is ischemia (lack of oxygen needed) present in the heart
muscle. There is evidence recently discovered that suggested that the HS cTnI testing
can detect this heart ischemia as early as 2 - 7 years before you have a heart attack.
Having access to this HS cTnI level regularly helps you detect when your heart is
getting blocked arteries early in the disease state which could be lifesaving for so many
unsuspecting heart patients! Since you often have no symptoms when your heart has
arteries getting clogged up, checking your HS cTnI level regularly makes great sense,
especially if you have any risk factors of cardiovascular disease.
We have recently learned that women often have a very unique way of developing heart
disease. Approximately 50% of women have isolated small vessel disease in their
hearts for 5-8 years, before they suddenly get large vessel disease in their hearts that
completely clogs their large heart vessels within 6 months. We do not understand what
the trigger is yet that causes these women with small vessel heart disease to suddenly
and quickly convert to large vessel disease. Since the large vessel disease in these
women converts so quickly (usually within 6 months) to 100% occlusion of their large
vessels, these women are often not clinically captured until they show up with a heart
attack in the ER. These women with small vessel heart disease will often have
symptoms as their small vessel heart disease worsens, such as sudden unexplained
fatigue or sudden worsening of exercise capacity (i.e. suddenly getting weak or SOB
after going up and down two aisles within the grocery store). The women with
symptomatic small vessel heart disease will often seek medical care for their noticeably
different circumstances that may lead to a nuclear stress test or a heart catheterization
being performed. Unfortunately neither the nuclear stress test or the heart
catheterization will detect small vessel disease within the heart, so these women get
tested and told that there is nothing wrong with their heart. The HS cTnI level testing is
one of the few ways the women with small vessel heart disease can be detected. If your
HS cTnI testing shows an elevated level and your nuclear stress test/heart cath appears
normal, you have just been identified as a patient with small vessel disease in your
heart. This small vessel heart disease can occur in men also but the studies suggest
there is a 4:1 higher incidence of women having the small vessel heart disease issue
compared to men.
