Advancing Patient Management - Genova Diagnositcs...Advancing Patient Management The Role of...

Advancing Patient ManagementThe Role of Genetics in Cardiovascular Disease

October 25, 2017

Doreen Saltiel, MD, FACC

Michael Chapman, NDMedical Education Specialist - Asheville

Doreen Saltiel, MD, FACCMedical Director – Genova Diagnostics

Technical Issues & Clinical Questions

• Please type any technical issue or clinical question into either the “Chat” or “Questions” boxes, making sure to send them to “Organizer” at any time during the webinar.

• We will be compiling your clinical questions and answering as many as we can the final 15 minutes of the webinar.

DISCLAIMER: Please note that any and all emails provided may be used for follow up correspondence

and/or for further communication.

Need More Resources? Ensure you have an account!

Advancing Patient Management

The Role of Genetics in Cardiovascular Disease

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3247.html

• At the end of this presentation, the attendee should:

– Have a better understanding of common genetic polymorphisms (SNPs) that impact cardiovascular disease

• APOE

• LP(a)

• MTHFR

– Understand the importance of the HPA axis and the gut on the development of cardiovascular disease

– Using case studies, better understand advanced lipid testing

Objectives

Clinical Pearl

Vascular disease is a “chronic” inflammatory disease

Gray, et al. Trends in Endocrinology & Metabolism, Vol 22, Issue 10:394 - 403

CORTISOL

Triad 1

VascularDisease

Brain

TRIAD 3

Immune

DetoxHormones

GUTThyroid IR/DM

Common Stressors• HPA axis triggers

– Sleep issues

– Life stressors

• Chronic infections

– All comers

• Toxins

– POPS and PCB’s

– Cigarette smoke

– Traffic exhaust

– Plastics

• Toxins cont.

– Heavy Metals

–Mercury: increases LDL, TG, decreases HDL

– Cadmium: induces IR and metabolic syndrome

– Decrease total antioxidant capacity

Inflammatory Diet!!!

Epidemiology

Image Source: World Heart Federation.

Epidemiology

• Cardiovascular disease (CVD) is the leading cause of death in U.S., despite guideline-driven care

• Recent decline in CVD death rate, but CVD still accounts for 40% of all deaths

• Total CVD healthcare costs in 2011 were $320.1 billion, projected to be $918 billion by 2030

• 50% of people who have had a heart attack have normal LDL cholesterol

Mozaffarian , et al. Circulation. 2015;131:e29-322. Sachdeva, et al. Am Heart J. 2009;157:111-117.e2 http://www.nlm.nih.gov/medlineplus/images/heart.jpg

100

80

60

40

20

0

Res

idu

al M

ajo

r C

oro

nar

y Ev

ents

(%

)

AFCAPS/TexCAPS

6,605

4S

4,444

LIPID

9,014

CARE

4,159

WOSCOPS

6,595Trial

N

HPS

20,536

Secondary Prevention Primary PreventionHigh Risk

62% 75% 75% 73% 69% 62%

-38% -25% -25% -27% -31% -38%

Red

uct

ion

in M

ajo

r C

oro

nar

y Ev

ents

(%

)

[-100]

[-80]

[-60]

[-40]

[-20]

0

Adapted from Libby P. J Am Coll Cardiol. 2005;46(7):1225-1228.

Majority of residual risk remains despite LDL lowering treatment

Genomics

Image Source: https://neuroendoimmune.wordpress.com/

• The most common type of polymorphism is a single point mutation in the genetic code: SNP

• SNPs occur ~ one in every 1000 nucleotides

• The average person has about 3 million SNPs

Facts About Polymorphisms

Image Source: https://www.puregenomics.com/whatsnppage.aspx

Cardiovascular SNP’s

• APOE

• LP(a)

• MTHFR

• Many Others

– LPL, APOB, LDLR, VDR

– COMT, CBS, GSH, GSS

– Factor V Leiden

– Factor II

Image Source: https://blog-biosyn.com/2012/11/28/123/

APOE

Image Source: Genaro Gabriel Ortiz, et al (2015). Genetic, Biochemical and Histopathological Aspects of Familiar Alzheimer's Disease, Alzheimer's Disease. Inga Zerr (Ed.), InTech,.

