Beating Cardiovascular Disease

Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Continuing Medical Education course
Sam Fillingane, D.O.
Cardiovascular Risk Reduction
Jackson, Mississippi
[email protected]
Disclaimers
• Speaker Bureau and Medical Advisory
Board for Health Diagnostics Laboratory
• Speaker Bureau for Singulex Laboratory
• Speaker Bureau for Astra Zeneca
Medication Generic/Brand Names
Brand Name
Actos-------------------------------------------------------Glucophage----------------------------------------------Januvia----------------------------------------------------Onglyza---------------------------------------------------Tradjenta--------------------------------------------------Byetta------------------------------------------------------Victoza-----------------------------------------------------Bydureon--------------------------------------------------Levemir----------------------------------------------------Lantus------------------------------------------------------Ergocalciferol--------------------------------------------Maximum D3---------------------------------------------Ranexa----------------------------------------------------Toprol XL--------------------------------------------------Bystolic----------------------------------------------------Plavix------------------------------------------------------Effient------------------------------------------------------Brillinta-----------------------------------------------------Coumadin-------------------------------------------------Synthroid--------------------------------------------------Crestor-----------------------------------------------------Lipitor ------------------------------------------------------Zocor-------------------------------------------------------Zetia--------------------------------------------------------Welchol-----------------------------------------------------
Generic Name
Pioglitazone
Metformin
Sitagliptin
Saxagliptin
Linagliptin
Exenatide
Liraglutide
Exenatide ER
Insulin Detemir
Insulin Glargine
Vitamin D2
Vitamin D3
Ranolazine
Metoprolol Succinate
Nebivolol
Clopidogrel
Prasugrel
Ticagrelor
Warfarin
Levothyroxine
Rosuvastin
Atorvastatin
Simvistatin
Ezetimibe
Colesevelam
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
with Sam Fillingane, D.O.
Module 1: The Scope of the Challenge
780,000 Deaths Yearly
From Major Cardiovascular
Diseases
Almost all of these CV deaths
could have been avoided!
US Dept of Health & Human Svs,
National Center for Health Statistics,
National Vital Statistics Report, Vol. 61, No. 6,Oct. 10, 2012
Tornado in Joplin, MO
Joplin Tornado - Wikipedia
Hurricane Katrina
Hurricane Katrina - Wikipedia
Annual Mortality from CVD
compared to Katrina and Joplin
CV Deaths
Deaths from Katrina and Joplin
0%
0.0026%
100%
National Vital Statistics Reports,; Oct 10,2012
Hurricane Katrina - Wikipedia
Joplin Tornado - Wikipedia
The storms causing
Hurricane Katrina
and the Joplin Tornado
caused 0.0026% the
death rate of caused by
CV disease yearly
Daily CVD Mortality Compared to
Katrina and Joplin
Deaths in 1 day from CV Disease
48%
National Vital Statistics Reports,; Oct 10, 2012
Deaths from Hurricane Katrina and Tornado in Joplin
52%
Annual CVD Mortality Compared to all
US Combat Deaths Since 1775
Total US Combat Deaths, 1775 to date
CV Deaths 2011
48%
52%
National Vital Statistics Reports,; Oct 10, 2012
United States Military Casualties of War-Wikipedia
CVD Distribution in America
My Home
Most of life’s success stories begin
with “Attitude”
To beat cardiovascular disease, we are going to
have to work on multiple attitudes!
Clinicians need a “winning attitude”to
beat cardiovascular disease!
Cardiovascular disease is
the number 1 killer of
people in the United
States, killing more
people than the next 4
causes of death
combined.
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
with Sam Fillingane, D.O.
Module 2: Cardiovascular Disease Process
Development of Cardiovascular Disease
Atherosclerosis: Lipoprotein Retention
Apo-B lipoproteins
Chylomicrons
VLDL, IDL, LDL,
Lp(a)
CRP, Lp-PLA2
Stabilization
Apo-A lipoproteins
HDL
Progression
Regression
LDL
HDL
Non-HDL
Inflammatory Factors
Development of Cardiovascular Disease
Atherosclerosis: Major Steps
Lipoprotein
Deposition
Maladaptive
Inflammation
Deposition of
apoB particles
•
LDL
•
sdLDL
•
Lp(a)
•
Chylo-R
Inflammatory
Response
•
hs-CRP
•
LpPLA2
•
MPO
• Fibrinogen
Counteracted
by apoA/HDL
•
ApoA
•
HDL
• Large HDL
Apoptosis
Calcification
Fibrosis
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
with Sam Fillingane, D.O.
Module 3: Recognizing and Treating the Key
Risk Factors for Cardiovascular Disease
Key Risk Factors for Plaque
and CV Disease
Diabetes
Dyslipidemia
Hypertension
Inflammatory
disease
Sleep
apnea
Genetics
Chronic kidney
disease
Depression
If you want to be good at
cardiovascular risk reduction:
Target causes of
inflammatory
response!
Inflammatory Factors and Arterial
Plaque
Inflammatory factors stimulate
secretion of chemokines,
leading to LDL penetration of
the endothelial lining, and
accumulation of cholesterol to
form plaque.
Erosions and Ulcerations
Inflammatory factors
also cause vessel
erosions and ulcerations
when they hang around
too long and
accumulate!
MPO levels
The ulcerations lead to
potential plaque rupture!
There are usually no
symptoms prior to the
plaque rupturing!
A Blood Vessel with No Inflammatory
Factors
In the absence of
inflammatory factors,
there are no blood
vessel erosions meaning
that there is no chance
of plaque eruptions!
In the absence of
inflammatory factors,
LDL has no interest in
penetrating the
endothelial sidewall and
dumping cholesterol that
would lead to plaque.
We need to identify cardiovascular
patients early!
Advanced cardiovascular laboratory testing
helps you identify patients at risk early!
We need to address additional
cardiovascular risk factors!
There is a need for more cardiovascular biomarkers to address
additional risk factors.
Although traditional risk factors produce reasonably accurate
estimates of risk in a population, they predict only 50-60% of
events in individual patients.
Additional risk factors would improve accuracy of decisions
regarding preventative therapies.
Rader DJ., “Inflammatory Markers of Coronary Risk”, N Engl J Med. 2000; Oct 19; 343(16):1179-82
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 4: Interpreting Advanced Testing Results –
Dyslipidemia and Atherogenic Components
The Traditional Lipid Profile:
An easy way to miss things in an insulin resistant
patient
Advanced CV Biomarkers
This is only the beginnings of what is being missed
Sniderman et al., “A Meta-Analysis of Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, and Apolipoprotein B as
Markers of Cardiovascular Risk”, Circ Cardiovasc Qual Outcomes. 2011;4:337-345
“Bad”/LDL Cholesterol Components on
Traditional versus Advanced
Lipid Profile
Traditional lipid profile
Advanced lipoprotein profile
