case study “sk” apoe-om3fa interaction kif6 ldl subclasses downloaded from dmitri vasin md drew...

Case Study “SK”

ApoE-OM3FA InteractionKIF6

LDL Subclasses

Downloaded from www.atheroregression.com

Dmitri Vasin MDDrew Garcia PA-C

Atherosclerosis Regression Clinic Bremerton WA, USA

Downloaded from www.renalremission.com

Doctors Are Not Scientist

• “Some doctors are scientists – just as some politicians are scientists – but most are not… [Scientists are] the kind of people who brush their teeth on only one side of their mouth to see whether brushing your teeth has any benefit”.

• “In their methods of working [doctors] are more like jazz musicians than scientists”.

Richard Smith, M.D. Editorial. BMJ June 14, 2004;328:doi:1136



Case Study “SK”

• 67 y.o. wm 6’2”, 225 lbs, BMI 29• Diagnosed with CAD by Nuclear stress test;

small areas of reversible ischemia; normal EF on ECHO; medical Tx recommended

• Meds: Atorvastatin 80 mg q. hs, Niaspan 1,000 mg q. hs, OM3FA 4 g a day, Perindopril 8 mg q.d., ASA 325 mg q.hs, Meotprolol XL 50 mg q.d.

• LDL decreased 80% on Atorvastatin



Case Study “SK”: ApoE 3/4On and off 4g/d and then on 1 g Omega-3 FA



Standard of Care?

• NCEP ATP III lipid panel guidelines Failed to identify

75% of patients under 55 (n=222) who had first MI

Akosah A. 8th World Congress on Heart Failure. JACC 2003, Vol. 41, No. 9



Residual Cardiovascular Risk in Major Statin Trials

Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.

62%69%73%75%

62%

75%

0

20

40

60

80

100

4S LIPID CARE HPS WOS AFCAPS /TexCAPS

LDL

N 4444 4159 20 536 6595 66059014

-36% -28% -29% -26% -27%-25%

Secondary High Risk Primary

Pat

ien

ts E

xper

ien

cin

g

Maj

or

Co

ron

ary

Eve

nts

, %


Looking Beyond the Numbers

● Vulnerable blood Advanced CVD Profile

plus Apo E

● Vulnerable plaque/artery Lp-PLA2

● Vulnerable myocardium NT-proBNP

Assessment Directs Comprehensive Therapy

Naghavi et al. Circulation. 2003;108


8

Subclasses Better Predictors of CVD

Biomarker Cutpoint n Sensitivity Patients NOT Detected by Biomarker

TRIG ≥ 150 mg/dL 1,723 39% 61%

HDL-C ≤ 40 mg/dL 1,768 40% 60%

TCHOL ≥ 200 mg/dL 1,015 23% 77%

LDL-C ≥ 130 mg/dL 481 11% 89%

%-HDL 2b ≤ 20 % 3,065 70% 30%

%-LDL IIIa+b ≥ 15% 4,036 92% 8%

BHL Internal Study 2006

30% had TG < 100 mg/dl30% had TG < 100 mg/dl

Inflammation Markers — How to Use?

Inflammation indicates that the process ofarteriographic progression may be occurring

• Key is to treat identified disorders more aggressively• Test for elevated levels of Lp-PLA2, hs-CRP, and Fibrinogen

Lp-PLA2 – initiation and progression of atherosclerosis

Blood levels are significantly elevated in advanced plaque stages

1. Ridker PM, et al, Circulation. 19982. Ridker PM, et al. New Engl J Med. 19973. Ridker PM, et al, Circ. 2001

4. Carpenter Keri LH, et al. FEBS Lett. 20015. Macphee CH, et al. Expert Opin Ther Targets. 20026. Packard CH, et al. New Engl J Med. 2000