• Discovered in the 1970’s as a component of lipoproteins

• Is a potent modulator of plasma lipoprotein/cholesterol concentrations

• Synthesized in the liver (75%), brain, spleen, kidneys, macrophages and adipocytes

• Both the exogenous and endogenous lipid metabolism pathways depend on APOE

– Exogenous Pathway via gut; endogenous pathway via liver

• Gut synthesizes chylomicrons; liver synthesizes VLDL

APOE: General Information Dose, et al. Lipids in Health and Disease. (2016) 15:121

• Exogenous pathway

– Chylomicrons (CM) via intestinal synthesis are released into the circulation where they acquire APOE

– CM transport dietary lipids to skeletal muscle, adipose tissue and the liver

– Lipoprotein lipase (LPL) lipolyzes CM → chylomicron remnants (CMR) and free fatty acids (FFA)

– Peripheral tissues (adipose, skeletal muscle) take up and store FFA

– CMR-APOE bind to hepatic surface receptors and undergo hepatic clearance

APOE: Lipoprotein MetabolismDose, et al. Lipids in Health and Disease. (2016) 15:121

• Endogenous pathway

– VLDL particles are synthesized and secreted by the liver w/ APOE

– VLDL transport endogenously synthesized TG, PL, cholesterol/esters to peripheral tissues

– LPL and hepatic lipase (HL) lipolyzes VLDL → FFA + intermediate density lipoproteins (IDL)

– IDL can be cleared by the liver via APOE mediated uptake or can be lipolyzed → FFA + LDL

APOE: Lipoprotein MetabolismDose, et al. Lipids in Health and Disease. (2016) 15:121

• Endogenous pathway cont.

– LDL does not contain APOE, instead has APOB-100 for cellular uptake

• Reverse cholesterol transport (RCT)

– Enables redirection of excess cholesterol from peripheral tissues to the liver via HDL/APOE cellular uptake

– In the vascular wall, APOE secreted by macrophages takes part in cholesterol efflux from atherosclerotic lesions

APOE: Lipoprotein MetabolismDose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal.

15 (2017) 359-365

Dietary fat

Exogenous pathway Endogenous pathway Reverse cholesterol transport

Adipose + sk muscle/macrophages

LPL

Gut

FFA

CMR

CMR

CM

VLDL synthesis

APOE synthesis

APOE

APOE

APOE R

VLDL IDL LDL

APOE

APOE APOE

LPL

APOB-100

FFA

LPL/HLAPOE

HDL

R

Adapted from: Dose, et al. Lipids in Health and Disease. (2016) 15:121

RR

LPL found in heart, skmuscle, adipose

APOE: Isoforms

• General

– APOE3 is most common, occurring ~ 77% of the population

– APOE2 occurs in ~ 8%

– APOE4 occurs in ~ 15%

• Lipoprotein binding preferences

– APOE2 and APOE3 preferentially bind to HDL

– APOE4 preferentially binds to VLDL

Dose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• LDL receptor (LDLR) binding affinity

– APOE3 and APOE4 bind to LDLR with similar affinity

– APOE2 defective in its receptor binding affinity

• Has ~ 1% of APOE3/4’s binding ability

• Plasma concentrations: APOE

– Lower in APOE4/4 compared to APOE3/3

• APOE plasma stability – E2 > E3 > E4

– APOE4 has higher catabolism rate thought to be secondary to:

– Higher affinity for APOE receptor

– Association with VLDL which rapidly converts VLDL remnants to LDL

APOE: Isoforms Dose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• Macrophage-APOE