Assessing the Patient’s Diet
Abnormally low HDL-C correlates with insulin
resistance.
Elevated TRIG indicates patient is eating too many
carbs, and correlates with insulin resistance.
Elevated Apo B and LDL-P indicate patient is
eating too much saturated fat.
Use Advanced CV Biomarkers to Keep
Your Patients Accountable for How
They Eat
Apo B and LDL-P are affected by saturated fat & carbohydrate intake
but I simplify it for my patients since most of the changes here relate to saturated fat
Use sdLDL as a measure of carbohydrate intake! *
*Note: The rule of thumb cited here for the relationship of grams of carbs consumed and specific sdLDL levels is based
on observations in my clinic. While evidence indicates that excessive carbohydrate consumption increases sdLDL, the specific
amount of carb consumption which causes a specific sdLDL level has not been independently established.
P. Siri, et al. “Influence of Dietary Carbohydrate and Fat on LDL and HDL Particle Distributions”, Curr Ath Repts, 2005. 7:455-459
M. Adiels, et al., “Overproduction of Very Low-Density Lipoproteins is the Hallmark of the Dyslipidemia in the Metabolic
Syndrome”, Arterioscler Thromb Vasc Biol. 2008; 28:1225-1236
These Next 4 Biomarkers are Vital!
These biomarkers can be used for:
1. Identifying who is insulin resistant
2. Identifying diabetic genetic expression
3. Identifying how well your treatment is working
at reducing diabetic genetic expression
CHD % Prevalence
20.0
NHANES Data has shown us
that 70% of patients with MI
across the United States are
insulin resistant or diabetic
15.0
10.0
5.0
0
Neither
DM
MS Both DM & MS
Diabetes 2003;52:1210-1214
Sterol / Stanol Testing:
Help with Statin and Cholesterol Blocker Decisions
Normal cholesterol absorption
Elevated cholesterol synthesis
This first time patient has a rather severely elevated Apo B & LDL-P which
measured > 95 percentile. Sterol/Stanol Testing showed that his Sterol Synthesis
Markers were severely elevated while he had normal Sterol Absorption Markers.
Sterol / Stanol Testing:
Help with Statin and Cholesterol Blocker Decisions
Elevated cholesterol absorption
Decreased cholesterol synthesis
This patient has excellent cholesterol synthesis control from her statin which has
caused a compensatory hyperabsorption of cholesterol from the intestines.
Because her Apo B & LDL-P are so good, no cholesterol blocker is needed.
Sterol / Stanol Testing:
Help with Statin and Cholesterol Blocker Decisions
Elevated cholesterol absorption
Decreased cholesterol synthesis
This patient has excellent cholesterol synthesis control from her statin which has
caused a compensatory hyperabsorption of cholesterol from the intestines.
Because her Apo B & LDL-P are not to my goal for her, a cholesterol blocker is
considered. Both Ezetimibe and Colesevelam could be used as cholesterol blockers.
Lp(a) elevation represents a genetically derived
cardiovascular risk factor by adding a
connecting peptide to LDL
particles
Recent Metanalysis that included 41,098
patients from three heart trials demonstrated
that the patients with Lp(a) levels in the top
10% had a 2 - 3 fold higher risk of MI than
those with the lowest Lp(a) levels. 1
In a recent prospective trial involving 3972
community dwelling adults > 65 years of age
and free of vascular disease, followed for an
median of 7.4 years, demonstrated that men
in the highest quintile of Lp(a) compared to
the lowest quintile had a 3 fold increase risk of
stroke, 2.54 fold risk of death from vascular
events, and 1.76 fold risk of death from all
causes. These same risks were not seen in
women in this trial.2
1. Ariyo AA, et al. NEJM. November 27,2003: 349 (22): 2108 -2115
2. Kamstrup PR, et al. JAMA. June 10, 2009; 301(22): 2331-2339
Lp(a) Mass and Lp(a) Particles Testing
Normal Lp(a) Mass, therefore no reflex testing needed for Lp(a) Particles Testing
Elevated Lp(a) Mass thus reflex testing was done to assess Lp(a) Particles, which was normal.
No treatment is need!
Elevated Lp(a) Mass with simultaneous elevated Lp(a) Particles level. Treatment needed.
Hormone therapy reduced the risk of cardiovascular
disease in women with high Lp(a) levels
NOTE: Hormone replacement therapy should be used very
selectively. It should not be used to reduce the general risk of
cardiovascular disease in women.
J.Danik et al., “Lipoprotein(a0, Hormone Replacement Therapy and the Risk of Future
Cardiovascular Events”, J Am Coll Cardiol. 2008 July 8; 52(s):124-131
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 5: Interpreting Advanced Testing Results –
Inflammatory Disease Process Biomarkers
Blocked Artery
Heart Attack
Ruptured Plaque
Heart Attack
> 2 years warning
Appr. 6 - 8 months warning
F Apple et al., Clinical Chemistry,2012; 58:5; 930-935
Marie-Luise Brennan, PhD. et al.,”Prognostic value of Myeloperoxidase in Patients with Chest Pain”, N Engl J Med
October 23, 2003; 349:1595-1604
MPO and Lp-PLA2:
Predictors of Plaque Rupture as Erosions
Develop when Inflammation is Chronic
hsCRP, MPO, Lp-PLA2
MPO & Lp-PLA2
MPO and Lp-PLA2:
Predictors of Plaque Rupture as Erosions
Develop when Inflammation is Chronic
MPO
Lp-PLA2
Predictor of Plaque Rupture
X
X
Released from
polymorphonuclear cells
X
Released from monocytes &
macrophages
X
Oxidizes LDL
X
Makes HDL impotent
X
X
Marie-Luise Brennan, PhD. et al.,”Prognostic value of Myeloperoxidase in Patients with Chest Pain”, N Engl J Med
October 23, 2003; 349:1595-1604
Inflammatory factors have to be
controlled in cardiovascular disease!
Endothelial inflamma.on is at the basis of cardiovascular disease! The pa.ent that controls endothelial inflamma.on is the pa.ent that beats cardiovascular disease!
If your pa.ent does not have an ac.ve infec.on or recent injury, hsCRP is a non-­‐specific marker of systemic inflamma.on but has been correlated with the level of endothelial inflamma.on present in his vasculature. Nothing improves hsCRP levels beGer than a regular exercise regimen!
Other things that improve hsCRP include the use of certain medica.ons and excellent care of inflammatory-­‐inducing medical condi.ons such as diabetes, OSA, depression, CKD, autoimmune disorders, hypertension, & dyslipidemia.
Kadoglou, et al., Eur J Cardiovasc Prev Rehabil. 2007 Dec; 14 (6):837-43
hs-CRP and Fibrinogen Levels
Represent the generalized inflammatory condition in
the endothelium
hs-CRP represents exercise quality,
in my clinical experience
Fibrinogen levels represents
exercise quantity,
in my clinical experience
When the 8 key disease states are controlled satisfactorily from an inflammatory state,
hs-CRP and fibrinogen represent the levels of exercise quality and quantity
Elwood, et al., Epidemiology - Br Heart J, 1993; 69: 183-187
Kadoglou, et al., Eur J Cardiovasc Prev Rehabil. 2007 Dec; 14 (6):837-43
Samia Mora, et al.,Circulation 2006; 114:381-387
Coppola G. et al. Int J Cardiol. 2006; Jan 4; 106(1):16-20
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 6: Interpreting Advanced Testing Results –