Lp-PLA2 and CRP: Independent and distinct inflammatory markers

CRP Lp-PLA2

Marker of systemic inflammation

Produced by liver in response to inflammatory reactions – acute phase reactant

May enhance late stage plaque progression promoting plaque instability

Most useful in otherwise healthy individuals

A potentially useful tool for the pharmacological management of CHD patients

Marker of vascular inflammation

An enzyme produced by inflammatory cells

Appears to be involved in the initiation of the early stage of the vascular inflammatory process

Minimal biovariability; Not affected by other inflammatory conditions

A specific target for pharmacologic intervention for the treatment of CHD

Lp-PLA2 and CRP: Independent and distinct inflammatory markers

Lp-PLA2 is an independent predictor of risk from CRP and should be ordered in conjunction with CRP as part of comprehensive risk profile in order to deliver a complete snapshot of the inflammatory process.

Additionally, when both Lp-PLA2 and CRP are elevated to the highest tertile levels, there is a multiplicative impact on risk.

CRP Lp-PLA2 Plaque Formation Acute, non-specific Stroke or Progression Inflammation Risk

- + + - + + - - + + + + + + ++ +++ +++ +++ +++ +++

Important guides in determining intensity of therapy


Case Study “SK”: ApoE 3/4On and off 4g/d and then on 1 g Omega-3 FA


Apo E Genotype Effects on Plasma Lipids

Apo E3 has “normal” lipid metabolism - no genotype impact Apo E2 versus Apo E4 - opposing effects on plasma lipids

● Apo E2 associated with slow conversion of IDL to LDL Decreases plasma cholesterol and increases triglycerides

● Apo E4 limits HDL-binding - inhibits normal cholesterol clearance process (reverse cholesterol transport or RCT) Increases total cholesterol, LDL, and TG and decreases HDL

Mamotte C, Sturm M, Foo J, van Bockxmeer F, Taylor R. Am J Physiol 1999 March;276(3 Pt 1):E553-E557

Therapeutic Implications of Apo E

Interactions between Apo E gene polymorphism, abnormal lipid profiles, and diet and drug therapy have been documented

Therapy targeting the lipid abnormalities resulting from the phenotypic expression of certain Apo E genotypes in response to environmental “stress” factors can mediate their impact on CVD

1. Dallongeville J, Lussier-Cacan S, Davignon J Lipid Res 1992 April;33(4):447-54.2 Schaefer EJ, Lamon-Fava S, Johnson S et al. Arterioscler Thromb 1994 July;14(7):1105-13.3. Sing CF, Davignon J. Am J Hum Genet 1985 March;37(2):268-85.4. Stengard JH, Zerba KE, Pekkanen J, Ehnholm C, Nissinen A, Sing CF. Circulation 1995 January 15;91(2):265-9.5. Wang XL, McCredie RM, Wilcken DE. Arterioscler Thromb Vasc Biol 1995 August;15(8):1030-4.

6. Wilson PW, Myers RH, Larson MG, Ordovas JM, Wolf PA, Schaefer EJ.

JAMA 1994 December 7;272(21):1666-71.

Apo E Genotype and CVD Risk

Apo E2 Response Apo E3 Response Apo E4 Response

Genotype 2/2 2/3 3/3 2/4 3/4 4/4

Population Frequency 1% 10% 62% 2% 20% 5%

CVD Risk Intermediate Normal Highest Risk

( 42%)

Ann Intern Med 2004 July 20: 141(2): 137-47

Apo E Genotype Correlation to Treatment Response


Genotype 2/2 2/3 3/3 2/4 3/4 4/4


Low Fat Diet1,2 LDL

small dense LDL LDL

small dense LDL LDL

small dense LDL

Moderate Fat Diet2 LDL

small dense LDL LDL

small dense LDL LDL

small dense LDL

Moderate Alcohol3 HDL LDL HDL HDL LDL

Effective Statin Response Beneficial No distinction Limited

1. Am J Clin Nutr 2003; 77: 1098-111 2. J Nutr 2004 134: 2517-2522

3. a) Am J Clin Nutr 2001 Apr; 73 (4): 736-45 b) Obes Res 2003 Oct; 11 (10) 1200-6 c) Atherosclerosis 2004 Mar: 173 (1); 79-87 d) J Neural Trans 2003 Apr: 110 (4) : 401-11 e) Proc Nutri Soc 2004 (65) 5-10 f) Art Thromb Vasc Biol 2002: AMy 1: 22 (5) 824-31