– Macrophage secreted APOE is atheroprotective – even if it has NO effect on plasma lipid levels

– APOE prevents cholesterol overload and the transformation of macrophages into foam cells

• Intestinal absorption: E4 > E3 > E2

– APOE4/4 absorbs cholesterol with higher efficiency than APOE3/3

– APOE2/2 has the lowest intestinal absorption

APOE: IsoformsDose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• APOE2/2: Type III hyperlipoproteinemia (HLP)

– Rare, inherited disease characterized by elevated total cholesterol and TG, high risk of premature CAD

• HLP requires E2/2, does not occur in heterozygotes

• Only small % (< 5%) of E2/2 carriers develop HLP

– APOE2/2 is necessary, but requires other factors:

• DM, obesity, IR, decreased LDLR activity, hypothyroidism, low estrogen levels

APOE: IsoformsDose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• APOE and brain homeostasis– Because of APOE’s role in lipid metabolism and transport, it plays a

role in brain homeostasis

– APOE regulates:• Lipid and glucose metabolism

• Neuronal signaling

– Astrocyte is main source of APOE• Transported to neurons where taken up by LDLR on neuronal surfaces

APOE: IsoformsDose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• APOE4 associated with increased Alzheimer’s ds; E2 is protective

– Post-mortem AD patient’s brains showed: APOE4 associated w/ increased lipid peroxidation and ROS (blood): ↑Oxidative stress

– APOE4 has a lower affinity for amyloid , thus impaired clearance→ accelerated aggregation and accumulation

– Because of its increased susceptibility to breakdown, APOE4 by-products cause neurotoxicity and promotes AD-like neurodegeneration

– Mitochondrial dysfunction occurs early in pathogenesis of AD, detected years before (E4 individuals) AD onset using PET scanning

APOE: IsoformsDose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• APOE, inflammation and oxidative stress

– APOE has anti-inflammatory and antioxidant properties

• Prevents lipid oxidation (LDL)

– Antioxidant properties are isoform dependent: E2 > E3 > E4

– APOE4 is:

• Associated with an overactive proinflammatory response

• Less effective at down-regulating microglia and peripheral macrophages → increased pro-inflammatory cytokine release

APOE: IsoformsDose, et al. Lipids in Health and Disease. (2016) 15:121Tudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• Diet and Lifestyle

– APOE isoform can influence effect of fish oil on lipid profile

• APOE4 patients supplemented with 3g/d fish oil (EPA/DHA) → worsening of advanced lipid profile; not seen with APOE3

– APOE3

• Quercetin: decreased blood pressure, TNF-

• Curcumin: increased ATP levels

APOE: IsoformsTudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• Diet and Lifestyle

– APOE4

• lipoic acid, acetyl-L-carnitine improve cognitive impairment (mice)

• Higher demand for Vitamin E

• Higher intestinal absorption Vitamin D and calcium

• Benefits from physical activity

– Decreased CV risk

– Improved cognition

APOE: IsoformsTudorache, et al. Computational and Structural Biotechnology Journal. 15 (2017) 359-365

• APOE isoform differences are associated with different phenotypic expressions

• APOE is key to lipid metabolism, neuronal function and inflammation

• Lipoprotein binding: E2/3: HDL; E4: VLDL

• LDLR affinity: E3/4 similar; E2 low

• Intestinal absorption: E4 > E3 > E2

• Plasma stability: E2 > E3 > E4

• Antioxidant: E2 > E3 > E4

APOE: Summary

Lipoprotein(a): Lp(a)

Image Source: http://www.lipoproteinafoundation.org/?page=understandlpa

• 4 categories of lipid disorders

– Elevated LDL

– Elevated TG

– Decreased HDL

– Elevated Lp(a)

• Elevated apolipoprotein B-100 (APOB) lipoproteins causally associated with ↑ CV risk: VLDL, IDL, LDL, Lp(a)