Insulin Resistance and Diabetes
Definitions
Diabetes Type 1 - A form of diabetes related to the destruction of pancreatic beta
cell function through an autoimmune mechanism usually occurring during childhood.
Diabetes Type 1.5 - A form of diabetes related to slow-onset autoimmune diabetes
in adults (Often called LADA - Latent Autoimmune Diabetes of Adults)
Diabetes Type 2 - A form of diabetes related to insulin-resistance and relative
insulin deficiency
Diabetes Type 3 - A hybrid form of diabetes affecting the brain’s production of
insulin and/or insulin resistance in the brain. This form of diabetes must coexist with
either Type 1 or Type 2 Diabetes. There appears to be a relationship between Type
3 Diabetes and Alzheimer’s Syndrome.
Making Sense of the Two Hour
Glucose Tolerance Test
2 Hour
Glucose
%BC
Loss
Insulin Resistance Syndrome (IRS)
100 - 139
1-49
Impaired Glucose Tolerance (IGT)
140 - 199
50-79
> 200
80-100
Diabetes Type 2
Advanced Diabetes Prevention and
Management Testing
Advanced diabetes
prevention and
management testing was
used on 2761 fasting high
risk patients being
evaluated for
evidence of insulin
resistance.
28% of the IR patients
would have been missed
had advanced testing not
been done
54% of the patients were identified with insulin
resistance using traditional glucose and HgbA1C
testing.
82%
54%
Patients Detected as Insulin Resistant
82% of the patients were identified as insulin
resistant using advanced testing
Advanced diabetes prevention and management
testing addresses 3 key areas
Glycemic Control
Insulin Resistance
Beta Cell Function
Advanced Diabetes Testing
Biomarker Overview
BG over 12 weeks
BG over 6 weeks
BG over 2 weeks
Brain SIR
Fat Cell SIR
POSSIBLE Recent Carb Excess
MAY indicate “Attitude Issue”
Extremely sensitive
biomarkers for IR
Pancreas SIR
Identifies LADA
Advanced Diabetes Testing can
include 2 hour GTT
JF
Diabetes Glycemic Control
Glucose - Testing the present blood sugar for comparison to other findings
HgbA1C - Looking at the overall blood sugar variability for the last 12 weeks
Estimated Average Glucose - A calculated value that tells you important average glucose values
Fructosamine - Looking at the overall blood sugar control for the last 6 weeks
Postprandial Glucose Index - Looking at the overall blood sugar control for the last 2 weeks
Diabetes Type 2 & Insulin Resistance
Leptin - A hormone secreted from the adipocytes that acts on receptors of the hypothalamus to
suppress appetite.
Adiponectin - A hormone secreted by adipocytes that assists with glucose regulation and fatty
acid oxidation.
Free Fatty Acids - Fatty acids not attached to other molecules, derived from triglycerides or
phospholipids, that provide ATP when metabolized.
Ferritin -An intracellular protein normally used as a measure of iron storage but this biomarker has
recurrently demonstrated epidemiologically to be a marker for insulin resistance syndrome.
Diabetes Type 2 & Insulin Resistance
Biomarkers for early-stage insulin resistance
∝-hydroxybutyrate
Oleic Acid
Linoleoyl-GPC
These are amazing new advanced biomarkers that are highly
sensitive to developing insulin resistance! These biomarkers
often shift as much as 1 1/2 - 2 years before any shift is seen
within the lipoproteins that we also use to watch for
developing insulin resistance (i.e. Apo A1, HDL-P, HDL2, Apo
B:Apo A1 ratio)
Diabetes Type 2 and Beta Cell Function
Insulin Level - Insulin levels are best measured in the fasting state and should be < 10 µU/ml 2 hours
Insulin
levels
arelevels
best measured
in the
fasting
and after
should
be < 10
2 hours
after aLevel
meal.- Insulin
So when
insulin
remain > 10
µU/ml
evenstate
8 hours
a meal,
thisµU/ml
is reflective
a meal. that
So when
insulin levels
remain
> 10 µU/ml
even 8 hours
afteroverworked.
a meal, thisAn
is reflective
ofafter
a pancreas
is struggling
to maintain
glucose
homeostasis
and thus
of a pancreas
that is ultimately
struggling develops
to maintain
glucose
homeostasis
thus overworked.
An
overworked
pancreas
beta
cell burnout
leadingand
to apoptosis
and systemic
overworked reaction
pancreas(SIR)
ultimately develops beta cell burnout leading to apoptosis and systemic
inflammatory
inflammatory reaction (SIR)
Proinsulin:C-Peptide Ratio - Probably the most sensitive measurement for pancreatic beta cell stress
Proinsulin:C-Peptide Ratio - Probably the most sensitive measurement for pancreatic beta cell stress
Anti-GAD - measurement of an autoimmune reaction that when seen in adults leads to a slow beta
Anti-GAD
- measurement
of an
autoimmune
reaction
that
seen
in adults leads
to a slow
beta
cell burnout
correlating with
developing
Diabetes
Type
1.5when
(Latent
Autoimmune
Disease
of Adults
burnout correlating with developing Diabetes Type 1.5 (Latent Autoimmune Disease of Adults
orcell
LADA)
or LADA)
55
Diabetes Type 2
By Far The Most Common Form of Diabetes!
Originates with Insulin Resistance Development
Insulin Resistance Syndrome - 2 Hour Glucose: 100 - 139
Impaired Glucose Tolerance - 2 Hour Glucose: 140 - 199
Diabetes Type 2 - 2 hour Glucose: > 200
Diabetes Type 2 has a pancreatic
beta cell component
Beta Cell Burnout
Fasting insulin levels can identify patients
with an overworked pancreas
• An overworked pancreas is common with insulin resistant patients!
• You can use this fasting insulin level to better assess how effective
your treatment for insulin resistance is.
Diabetes Type 2 has a
genetic component
The genetic expression
can be assessed by looking
at the effect of your treatment
on the Apo A-1, HDL-P,
HDL2-C, and the
Apo B:Apo A-1 Ratio
The genetic expression can also be
assessed by advanced biomarkers.
These new biomarkers appear to be
more sensitive to insulin resistance
changes than earlier lipoproteins
observed for this.
Ignoring that genetic component is like trying to mop up water
from a leaking pipe without turning off the water source!
The Ultimate Target For Diabetes
Type 2 Treatment
Inflammation
Inflammation Related To Blood Sugar
Blood Sugar
Diabetes Type 2 has an inflammatory
component
Basic Inflammatory Factors
Organ Specific Surrogate Inflammatory Markers
Liver
Pancreas
Brain
Fat Cells
Kidney
In Summary
Advanced diabetes testing offers you the ability to
assess whether a patient has: 1) adequate glucose
control, 2) insulin resistance, and 3) beta cell function
disparity.
Advanced diabetes testing gives you tools that lets you
follow the progress of your insulin-resistant patients in
a systematic manner helpful to both you and the
patient.
Advanced diabetes testing helps you avoid overlooking
someone who has insulin resistance problems that
might not be noticed by conventional laboratory testing.
ADA/ AACE
Prediabetes Treatment Standards
 HbA1C
goal < 6.5%
• Diet, weight loss (7%), exercise 150 min/week
• Screen for and treat HTN, CVD/dyslipidemia, CKD, obesity
• Therapy:
• Metformin
• If HbA1C goal not met in 3-6 mos, add acarbose, or with caution, TZD,