Apo E Genotype Correlation to Treatment Response


Genotype 2/2 2/3 3/3 2/4 3/4 4/4


Soluble Fiber1 LDL LDL LDL

Fish Oil2

TG small dense LDL

HDL

TG small dense LDL

HDL

TG small dense LDL

HDL LDL

Plant Sterols3 LDL Apo B

LDL Apo B

LDL Apo B

Soy Protein4 Apo B Apo B Apo B

1. a) Am J Clin Nutr 1997 Sep; 66 (3): 584-90 b) Metabolism 1993 (42): 585-932. Arterioscler Thromb Vasc Biol 2000 Aug; 20 (8): 1990 -73. Nutrition 2002 Jul-Aug: 18 (7-8): 561-54. Nutr Metab Cardiovasc Dis 2000 Dec: 10 (6): 315-22

Apo E Genotype Response Treatment Summary

Apo E Genotype Treatment Surrogate Markers Response

Apo E2

Statin

Moderate Alcohol

Low Fat Diet

LDL

LDL / HDL

Small Dense LDL / limited LDL

Beneficial

Beneficial

Not Recommended

Apo E4

Statin

Moderate Alcohol

Low Fat Diet

Limited LDL

LDL / HDL

LDL / TG / small dense LDL

Limited

Not Recommended

Beneficial

Increases decreases

Therapeutic Implications of Apo E

When managed with treatment algorithms based on the routine CVD analytes supported by consensus guidelines (without Apo E genotype), a significant percentage of patients will be:● sub-optimally treated● managed in a limited way with a “one diet, standard drug therapy regimen

fits all” approach

Conditions for which an Apo E genotype is applicable to make treatment decisions to reduce progression of vascular disease in patients with known hyperlipidemia and/or vascular disease include:● Pharmaceutical recommendation● Diet Recommendation● Alcohol recommendation

Apo E Genotype and CVD Management

Heterogeneity of gene-environment interaction

Heterogeneity of therapeutic response to “accepted” treatments

Establish Apo E genotyping as an important adjunct to an aggressive, targeted, and effective cardiovascular disease management program

● Pharmaceutical Recommendation● Diet Recommendation● Alcohol Recommendation

…..allowing personalization of:


Apo E ¾ Implications for “SK”

• A LOT of exercise• Low (really low) fat diet, including avoidance

of OM3FA, unless indicated for non-lipid effects

• Imperative target to lose waist size/weight to optimal

• Avoidance of alcohol



Case Study “SK”: Apo E 3/4LDL gels On 4g/d and 1 g/d ofOmega-3 FA

4g/d OM3FA

Off OM3FA



Case Study “SK”: Apo E ¾HDL gels On 4g/d and 1 g/d of Omega-3 FA

Off

OM

3FA

4g/d

OM

3FA


Case Study “SK”: ApoE 3/4On 4g/d, 1 g/d and 1+g/d of Omega-3 FA


Downloaded from www.renalremission.comDownloaded from www.atheroregression.com

Case Study “SK”: ApoE 3/4On 4g/d, 1 g/d and 1+g/d of Omega-3 FA


Case Study “SK”Summary of OM3FA and Apo E interactions

• LDL (total and subclasses) trended parallel with dose of OM3FA, with high dose of OM3FA associated with NEGATIVE changes

• HDL (total and especially subclasses) trended reciprocal to dose of OM3FA, with higher dose associated with NEGATIVE changes

• OM3FA are used in SK for its non-lipid effects, i.e. to decrease in CV mortality (GISSI, GISSI-HF trials)