• Raising HDL does not improve CV risk

Lp(a): General InformationTsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Apo(a) synthesized in liver, docks to LDL, forms a disulfide bond with APOB

• The Lp(a) LDL component is from “a newly synthesized” APOB and NOT from VLDL

• Lp(a) longer in plasma than LDL – may be secondary to fact that APO(a) attached near the LDLR binding site – thus interfering with receptor binding

Lp(a): MetabolismTsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Clearance mechanism not well defined

• LDLR modest role

– Statins increase LDLR sites and do not Lp(a), they ↑ Lp(a)

– PCSK9 inhibitors also increase LDLR sites, and they do Lp(a)

• PCSK9 inhibitor: evolocumab

Lp(a): Metabolism

http://www.amsbio.com/images/featureareas/cellular-metabolism/cell-metabolism-mitochondrion-overview.png

Tsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Enhances risk prediction when added to traditional RF

– 39.6% reclassified from intermediate risk to low or high risk

• Risk and Lp(a)

– There is an increased MI risk at levels > 30mg/dl

• 126,634 pts with 1.3 million person-years follow-up

• Risk started to increased at levels > 24mg/dl

• The higher the Lp(a) level, the greater the risk

– 30% population have Lp(a) levels > 25-30mg/dl

Lp(a): CVDTsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Risk cont.

– Even in those with optimal LDL, elevated Lp(a) still increased risk – not LDL-P (study did not evaluate LDL-P)

– 70-80% of those at risk for CVD have low Lp(a) and majority of risk driven by APOB

• APO(a) and plasminogen

– APO(a) derived from plasminogen gene (duplication and remodeling)

– Plasminogen is a proenzyme converted to plasmin by plasminogen activators: tPA (endogenous, iatrogenic), urokinase (iatrogenic)

– Plasminogen almost always in excess of Lp(a) – except very high Lp(a)

Lp(a): CVD Tsimikas. J Am Coll Cardiol 2017;69:692-711

• Atherogenic risk

– Lp(a) quantitatively carries all of the atherogenic risk of the LDL particle

– Lp(a) is more atherogenic than LDL because it contains both APOB and APO(a)

– APO(a), similar to APOB, potentiates atherothrombosis via inflammation – thru its content of oxidized phospholipids (ox-PL, ox-LDL)

Lp(a): CVD Mediated MechanismsTsimikas S. J Am Coll Cardiol. 2017;69:692-711

Adapted from: Tsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Elevated Lp(a) mediates MI, stroke, PAD

• Most potent genetic association with CAD

– More potent than: LDL, PCSK9, 9P21 variants

• LPA gene is probably the strongest monogenetic risk for CAD

– Published data consistent with a causal association

• Those with alleles that do not express APO(a) have a low CVD risk

• Traditionalists, only measure Lp(a) once in a lifetime

Lp(a): GenomicsTsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Racial differences exist in Lp(a) levels, APO(a) isoforms, and LPA SNPs

• Independent risk factor in all racial groups with:

– African descent has the highest Lp(a) levels, followed by South Asians, Caucasians, Hispanics, and East Asians

– Geographic migration of LPA gene out of Africa with additional modifications

• Clinical expression of disease is variable

Lp(a): CVD Risk and RaceTsimikas S. J Am Coll Cardiol. 2017;69:692-711

• There is NO definitive data that statins ↑ Lp(a), HOWEVER, evaluating current published reports suggests that statins ↑Lp(a) by 10-20%

• Pre and post treatment Lp(a), APOB assessment documented an 11% increase in Lp(a) and a 24% increase in APOB

• If using statins:

– Some may not receive full benefit

– Non responders – consider majority of ox-PL on Lp(a), not LDL

Lp(a): StatinsTsimikas S. J Am Coll Cardiol. 2017;69:692-711

Lp(a): Current Therapies

• Niacin

– Decreases Lp(a): 19% - 39%

• PCSK9 inhibitors

– Decrease Lp(a): 20% - 30%

• Estrogens

– Decrease Lp(a): 15% - 20%

• Mipomersen

– Antisense oligonucleotide (ASO)