DPP4i or GLP-1
ADA/AACE
Diabetes Treatment Standards
 HbA1C
goal 6.5% if young/healthy, 7.0% otherwise, higher in some situations
• Limit carbs, saturated fat
• Aggressive control of HTN
• Biomarker goals:
LDL-C <100, or <70 with CVD
HDL-C >40 (male) or 50 (female)
TG <150
statins if over 40 yrs and any other risk factors
add fish oil, fibrate or niacin (monitor glucose closely) if necessary
ADA/AACE
Diabetes Treatment Standards
•Therapy
• Initial HbA1C < 7.5%
• monotherapy with metformin, acarbose, TZD or GLP-1
• if HbA1C goal not met at 3 mos, dual therapy (add a second agent from
above list or SGLT2, basal insulin, colesevalam, bromocriptine QR)
• If HbA1C goal not met at 3 mos, triple therapy (add a third agent from
above list or insulin)
• Initial HbA1C > 7.5% and < 9.0%
• start with dual therapy per above
• Initial HbA1C > 9.0%
• Consider starting with insulin plus oral agents, esp with diabetes symptoms
The Fillingane Diabetes Treatment to Goal Plan
(This is an experimental protocol used in my clinic, and is not a standard diabetes protocol)
1
Turn off
Genetic Expression
Best done by
use of Actos
and an incretin
product, while
limiting carbs
strictly to < 25
grams every
4 hours
2
Treat pre-diabetes
and diabetes with
emphasis on
inflammatory responses
Target Organ SIR
Liver - sdLDL < 20
Pancreas - Fasting Insulin < 10
Adipocytes - Adiponectin > 16
Leptin:BMI Ratio < 0.66
Cystatin C eGFR > 90
Generalized Inflammatory
Response
hs-CRP < 1
fibrinogen < 390
Follow effect
by monitoring
Apo A1, HDL-P,
HDL2, and
Apo B:Apo A1 ratio
to green zones
Chronic Inflammatory Effect
Myeloperoxidase (MPO) < 350
Lp-PLA2 < 200
3
4
4
5
Treat pre-diabetes
and diabetes with
careful control of
low carb/reduced
fat diet (< 25 grams
carbs every 4 hours)
Treat pre-diabetes
and diabetes type
2 with plans of
disease
state reversal
Treat lipids
with emphasis
on regression
of atherosclerosis
Follow effect
by monitoring
sdLDL to < 20
If patients experience
premature
hypoglycemia
(i.e. feelings of low BS
when actual BS is >100)
teach them the
“Peanut Butter & Water
Trick”
This can only
be done when
you use Actos
with an incretin
product, and
this combo tx
only works if you
have the infl.
effect controlled
Add basal analogue
insulin if HgbA1C
remains > 6 or if Fasting
Insulin Level is > 20
Aim for HgbA1C <
6.0
Patel N, et al. J Am Heart Assoc 2012; 1:e003152
Ayo Toye and Dominique Gaugier, Genome Biol. 2003; 4(12):241
Armato J, DeFronzo RA, Abdul-Ghani M, Ruby R. Endocr Prac. 2011 Nov. 8:1-21
Diethelm Tschoepe and Bernd Stratmann. Eur Heart J Suppl. 2006 Oct 88: F34-F39
A Garg, SM Grundy, and RH Unger. Diabetes 1992; 41:1278-1285
Get LDL-P
< 900
or
Apo B < 50
Ideally it is nice
to get HDL-C > 50
and HDL-P > 35
but emphasis is on
the LDL-P & ApoB
goals
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 7: Interpreting Advanced Testing Results –
Cardiovascular Genetic Factors
Apo E testing can give you an idea how
difficult a cardiovascular fight you
and your patient are getting into
• Apo E2 confers likelihood of higher
triglycerides and VLDL
• Apo E3 is most common Apo E
isoform
• Apo E4 confers higher
atherosclerosis, higher LDL levels,
and higher levels of Alzheimer’s
Syndrome
MTHFR
(Methylenetetrahydrofolate reductase)
folate
dihydrofolate
tetrahydrofolate
MTHFR
methylene-THF methyl-THF
All of the biological functions of folic acid are performed by tetrahydrofolate
Folic Acid does not cross the blood-brain barrier,
but L-Methylfolate does
Both MTHFR Genetic
Abnormalities are treated
by L-Methylfolate 15mg daily
Heterozygous MTHFR Genetic Abnormality C677T - 71% of MTHFR produced
Homozygous MTHFR Genetic Abnormality T677T - 35% of MTHFR produced
Tryptophan
Hydroxylase
Tryptophan
(Enzyme)
MTHFR
Serotonin
(Mood , sleep, appetite
concentration, memory)
Melatonin
(Circadian Rhythm)
(Enzyme)
L-Methylfolate + BH4
L-methylfolate 15mg = folic acid 104mg
(Fifth breakdown product of folic acid)
Tyrosine
Hydroxylase
Both L-Methylfolate and MTHFR regulate BH4
activity that promotes production of serotonin,
melatonin, dopamine, norepinephrine, and nitric
oxide
Tetrahydrobiopterin = BH4
Stahl, SM. CNS Spectr. Vol 12, No 10. 2007:739-744
Tyrosine
Dopamine
(Motivation, reward driven,
attention, ADD when deficient)
BH4
Arginine
Nitric Oxide
Norepinephrine
(Decision making)
How Common Is MTHFR Genetic
Abnormality?
Varies considerably by ethnicity
25% to 75% have one or two copies of
the 677 gene mutation
26% to 59% have one or two copies of
the 1298 gene mutation
The number specifies the position within the gene
MTHFR Genetic Abnormalities lead to
blood vessel issues
Adrenaline
Inflammation increases
leading to erosions &
plaque rupture
Vasoconstriction
in patient’s that
need vasodilation
Nitric Oxide
Patients prone to venous clots are
evident
Heterozygosity for factor V Leiden occurs in approximately 3 -­‐8% of the U.S. and European popula.on. Prevalence for the prothrombin muta.on is similar in these same popula.ons.
Heterozygous carriers of factor V Leiden have an 8 fold increase in risk of venous thromboembolism. Homozygous carriers of factor V Leiden have an 80 -­‐ 100 fold increased risk of venous thromboembolism.
Compound heterozygotes for factor V Leiden as well as prothrombin muta.on or pa.ents with homozygous prothrombin muta.on alone have a 10 -­‐ 15 fold increased risk of venous thromboembolism.
The presence of prothrombin muta.on increases the risk of a second venous thromboembolism event.
VKORC1 & CYP2C9 testing for
warfarin management
VKORC1 (Vitamin K epoxide reductase complex 1) genetic testing can help identify low,
intermediate and high dose warfarin patients.
CYP2C9 variant alleles also affect warfarin dosing and can be tested in your warfarin patients.
There are many CYP2C9 inhibitors including amiodarone, sulfamethoxazole, quinolones,
macrolides, metronidazole, fluconazole, high doses of acetaminophen and vitamin K containing
food.
Now you can know for sure if your aspirin,
clopidogrel, prasugrel, or ticagrelor is working!
We no longer have to guess to see whether or not our patients
have effective treatment for prevention of platelet aggregation.
You can save your patients so much trouble by doing this simple
urine test for medication effectiveness for treatment of platelet
aggregation!
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 8: Interpreting Advanced Testing Results –
Hypertension and Myocardial Stress
Why Early Identification and Aggressive
Treatment of Hypertension Matters
Prehypertension and hypertension independently correlate with
significantly increased morbidity and mortality from CVD
NHANES data indicates only 53% of those treated for HTN were
controlled to < 140/90
Framingham Heart Study data indicates only 48% of those treated for
HTN were controlled to <140/90
Hypertension. 2008; 51:1403-1419, P van den Hoogen et al., N Eng J Med (2000): Vol 342, No 1: 1-8
Why Early Identification of HTN Matters