KIF6 Trp719Arg and CHD

● Up to 50% increased risk of CHD in carriers of a common KIF6 variant

– KIF6 719Arg is the risk variant

– ~60% of Caucasians carry one or two risk variant of the gene

– KIF6 encodes a kinesin, a molecular motor protein

● Statin therapy can provide substantial and significant benefit in carriers

Previous Genetic Studies of KIF6 719ArgRisk of CHD in 5 Prospective Studies

● Carriers of the KIF6 719Arg variant (60% of Caucasians) are at greater risk of coronary events compared with noncarriers

● More than 49,000 participants

Patients with prior MI

Patients with LDL-C >178mg/dL

Men and women of ≥65 years old

Middle-aged Americans

0.5 21 1.5 2.5

Initially healthy middle-aged women

ARIC

WHS

CHS

Placebo arm of WOSCOPS

Placebo arm of CARE

Adjusted Risk Ratios

WHS: Shiffman et al. J Am Coll Cardiol 2008; 51:444

ARIC: Bare et al. Genet Med. 2007; 10:682

CHS: Shiffman et al. Arterioscler Thromb Vasc Biol. 2008; 1:173

CHD Event Reduction by PravastatinAccording to KIF6 719Arg Carrier Status

● Carriers of the 719Arg risk allele received significant benefit from pravastatin therapy

● In WOSCOPS, risk reduction was significantly greater in carriers than in noncarriers (Pinteraction = 0.003)

0

2

4

6

8

1.4%

Carriers Non-carriers

CARE WOSCOPS

Non-carriersCarriers

3.5% 4.9%*

P = 0.005 P < 0.0001

Absolute Risk Reduction (%)

3.5% 5.5%* 0.1%

All All

0

5

10

15

20

0 6 12 18 24 30 36

0

5

10

15

20

0 6 12 18 24 30 36

0

5

10

15

20

0 6 12 18 24 30 36

0

5

10

15

20

0 6 12 18 24 30 36

38

Coronary Events According to KIF6 719Arg Carrier Status in PROSPER Patients with Prior Vascular Disease

HR=0.66 HR=0.94

719Arg Carriers Noncarriers

Pravastatin

Placebo

● Among patients with prior vascular disease, carriers of KIF6 719Arg risk allele received substantial and significant reduction of coronary events, whereas noncarriers did not

– 34% relative risk reduction in carriers● Among patients without prior vascular disease, no significant event reduction

Months of follow up Months of follow up

Fatal or nonfatal CHD

P=0.002 P=0.64

CH

D d

eath

or

maj

or

CH

D e

ven

ts (

%)

39

LDL-C Lowering by Pravastatin Therapy In the Elderly with Prior Vascular Disease

● In PROSPER, substantial and significant difference in reduction of events between carriers and noncarriers was observed despite similar reduction of LDL-C levels

● A similar observation was made in PROVE IT–TIMI 22

● An indication of the pleiotropic effect of statins among 719Arg carriers

PROSPER Study

LDL

Cho

lest

erol

(m

mol

/L)

KIF6 Carriers

Noncarriers

Pravastatin

Placebo

1.0

2.0

3.0

4.0

Baseline 3 6 12 24 36Months of follow-up

Statin Intensity and CHD Event ReductionAccording to KIF6 719Arg Carrier Status

● KIF6 carriers received greater benefit from 80mg atorvastatin, compared with 40mg pravastatin, than did noncarriers

● NNT for atorvastatin vs pravastatin:– 10 for KIF6 carriers – 125 for noncarriers

Dea

th o

r m

ajo

r C

V e

ven

ts KIF6 Carriers Noncarriers

Months of follow-up Months of follow-up0 3 6 9 12 15 18 21 24 27 30

0

10

20

30

40

0 3 6 9 12 15 18 21 24 27 300

10

20

30

40

p≤0.001P=1.0

Pravastatin

Atorvastatin

Pravastatin

Atorvastatin

PROVE IT—TIMI22

LDL-C Lowering by Statin Therapy Similar Reduction in KIF6 Carriers and Noncarriers