– ASO to APOB

– Decreased Lp(a): 25%

– Still free APO(a)

• ASO’s to APO(a) (in trials)

– Decreased Lp(a): > 80%

– Significant decrease in: ox-PL, monocyte response

Tsimikas S. J Am Coll Cardiol. 2017;69:692-711

• Independent risk factor for CVD, stroke, PAD

• Large genetic component, phenotypic expression variable

• Both atherogenic and prothrombotic

• Primary contributor to CVD residual risk

• Statins increase Lp(a) by 10% - 20% - ? Optimal benefit

• Statin non-responders, think Lp(a)

• Niacin a viable option to decrease Lp(a), E’s and PCSK9’s too

• ASO’s on the horizon

Lp(a): Summary

MTHFRSAM = S-adenosylmethionineSAH = S-adenosylhomocysteineHomocysteine = HcyMAT = Methionine adenosyltransferaseSAHH = S-adenosylhomocysteine hydroxylase

Image Source: http://www.easytolovebut.com/?p=2782

• General

– SAM is the universal methyl donor

– SAH inhibits most methyltransferases, so must be metabolized to homocysteine (hcy) to avoid accumulation

• Regulation

– ↑ SAM inhibits MTHFR and activates CBS activity

– ↑ Methionine →↑ SAM → hcy bkdwn via transsulfation pathway

– Methionine → SAM → conservation hcy + remethylation

MTHFR: RememberBlom, et al. J Inherited Metab Dis (2011) 34:75-81Crider, et al. Adv Nutr 3: 21-38, 2012

Methylation

Thyroid Brain

Blood Vessel

DDAH: Dimethylarginine DimethylaminohydrolaseADMA: Asymmetric Dimethylarginine

DDAH

ADMA

Blom, et al. J Inherited Metab Dis. (2011) 34:75-81Crider, et al. Adv Nutr. 3: 21-38, 2012Hall, et al. Arterioscler Thromb Vasc Biol. 2014;34(9):2160-2167Voutilainen, et al. Plos One 2007(1) e181Cooke, et al. Arterioscler Thromb Vasc Biol. 2011 July; 31(7): 1462-1464

• 80% ADMA degraded in cell by DDAH• DDAH activity decreased by oxidative

stress, ROS, inflammation, etc

Methylation and COMT Blom, et al. J Inherited Metab Dis. (2011) 34:75-81Crider, et al. Adv Nutr. 3: 21-38, 2012Hall, et al. Arterioscler Thromb Vasc Biol. 2014;34(9):2160-2167Voutilainen, et al. Plos One 2007(1) e181Cooke, et al. Arterioscler Thromb Vasc Biol. 2011 July; 31(7): 1462-1464

COMT = catechol-O-methyl transferaseGSH = Glutathione-S-transferase

Additional Important

LDL particle number (LDL-P)

Image Source: http://www.mpbio.com/product.php?pid=0859392&country=223

LDL-P is a more sensitive biomarker and prognostic indicator of coronary events. “In those with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.”

Cromwell, et al. J Clin Lipidol. 2007; 1(6): 583-592Otvos, et al. J Clin Lipidol. 2011; 5(2): 105-113

Small LDL

Large LDL

CholesterolBalance

100 mg/dL 100 mg/dL

Same LDL-C level, the # of LDL particles vary

Up to 70%More Particles

Curr Atheroscler Rep 2008 Oct;10(5):377-85

Lp-PLA2

Image Source: Zalewski A, et al. Clinical Chemistry. 2006;52(9):1645-50.

