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Advancing Patient ManagementThe Role of Genetics in Cardiovascular Disease
October 25, 2017
Doreen Saltiel, MD, FACC
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Michael Chapman, NDMedical Education Specialist - Asheville
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Doreen Saltiel, MD, FACCMedical Director – Genova Diagnostics
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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.
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Need More Resources? Ensure you have an account!
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Advancing Patient Management
The Role of Genetics in Cardiovascular Disease
http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3247.html
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• 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
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Clinical Pearl
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Vascular disease is a “chronic” inflammatory disease
Gray, et al. Trends in Endocrinology & Metabolism, Vol 22, Issue 10:394 - 403
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CORTISOL
Triad 1
VascularDisease
Brain
TRIAD 3
Immune
DetoxHormones
GUTThyroid IR/DM
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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!!!
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Epidemiology
Image Source: World Heart Federation.
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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
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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
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Genomics
Image Source: https://neuroendoimmune.wordpress.com/
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• 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
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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/
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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,.
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• 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
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• 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
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• 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
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• 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
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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
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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
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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Lipoprotein(a): Lp(a)
Image Source: http://www.lipoproteinafoundation.org/?page=understandlpa
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• 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
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• 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
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• 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
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• 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
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• 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
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• 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
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Adapted from: Tsimikas S. J Am Coll Cardiol. 2017;69:692-711
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• 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
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• 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
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• 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
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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
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• 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
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MTHFRSAM = S-adenosylmethionineSAH = S-adenosylhomocysteineHomocysteine = HcyMAT = Methionine adenosyltransferaseSAHH = S-adenosylhomocysteine hydroxylase
Image Source: http://www.easytolovebut.com/?p=2782
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• 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
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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
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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
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Additional Important
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LDL particle number (LDL-P)
Image Source: http://www.mpbio.com/product.php?pid=0859392&country=223
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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
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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
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Lp-PLA2
Image Source: Zalewski A, et al. Clinical Chemistry. 2006;52(9):1645-50.
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• 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.
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• 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..
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• 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.
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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
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Case 1: 47 year old female
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Case 1: GI Effects
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Case 1: Lipids
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A1298C: impactsCOMT, BH4
Case 1: Genomics
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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
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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
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Case 1: 4 Month Follow-up
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Case 1: 4 Month Follow-up: Lipid markers
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WHAT DO YOU THINK?
WHAT DO YOU WANT TO DO?
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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
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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
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Case 1: 10 Month f/u – 6 Months Post Mold tx
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Addressing the root cause decreases inflammation, oxidative stress
decreases CV risk
Clinical Pearl
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Doreen Saltiel, MD, FACCDirector of Medical Education
Genova Diagnostics
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QUESTIONS
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Targeted Treatments
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• 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
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• 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)
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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
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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
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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
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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)
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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
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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
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Questions?
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Michael Chapman, NDModerator
Doreen Saltiel, MD, FACCPresenter
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Additional Questions?
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November 15, 2017
Updated Guidelines for Assessing
& Treating SIBOChristine Stubbe, ND, FABNO
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Upcoming LIVEGDX Webinar Topics
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Advancing Patient ManagementThe Role of Genetics in Cardiovascular Disease
October 25, 2017
Doreen Saltiel, MD, FACC