HTN independently correlates with significantly increased morbidity
and mortality from CVD



Risk factors for HTN and CVD are shared (dyslipidemia, metabolic
syndrome, DM)
HTN causes progressive complications

Vision, kidney, cardiovascular, stroke

Risk of complications is reduced with early detection and effective blood
pressure control
Diagnosis is simple

140/90 is general threshold for HTN and the BP goal for HTN patients
without clinical CVD, diabetes or CKD

130/80 or lower is goal with clinical CVD, high CVD risk, diabetes or CKD
Treating Hypertension

First Line Therapy



Lifestyle (American Heart Association DASH diet and exercise,
smoking cessation, alcohol moderation)
ACEI or ARB; CCB or thiazide diuretic can also be used (two
medications recommended if BP > 160/100)
With clinical CVD (angina, STEMI, LVD, HF), consult AHA
Guidelines for therapy guidance

If not at goal in 2-3 months: Add beta blocker, calcium channel


If not at goal in 2-3 months: Add another agent from above list
If not at goal in 2-3 months: Consult AHA Resistant Hypertension
blocker or thiazide diuretic
treatment guidelines
Adapted from Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease, Circulation 2007;
115:2761-2788, and AACE Comprehensive Diabetes Management Algorithm, Endocr Pract. 203; 19 (No.2)
Biomarkers of Heart Stiffening & CHF
HS Cardiac Troponin I
HS cTnI, NT-proBNP, & Galectin-3
HS cTnI - Ischemia
NT-proBNP - Calcification
Galectin-3 - Fibrosis
NT-proBNP and Galectin 3:
Measurements of a Stiffening Heart
NT-proBNP Key Facts
1. Correlates with heart calcification and stiffening
2. Responds to multiple treatment options including salt restriction,
spironolactone, ACE inhibitor and ARBs, certain Beta Blockers, and possibly
ranolazine
Galectin 3 Key Facts
1.Correlates with heart fibrosis and stiffening
2. Few treatments are available. Modified citrus pectin is showing some
promise in preliminary studies
Vedat Davutoglu, et al. Eur J Heart Fail. 2005; 2005, 7(4):532-536
Jennifer E. Ho, MD, et al. J Am Coll Cardiol. 2012; 60(14):1249-1256
NT-proBNP is an important test
regarding the heart’s condition
Smaller eleva.ons between 125-­‐449 are consistent with diastolic dysfunc.on or mild CHF.
Larger eleva.ons above 450 are consistent with heart failure.
Treatments include salt restric.on in diet, medica.ons including diure.cs/
angiotensin inhibitors/certain B-­‐blockers, and exercise.
There is some evidence to suggest that ranolazine is going to be helpful
Kleber FX and Wensel R., Drugs, 1996 Jan; 51(1):89-98
Galectin 3
De Boer, et al., Annals of Medicine, 2011; 43: 60-68
HD cTnI Facts
HS cTnI Level
•Only produced in the heart
•Released into the bloodstream through normal turnover (normal levels)
•Released into the bloodstream upon cardiomyocyte injury (cardiac
dysfunction levels)
The difference between 1st and 2nd
generation TnI levels
50
40
40 pg/ml
Smallest amount of
detectable cTnI
levels in pg/ml
The first generation
cTnI level is not sensitive
enough to detect ischemia
30
20
10
4.5 pg/ml
0.78 pg/ml
Am Heart J 2010;160:583-94
cTnI
HD cTnI
Coronary ischemia
is first seen at this level
and only detectable by
the HD cTnI testing
HD cTnI levels predict silent ischemia
98 patients
with stable
angina
Monitored over 24 hr period
BP, EKG, Angina questionnaire
17 patients (+) ischemia
HD cTnI
16.1 +/- 23.0 pg/ml
81 patients (-)
ischemia
HD cTnI
5.1 +/- 7.9 pg/ml
p factor < 0.0001
A. Shah et al., JACC March 27, 2012: Volume 59, Issue 13
TIMI 35 Results Related to HD cTnI
Testing Pre- and Post-Stress Testing