• Lp-PLA2

– Lp-PLA2 is produced primarily by monocytes and macrophages

– Lp-PLA2, as opposed to CRP (a nonspecific inflammatory marker), when released is specific for vascular inflammation and is pro-atherogenic

• This enzyme cleaves oxidized phospholipids generating pro-inflammatory molecules and oxidized fatty acids (triggers of the inflammatory cascade)

– Lp-PLA2 lipoprotein association is dynamic depending on the environment

• Its lipoprotein association determines its function: anti vs pro-oxidant

Independent RF: Lp-PLA2

Persson, et al. Arterioscler Thromb Vasc Biol. 2007;27:1411-1416Maiolino, et al. World J Cardiol. 2015; 7(10): 609-620Kim, et al. Nutr Metab. (2016) 13:3Wang, et al. J Geriatr Cardiol. 2017; 14: 135-150.

• Lp-PLA2

– With inflammation, 80% bound to LDL (APOB) and 20% HDL, and Lp(a) when Lp(a) > 30mg/dl

– It is found within the atherosclerotic plaque in thin fibrous caps, ruptured plaques as well as in advanced atherosclerotic lesions

– Elevated Lp-PLA2 levels are associated with increased cardiovascular events in presumed healthy, high risk (Met-S), and known CAD

– No large studies that consistently demonstrated that lowering Lp-PLA2 decreased events event rates

Independent RF: Lp-PLA2

.

Persson, et al. Arterioscler Thromb Vasc Biol. 2007;27:1411-1416Maiolino, et al. World J Cardiol. 2015; 7(10): 609-620Kim, et al. Nutr Metab. (2016) 13:3Wang, et al. J Geriatr Cardiol. 2017; 14: 135-150..

• Genetic determinants

– Caucasians carry higher Lp-PLA2 activity than Hispanics and African-Americans

– 10% lower in females than males

• Possibly 20 to increased estrogens, which down-regulate the enzyme activity

– The Lp-PLA2 gene (PLA2G7) is associated with multiple polymorphisms – some increase activity, some decrease activity

Independent RF: Lp-PLA2

Persson, et al. Arterioscler Thromb Vasc Biol. 2007;27:1411-1416Maiolino, et al. World J Cardiol. 2015; 7(10): 609-620Kim, et al. Nutr Metab. (2016) 13:3Wang, et al. J Geriatr Cardiol. 2017; 14: 135-150.

Case Studies

Case 1: 47 year old female

• Pertinent history– Father died at 47 of a massive

heart attack (FH)

– Stressful job – lawyer; sleeps 6 hours each night

– Diet is SAD – mainly fast food

– Bowel habits – irregular

– Hormones: still cycling

• Pertinent exam findings– Mildly overweight – mainly

abdominal obesity waist circumference ~ 37”

– Hypertension – 145/90

• Pertinent labs– FBS = 120, Fasting Insulin = 16,

HbA1c = 5.9, Adiponectin = 10

– Thyroid: TSH= 1.0, T4 = 1.3, T3 = 3.5

w/o antibodies

– Vitamin D = 30

– Pregnenolone = 80

Case 1: 47 year old female

Case 1: GI Effects

Case 1: Lipids

A1298C: impactsCOMT, BH4

Case 1: Genomics

Case 1: Summary - Treatment

• Sleep 8 hours

• Meditation, coherence training, gentle exercise

• Adaptogens, DHEA, multivitamin, MgHPA: Sleep, work, etc

• Diet: ↑ Fat (good fat), low carbohydrate (75grams), mod protein (plant based), gluten free, dairy free, yeast freeMet-S: IR, WC, FBS, HTN

• LDL-P, HDL-P: Niacin, balanced O3, CoQ10

• HS-CRP: ↓inflammatory burden, O3, curcumin/quercetin

• Homocysteine: Methyl B vitamins, methyl folateVascular

• Trimethoprim-sulfamethoxazole x 10 days; Nystatin x 2 months, oil of oregano x 6 months

• ProbioticsGut

Case 1: 4 Month Follow-up

• Pertinent history

– Sleeping 8 hours, still fatigued – and has no energy

– Stressful job – lawyer

– Diet is yeast free, gluten, dairy free

– Bowel Habits – regular – 2-3x/d

– Hormones: still cycling

• Pertinent exam findings– Lost 15 pounds

– Normotensive

• Pertinent labs– FBS = 100, Fasting Insulin = 16,

HbA1c = 5.9, Adiponectin = 10

– Vitamin D = 75

Case 1: 4 Month Follow-up

Case 1: 4 Month Follow-up: Lipid markers

WHAT DO YOU THINK?