120

100

80

60

40

20

LD

L (

mg

/dL

)

Baseline 30 Days 4 Mo 8 Mo 16 Mo

KIF6 Carriers

Noncarriers

Pravastatin

Atorvastatin

Time of Visit

PROVE IT

● Similar reduction of LDL-C levels in carriers and noncarriers

● However, event reduction was significantly greater in carriers

KIF6 Variant: Carriers and Noncarriers

Carriers

● Carriers of the deleterious gene variant might benefit from aggressive treatment of modifiable CHD risk factors

Noncarriers

● The absence of significant benefit from intensive statin therapy in noncarriers does not preclude the possibility that a portionof noncarriers do benefit from statin therapy

● But it does suggest that noncarriers may be treated with standard statin therapy and also with other lipid-modifying drugs or by strategies that target other risk factors such as hypertension, diabetes, or smoking

KIF6 719Arg Variant and CHDSummary

● Associated with risk of CHD in 5 prospective studies– ARIC, WHS, CHS, CARE, and WOSCOPS

● Carriers at up to 50% higher risk

● Risk estimate unchanged after adjustment for traditional risk factors

● 60% of Caucasians carry the risk allele

● Carriers received significant event reduction from statin therapy– Standard-dose pravastatin vs placebo– High-dose atorvastatin vs standard-dose pravastatin

Our Take* Primary Prevention and KIF6

●Age <70– KIF6 AA or AT: maximal

dose potent statin (Atorva 80 or Rosuva 20-40)

– KIF6 TT: non-stain therapy (Niacin, Fibrate, Resin, Omega3 FA), statin as 3rd or 4th line therapy

●Age >70● Regardless of KIF6

status: – non-stain therapy

(Niacin, Fibrate, Resin, Omega3 FA), statin as 3rd or 4th line therapy

*Represents current position of Atherosclerosis Regression Clinic *May or may not reflect position of Celera and/or contributing authors


Our Take* Secondary Prevention and KIF6

●KIF6 AA or AT– maximal dose potent

statin (Atorva 80 or Rosuva 20-40)

– non-stain therapy (Niacin, Fibrate, Resin, Omega3 FA**)

●KIF6 TT– non-stain therapy

(Niacin, Fibrate, Resin, Omega3 FA**)

– statin as 3rd or 4th line therapy: Pravastatin 20-40 mg QHS

*Represents current position of Atherosclerosis Regression Clinic ;May or may not reflect position of Celera and/or contributing authors**Limit to 1g qd for ApoE ¾ or 4/4 genotype


Risks of Not Using Berkeley● May miss a lipid disorder or other risk biomarker

● Can’t target intervention or degree of aggressiveness, i.e.; 1,000 mg of niacin or 1,500 mg, 2,000 mg…? 10 mg/d of statin or 40 mg? Combination drug therapy (statin / niacin / fenofibrate) ? Aggressiveness of goal setting? When is it imperative to initiate medication (rather than lose weight)?

● Can’t monitor patient responsiveness to treatment and determine whether to continue to optimize treatment You need greater discrimination to determine if the treatment

plan is effective Monitoring Apo B, LDL IIIa+b, LDL IVb, and HDL2b are key to

monitoring the patient’s progress


Case Study “SK”Summary

• Multiple risk factors were still present despite “optimal” ATP III panel

• OM3FA were clearly associated with adverse changes in LDL and HDL subclasses, as expected with Apo E ¾ genotype

• Even small dose (1 g/d) of OM3FA was associated with adverse lipid effects

• ApoE genotyping can help in individualizing lipid lowering therapy choices (as well as diet, EtOH, and exercise recommendations)

• KIF6 genotyping allowed to optimize statin brand/dose recommendations



Final Comment

48

“If you aren’t confused, you don’t know what’s going on.”Jack WelshFormer CEO General Electric


case study “sk” apoe-om3fa interaction kif6 ldl subclasses downloaded from dmitri vasin md drew...

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