120 patients received nuclear stress tests along with pretest HD cTnI
levels and 2 and 4 hour posttest HD cTnI levels
cTnI levels were unchanged in patients that had no ischemia evident
on nuclear stress testing
Patients with mild ischemia evident on nuclear stress test had a
median 1.4 pg/ml (24%) increase of HD cTnI levels comparing preand 4 hour post-stress test HD cTnI levels
Patient with moderate ischemia evident on nuclear stress test had a
median 2.1 (40%) pg/ml increase of HD cTnI levels comparing preand 4 hour post-stress test HD cTnI levels
These changes in troponin levels were not detected using standard
troponin testing
M. Sabatine et al., European Heart Journal; 2009(30): 162-169
Elevated cTnI Predicts CVD Death
Minnesota Heart Survey
9.0
6.8
Odds Ratio
predicting CVD
8.5 fold
increase
risk of
CVD
4.5
2.3
0
< 10 pg/ml
HD cTnI Levels
F Apple et al., Clinical Chemistry,2012; 58:5; 930-935
> 10 pg/ml
Elevated HS cTnI Levels Can Predict
CHF
Sundstrom et al., Euro Heart Journal (2009) 30:773-781
NT-proBNP and HD cTnl Levels
Are Synergistic in Predicting Mortality
Lori B Daniels et al, J Am Coll Cardiol 2008 August 5; 52(6): 450-459
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 9: Interpreting Advanced Testing Results –
Metabolism, Sleep Apnea and Depression
Omega 3 Index
Omega 3 Fatty Acids
An Emerging Cardiovascular Risk Factor
Titrate fish oil dose to achieve Omega 3 Index of 8%.
Standard EPA/DHA Dosing Recommendation:
If Omega 3 Index is 4% to 8%, 0.5 to 1 G per day
If Omega 3 Index is less than 4%, 1 to 2 G per day
Retest in 4 to 6 weeks and titrate dose
In my experience, most patients will need at least 6 - 10
capsules of fish oil per day to achieve an Omega-3 Index > 8.0.
The Mini Fish Oil Capsules at 1290 mg are much smaller than
standard fish oil capsules and thus are often better tolerated.
Vitamin D deficiency has become a recent
“hot topic” in cardiovascular risk factors
NHANES data showed that low levels of Vitamin D were associated with an 80% increase in PAD as well as an increase in all-­‐cause mortality. Framingham Offspring Data studied showed the moderate Vitamin D deficiency was associated with increased cardiovascular disease despite mul.variable analysis.
Wang TJ, et al: Circula.on 2008: 117(4); 503-­‐11
Melamed ML, et al: Atheroscler, Thromb Vasc Biol 2008: 28(6): 1178-­‐1185
Melamed ME, et al., Arch Int Med: 168(15): 1629-­‐1637 Causes of Vitamin D deficiency include: low consump.on such as seen in vegetarian diets, low sunshine exposure, dark skin, aging kidneys unable to convert vitamin D to its ac.ve form, inability to absorb vitamin D (i.e. Crohn’s Disease, Celiac Disease, Cys.c Fibrosis), and obesity.
Vitamin D3
The Only Vitamin that is also a Hormone
Vitamin D3
Activates genes that release neurotransmitters, especially serotonin
NIH estimates
estimates that
that 80
80 -- 90%
90% of
of our
our Vitamin
Vitamin D
D levels
levels come
come from
from sunshine
sunshine exposure
exposure
NIH
Maylead
leadto
toSeasonal
SeasonalAffective
AffectiveDisorder
Disorder(SAD)
(SAD)
May
Seasonaldepression
depressionoccurring
occurringwhen
whensunshine
sunshineexposure
exposureisislimited
limited
Seasonal
causinglimited
limitedserotonin
serotoninproduction
production
causing
Greenblatt, JM. The Breakthrough Depression Solution, Psyc. Today: Nov 14, 2011
Assessing Vitamin D Deficiency
Vitamin D level is significantly low and needs supplementation
Vitamin D deficiency replacement recommendations:
< 20 ng/ml
50,000 units 3x/wk
Ergocalciferol
21 – 40 ng/ml 50,000 units 2x/wk
41 – 50 ng/ml 50,000 units 1x/wk
Maximum D3
< 20 ng/ml
10,000 units 3X/wk
21 - 40 ng/ml 10,000 units 2X/wk
41-50 ng/ml 10,000 units 1X/wk
Thyroid function can impact
cardiovascular health
Thyroid func.on is an oken-­‐
overlooked factor that has been correlated with cardiovascular health.
The TSH biomarker is a simple screening tool for hypo-­‐ or hyperthyroid state.
Titrate oral thyroid hormone to return TSH to within normal range.
Homocysteine Levels
Having difficulty getting respect!
Homocysteine is an area of controversy
in cardiovascular disease!
There are conflic.ng reports related to homocysteine and its importance in cardiovascular treatment. Elevated homocysteine levels do tend to correlate with endothelial dysfunc.on and are thus another indicator of pa.ent risk. Homocysteine is converted back to methionine when you treat with Vitamin B6, B12, folic acid (or L-­‐methylfolate), or trimethlyglycine (a methyl donor).
Studies are ongoing to establish the best clinical steps for high homocysteine. In my experience, treatment with L-­‐methylfolate and Vitamin B12 seems to be useful in high risk CV pa.ents.
Today’s Advanced CV Tests Offer So Much
More Information!
Patient’s MTHFR
genetic abnormality
relates to his
homocysteine elevation
and his inflammatory
status as well as
causing
problems with nitric
oxide production
17.8 initially
Depression: Importance of Screening

Depression is associated with cardiovascular disease

Screening for depression is quick and easy using these two
questions (a “yes” to either suggests depression or need for further
screening*):

“Over the past two weeks, have you ever felt down, depressed, or hopeless?”

“Over the past two weeks, have you felt little interest or pleasure in doing things?”

Several factors which can contribute to cardiovascular disease can
also contribute to depression – treating these may improve both