WHAT DO YOU WANT TO DO?

Case 1: 4 Month Follow-up

• Additional history– Mold exposure: yes- water leak

and obvious mold – never addressed

• Additional labs– VCS test

– C4a

– C3a

– TGFB1

– NutrEval

• Results– VCS test failed

– C4a: 11,550

– C3a: normal

– TGFB1: 15,550

– Genomics: • 11/3/52B (multiple susceptibility)

• DQ2/DQ8: negative

• CBS – no SNP

– NutrEval: methionine, glycine, serine, sarcosine, B-vitamins, glutathione: optimum

Case 1: Summary - Treatment• Sleep 8 hours

• Diet: ↑ Fat (good fat), low carbohydrate (75grams), mod protein (plant based), gluten free, dairy free, yeast free

• Meditation, coherence training, walking

• Adaptogens, DHEA

HPA: Sleep, diet, work

• Cholestyramine: titrate to 4 packets a day – 2 hours before or after food

• RemediationBiotoxin illness

• LDL-P, HDL-P: Niacin, balanced O3, CoQ10

• HS-CRP: ↓inflammatory burden, O3, curcumin/quercetin

• Homocysteine: Methyl B vitamins, methyl folateVascular

• Multivitamin, Mg, ProbioticsGeneral

Case 1: 10 Month f/u – 6 Months Post Mold tx

Addressing the root cause decreases inflammation, oxidative stress

decreases CV risk

Clinical Pearl

Doreen Saltiel, MD, FACCDirector of Medical Education

Genova Diagnostics

QUESTIONS

Targeted Treatments

• Diuretics

– Decrease: Na, K, Mg, Cl, PO4, Cl, Zn, Iodide, CoQ10, Folate, B1, B6, B12, Selenium

– Increase: Homocysteine, Glucose, Creatinine

• Beta Blockers

– Decrease: CoQ10

• Ace Inhibitors + ARB’s

– Decrease: Zinc

• Statins

– Decrease: CoQ10, Selenium, O3 FA, Vitamin E, Vitamin A, Vitamin D, Carnitine, Free T3 (FT3)

– Increase: Lp(a)

Nutrient Depletion: Drug Induced

• Total LDL

– RYR: 2400-4800mg QHS

– Balanced O3 FA• 3:2 EPA: DHA

• 2:1 O3:GLA

• 10:1 O3: G/D mixed tocopherols

– Niacin: 500mg – 2000mg QPM

– Plant sterols: • Moducare: 2 BID (2-3 grams/D)

Targeted Treatments

• LDL Particle #

– Niacin: 500mg – 2000mg QPM

– Balanced O3

– Statins: Q week: PM

• LDL Particle Size (B→A)

– Niacin: 500mg – 2000mg QPM

– Balanced O3

– Plant Sterols/Moducare: 2 BID (2-3g/d)

Targeted Treatments

• APO B

– Niacin: 500mg – 2000mg QPM

– Balanced O3

• LDL Oxidation

– EGCG: 500mg BID

– Aged Garlic: 1200mg BID

– MUFA: • Olive leaf extract 500mg BID,

• Olive oil: 3-4 tablespoons = 40-50gms

– Lycopene: 10mg BID

• Inhibit/ ↓ LDL glycation

– Carnosine: 500mg BID

• ↓ LDL Burden

– RYR: 2400-4800mg QHS

– Berberine: 500mg BID

– Plant Sterols: Moducare 2 BID

• Inhibit PCSK9

– Berberine 500mg BID

Targeted Treatments

• HDL Particle #

– Balanced O3

– Niacin

– Pantethine: 450mg BID

• ↓ Cholesterol Absorb

– Plant Sterols

– EGCG

– Sesame

– Fiber: 40-50g/day

• Improve HDL Function

– ↓ Inflammation

– Quercetin: 500mg BID

– Pomegranate: 8oz or 1 cup seeds QD

• ↑/improve Reverse Chol Transport

– Lycopene: 20mg QD

• ↓ TG

– Balanced O3

– Niacin

Targeted Treatments

• ↓ TG

– Balanced O3

– Niacin

• ↓ Cholesterol Absorb

– Plant Sterols

– EGCG

– Sesame

– Fiber: 40-50g/day

• ↑Bile Acid Excretion

– Plant Sterols

– Sesame

– Fiber

• Inhibit NADPH oxidase

– NAC

– Berberine

– Resveratrol: 250mg QD

– Lycopene

– Curcumin

– Luteolin

Targeted Treatments

• ↓ Lp(a)– **NAC + Vitamin C

• NAC: 500mg BID

• Vit C: 500mg-1000mg BID

– **Niacin

– Aged Garlic: 1200mg BID

– O3 FA (balanced)

– E’s

– Tocotrienols: 200MG QPM

– CoQ10: 300mg QD-BID

– L-Carnitine: 500mg -3g BID

• Lp(a)

– Proline: 500mg-1g BID

– Lysine: 500mg-1g BID

– Flax seed

– ** If cannot lower: Nattokinase 50 BID + Vitamin C: 2 gms QD

– Note: Statins: increase Lp(a)

Targeted Treatments

• Lp-PLA2

– Niacin

– O3

– Statins

– Fibrates

• HS-CRP

– Exercise

– Balanced O3

– Curcumin: 1g BID

– Quercetin: 500mg BID

• Homocysteine– Genetics

– Methyl Folate: 1-2g/D

– Methyl B vitamins

– TMG: 500mg BID

– SAM-e: 400mg BID -TID

– Aged Garlic: 600mg-1200mg BID

• Inflammation– Balanced O3

– Curcumin: 1G BID

– Quercetin: 500mg BID

– Aged Garlic: 600mg -1200mg BID

Targeted Treatments

• Fibrinogen

– Curcumin: 1g BID

– Aged Garlic: 1200mg BID

– G/D Tocotrienols: 200mg QPM

• Stabilize Plaque

– Balanced O3

– Vitamin K2Mk7

– Aged Garlic

– Statins

• Plaque Burden/ progression/↑regression

– Balanced O3

– Vitamin K2Mk7

– Aged Garlic

Questions?

Explore

WWW.GDX.NET for more information and

educational resources, including…

LEARN GDX – Brief video modulesLIVE GDX – Previous webinar recordings

GI University – Focused learning modules

Conferences – Schedule of events we attend

Test Menu – Detailed test profile information________

MY GDX – Order materials and get results

Michael Chapman, NDModerator

Doreen Saltiel, MD, FACCPresenter

US Client Services: 800-522-4762

UK Client Services: 020-8336-7750

Please schedule a complimentary appointment with one of our Medical Education Specialists for questions related to:

– Diagnostic profiles featured in this webinar

– How Genova’s profiles might support patients in your clinical practice

– Review a profile that has already been completed on one of your patients

We look forward to hearing from you!

Additional Questions?

November 15, 2017

Updated Guidelines for Assessing

& Treating SIBOChristine Stubbe, ND, FABNO

Register for upcoming LIVEGDX Webinars online at WWW.GDX.NET

Upcoming LIVEGDX Webinar Topics

Advancing Patient ManagementThe Role of Genetics in Cardiovascular Disease

October 25, 2017

Doreen Saltiel, MD, FACC