Severe depression may require referral to a specialist

Mild depression that does not respond to the measures outlined
here may require medication or specialist referral beyond the scope
of this course.
*American Family Physician. 2002 Sep. 15; 66(6): 1001-1009. LisaSharp et al., “Screening for
Depression Across the Lifespan”
Mental Health Factors
Factory
Substrate
Sleep
Brain Chemicals
Depression: Importance of Sleep
Insufficient sleep can contribute to depression
Causes of insufficient sleep can include:
•
•
•
•
Obstructive Sleep Apnea (also correlated with CVD)
Lack of Effective Exercise (also correlated with CVD)
Restless Leg Syndrome
Narcolepsy
Depression: Metabolic Factors
Certain metabolic factors also associated with CVD may contribute
to depression, possibly by interfering with brain chemical
production:
• Problems with folate metabolism, esp. with MTHFR genetic abn.
(L-methylfolate may help)
• Omega-3 Fatty Acids deficiency (fish oil titrated via Omega-3
index may help)
• Vitamin D deficiency (supplementation titrated via Vitamin D
testing)
S. Stahl, CNS Spectr 2007; 12(10):739-744
J. Greenblatt, Psych Today, Nove14 2011
Obstructive Sleep Apnea:
Overview
Obstructive Sleep Apnea = repeated episodes of complete or partial blockage
of upper airway during sleep
Symptoms: fatigue, depression, morning headache, snoring, sudden awakening
during night
Risk factors: overweight, smoking, HDL, CVD risk factors
Diagnosis: history or sleep study (polysomnogram or PSG)
Stages:
•
Mild – 5 to 14 episodes/hour
•
Moderate – 15 to 29 episodes/hour
•
Severe – 30 + episodes/hour
Int J Cardiol. 2013 Sep 8. pii: S0167-5273(13)01671-9. doi:10.1016/j.ijcard.2013.08.088.
Patients with severe OSA
have nearly twice the risk
of CVD and over twice
the risk of stroke as
patients with mild or no
OSA. Moderate OSA also
increases these risks.
Three Physical Exam Characteristics
To Look For In Sleep Apnea Patients
Drooping Soft Palate
Enlarged or Elongated
Tongue
Bilateral Intranasal
Airway Obstruction
Obstructive Sleep Apnea:
Treatment
Mild
•
Weight loss
•
Sleep on side or on wedge pillow
•
Avoid alcohol / sleeping pills
•
Oral appliances that keep tongue forward
•
Consideration of CPAP
Moderate/Severe
•
CPAP or BiPAP
•
Good comfortable fit is key
Moderate/Severe Obstructive Sleep Apnea:
Treatment Evaluation
CPAP devices let you track
usage.
At least 4 hours of CPAP
use per night is the
goal.
There is much more involved in
effectively managing OSA.
Check back for more on this
topic as our CME curriculum
expands
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
Module 10: Interpreting Advanced Testing Results –
Chronic Kidney Disease
Why Early Identification of Chronic
Kidney Disease Matters
CKD independently correlates with significantly increased morbidity
and mortality from CVD
GFR 15-59 mL/min/1.73 m
GFR 60-89 mL/min/1.73 m
GFR 90-150 mL/min/1.73 m
28.4
Percentage
Occurrence
30.0
20.4
22.5
16.7
14.2
15.0
7.5
17.6
4.4 5.0
6.6 5.5
9.3
4.8 3.9
0
All-Cause Mortality
ASCVD Events
Manjunath G, et al. J Am Coll Cardiol. 2003;41:47-55.
De Novo ASCVD Recurrent ASCVD Events
Screening for CKD
 Early CKD is often undertreated

Easy to recognize with advanced biomarkers

Cystatin C is considered very accurate at eGFR estimation in
early CKD while standard BUN/creatinine calculations (MDRD,
Cockcroft Gault GFR) are not considered highly reliable until
CKD Stage 3
 Screen patients with




Hypertension
Diabetes
Dyslipidemia/CVD
CVD risk biomarkers
Markers of CKD


Blood tests

Decreased eGFR

Elevated cystatin C

Elevated serum creatinine
Spot urine tests

Microalbuminuria
 > 3 mg/dL)

Proteinuria
 >250 mg/g (male)
 >355 mg/g (female)

Albumin/creatinine ratio
 >17 mg/g (male)
 >25 mg/g (female)
Staging of CKD
1.
2.
3.
4.
5.
Microalbuminuria with eGFR >= 90
Microalbuminuria with eGFR 60 to 89
eGFR 30 to 59
eGFR 15 to 29
eGFR <15
May require nephrology consultation
when eGFR <60
Slowing CKD and Reducing
CVD Risk
Control Hypertension, Diabetes
Control CVD


Recognize and treat dyslipidemia
Benefits of statin therapy:
Urine Protein Excretion (g/24 hr)


Bianchi S, et al. Am J Kidney Dis. 2003;41:565-570.
3.0
Before Treatment
1 Year
North
2.3
1.5
0.8
0
Atorvastatin + ACE/ARB
Placebo
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
with Sam Fillingane, D.O.
Clinical Case 1: EC
EC’s Diabetes Prevention and
Management Panel
12/03/12
EC’s Glucose Control Appears Good
12/03/12
It appears obvious here
how so many pre-diabetics
and diabetics are slipping
through the cracks of our
older lab analysis markers
The 75 Gram Glucose Challenge Exposed Her Level of IR
Early Recognition of Developing
Diabetes is Good!
Lipoprotein changes that confirm the presence of insulin resistance
Advanced diabetes testing - evidence of insulin resistance
New amazingly sensitive
biomarkers to detect IR
as much as 1 1/2-2 years
before the lipoproteins
show evidence of IR
EC’s Beta Cell Function Analysis
12/03/12
Fasted for 8 hours prior to lab draw
sdLDL-C levels reflect carbohydrate intake
The excess intake of carbohydrates as noted by this significantly
elevated sdLDL-C level noted above suggests there is plenty of
room for dietary improvement to lessen the workload of the patient’s
pancreas. Decreasing the patient’s dietary intake of carbohydrates
to < 25 grams of carbohydrates every 4 hours will help!
EC’s Inflammation Related To Her
Insulin Resistance
12/03/12
Generalized Inflammation
Organ Specific Surrogate Inflammatory Markers
Liver
Pancreas
Brain
Fat Cells
Kidneys
EC’s Advanced Diabetes Panel
7/23/13
EC’s Glucose Control Appears To Be
Improved
7/23/13
7/23/13
Questions To Be Asked:
1. Is there any remaining insulin resistance/diabetic genetic expression?
2. Is there any beta cell stress causing systemic inflammatory reaction?
3. How is the diabetes related inflammatory response ?
Not asking the above questions or not taking care of the above issues
is why so many patients go on to develop small vessel and large vessel
cardiovascular disease issues!
12/03/12
Insulin Resistance after 8 months of
therapy
7/23/13
EC
7/23/13
Insulin Resistance based on the lipoproteins
7/23/13
5/06/13
12/23/12
Insulin Resistance based on advanced diabetes testing
7/23/13
5/06/13
12/23/12
The insulin resistance remaining above is reflective of persisting
Diabetic Genetic Expression
Beta Cell Function
7/23/13
5/16/13
7/23/13
Previous Beta Cell Function Testing
12/23/12
sdLDL-C testing shows improvement in carbohydrate intake
7/23/13
5/16/13
12/23/12
EC’s Inflammation Related To Her
Insulin Resistance
7/23/13
Generalized Inflammation
7/23/13
5/16/13
12/03/12
Organ Specific Surrogate Inflammatory Markers
7/23/13
5/16/13
12/03/12
Liver
7/23/13
Pancreas
Brain
5/16/13
7/23/13
12/03/12
7/23/13
5/16/13
Fat Cells
7/23/13
Kidneys
12/03/12
12/03/12
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
with Sam Fillingane, D.O.
Clinical Case 2: NR
Case 2 NR: New Insulin Resistant Patient
12/05/12
Apo E4 is
high risk for
infl/plaque/rupture
Overeating
sat. fats
Overeating carbs
No evidence here
of insulin resistance
Chronic inflammation
is elevated but not
dangerously yet
2 hour GTT: FBS - 81
2 hour Glucose - 122
Genetic risk
for low brain
chem. & NO
Vitamin D level
is low (needs to
be between 50-70
for neuro protection
Insulin Resistant Syndrome (IRS)
Case 2 NR: New Insulin Resistant Patient
12/05/12
Insulin
Resistance
Note that the first page biomarkers that are used to pick up
on insulin resistance did not show evidence of it like the advanced diabetes panel
Case 2 NR: New Insulin Resistant Patient
12/05/12
Above the 90th percentile of worst “bad
cholesterol levels in the U.S.
Overabsorbing
saturated fat
Over-synthesizing
bad fat
Badly deficient of Omega-3 Fatty Acids
Insulin Resistance is noteworthy on the NMR biomarker analysis!
Case 2 NR: New Insulin Resistant Patient
12/05/12
Medications Prescribed
Rosuvastatin (Crestor)- 10mg - 1 tab daily at bedtime po
Vitamin D2 (Ergocalciferol) - 50,000 units - 1 capsule twice/week po
Fish Oil (Omega-3 Fatty Acids) - 1000 mg - 6 capsules once/day po
L-methylfolate (Deplin) - 15mg - 1 capsule daily po
Case 2: NR
8/26/13
3rd Office Visit
8/26/13
Significant improvement in
“Bad Fat”
Much less carb intake!
Lipoprotein evidence of insulin
resistance showed up later than
the DPMP biomarkers as they
are less sensitive to acute changes
Chronic Inflammatory
changes are slow to improve
1st Office Visit
12/05/12
2nd Office Visit
3/27/13
Case 2: NR
8/26/13
3rd Office Visit
8/26/13
The MTHFR genetic defect
is present in both 677 &
1298 sites. Deplin 15mg
needed daily forever!
The FFA elevation suggests
that attitude needs improvement
The blood sugar control
may be slightly worse, but
the inflammation related to
her insulin resistance is better
Vitamin D level is now good!
Fat Cell Inflammation is better!
2nd Office Visit
3/27/13
1st Office Visit
12/05/12
Case 2: NR
8/26/13
1st Office Visit
12/05/12
3rd Office Visit
8/26/13
Glycemic control
is gradually worsening
despite lessening carbs
in diet
Actos is
started
Insulin Resistance
is clearly evident
and worse than before
2nd Office Visit
3/27/13
Case 2: NR
8/26/13
8/26/13
3/27/13
Goal LDL-P is < 900
Amazing improvement in “Bad Lipid” control
8/26/13
Missing doses of Crestor
Omega-3 Index is almost to goal of > 8.0%
8/26/13
3/27/13
3/27/13 12/05/12
Case 2: NR’s Inflammation Related To
Her Insulin Resistance
All inflammation
appears to be
in control now!
Generalized Inflammation
8/26/13
3/27/13
Organ Specific Surrogate Inflammatory Markers
Liver
Pancreas
Brain
Fat Cells
Kidneys
12/05/12
Beating Cardiovascular Disease:
Understanding the Meaning and Value of
Key Risk Factors
with Sam Fillingane, D.O.
Clinical Case 3: JF
Case 3 JF: New Advanced IGT
Presentation
3/28/13
3/19/13
Overeating sat. fat
Overeating carbs
causing liver SIR
Insulin Resistant
Diabetic Genetic Expression
Exercise quality is
insufficient
Exercise regularity is
insufficient
Evidence of previous problem
with heart fibrosis
Case 3 JF: New Advanced IGT
Presentation
3/28/13
3/28/13
He has both MTHFR
genetic allele
abnormalities
Evidence of
insulin resistance
Evidence of CKD
Stage 2
3/19/13
Case 3 JF: New Advanced IGT
Presentation
3/28/13
3/28/13
3/1913
Glycemic control
problems suggest
moderate problem
with insulin resistance
Insulin Resistance
biomarkers actually
suggest the problem
with IR is severe
The pancreas is
mildly overworked
causing mild SIR
2 hour GTT
His 2 hour GTT suggests
that his Insulin Resistance
has taken him to the
advanced stages of IGT
(essentially a Type 2
Diabetic)
Case 3 JF: JF’s Inflammation Related
to his Insulin Resistance
Generalized Inflammation
3/28/13
Exercise quality is only slightly improved
Exercise quantity is slightly insufficient
Organ Specific Surrogate Inflammatory Markers
Liver
Pancreas
Eating less carbs but
not to goal
Pancreatic SIR has resolved
Brain
Fat Cells
Fat cell SIR is severe
Kidneys
Renal SIR is apparent
3/19/13
Case 3 JF: New Advanced IGT
Presentation
Medications Prescribed
Pioglitazone (Actos)- 30mg - 1 tab daily at bedtime
Extenatide ER (Bydureon) - 2mg - Take 2mg subQ once/week
Modified Citrus Pectin - 600mg - 1 tab twice per day
Rosuvastatin (Crestor) - 10mg - 1 tab daily at bedtime
L-methylfolate (Deplin) - 15mg - 1 capsule daily
Case 3:
7/28/13
5/01/13
Much improved carb intake
Insulin Resistance
appears to have
improved
substantially!
Exercise quality has improved substantially
He is skipping days of exercise
Previously seen heart fibrosis has not returned
3/27/13
Case 3:
7/28/13
5/01/13
The elevated FFA
on this follow-up
visit is c/w with
overeating carbs
within 5 days of this
known blood draw.
This is an
attitudinal issue!
The elevated
homocysteine level
is due to the
MTHFR
genetic
abnormality
Good improvement in
glycemic control
Fat cell
inflammation has
improved
considerably!
3/27/13
Case 3:
7/28/13
5/01/13 3/28/13
7/28/13
Glycemic control has
improved!
Fat cell SIR has
improved
Insulin Resistance is still
present, albeit evidence of
IR not apparent with
lipoproteins
seen on front page
SIR = Systemic Inflammatory Response
Case 3 JF’s Inflammation Related
To His Insulin Resistance
Generalized Inflammation
SIR = Systemic Inflammatory Reaction
7/28/13
Exercise quality has improved
Exercise quantity is not quite enough
Organ Specific Surrogate Inflammatory Markers
Liver
Liver SIR has resolved with
reduced carb intake
Pancreas
Brain
Fat Cells
Kidneys
Fat cell SIR has
resolved
5/01/13
3/28/13
Any Questions?