Important or Imposter? HDL - Cholesterol

The wider roles of HDL

HDL and Reverse Cholesterol Transport

Phospholipid GlycosphingolipidCholesterol

Lipid RaftNormal Cell Membrane

Membrane rafts are small (10–200 nm), heterogeneous cholesterol & sphingolipid-enriched domains.

ABCA1

Lipid-poor apoAI Nascent,

discoidal HDL

DiffusionSR-B1

CE

LCATMature,

spherical HDL

ABCG1DiffusionSR-B1

Pharmacologic Inhibition of CETP: A Novel HDL-raising Strategy

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEFC

Feces

Pharmacologic Inhibition of CETP: A Novel HDL-raising Strategy

A-I

Liver

CECE

FCFCLCAT

FC

Bile

SR-BI

A-I

ABCA1

Macrophage

CEB

LDLR

VLDL/LDL

CETP

CE

TG

FC

Feces

A-I

CEFC

FCLCAT

Bile

SR-BI

A-I

ABCA1Macrophage

Feces

FCBA

Liver receptor X (LXR) Promotes Reverse Cholesterol Transport:

ABCG1

FCLXR

LXR

LXR

FC

ABCA1ABCA1

LXR

LXR

HDL Clinical Conditions

CONDITION HDL level CVD risk

Apo A1 deficiency absent severe

Tangiers disease (ABC A1 defect) very low ? increased

LCAT deficiency (& fish eye disease) very low ? uncertain

Apo A1 Milano (dimer formation) very low ? reduced

SRB1 deficiency (female infertility)very high ? unaltered

CETP deficiency very high ? reduced

Beyond HDL-C: Laboratory assessment of reverse cholesterol efflux (by plasma)

HDL Therapy

DRUG(S) Mechanism and HDL effect CVD effect

Ezetimibe, fish oil Nil relevant? Neutral mild benefit

BAS resins FXR Mild increase mild benefit

Statins HMGCoARI Mod. increase major benefit

Fibrates PPAR alpha Mod. increase benefit in MS

Niacin Reduced catabolism Increase ?benefit

CETP Inhibitors CETPI Huge increase uncertain

Novel (eg antiPCSK9) PCSK9Mild increase uncertain

HDL Evidence: Epidemiology and trials

STUDY or TRIAL HDL observation CVD effect

Observational (eg Framingham) inverse relation protective

Angiographic (Niacin, eg CLASS) large increase regression(CETP, eg ILLUSTRATE) large increase neutral

RCT (Niacin, eg AIM-HIGH) large increase flawed neutral(Fibrate, eg VA-HIT) small increase protective(Fibrate in MS, eg FIELD) small increase protective

(Torcetrapib, eg ILLUMINATE) very large increase detrimental(Dalcetrapib, eg DALOUTCOMES) large increase neutral

Antioxidative Activity

AntithromboticActivity

Potential Antiatherogenic Actions of HDL

Anti-infectious Activity

EndothelialRepair

Chapman MJ, et al. Curr Med Res Opin. 2004;20:1253-1268.Assmann G, et al. Annu Rev Med. 2003;53:321-341.

AntiapoptoticActivity

ReverseCholesterolTransportCellular

CholesterolEfflux

Anti-inflammatoryActivity

VasodilatoryActivity

HDL

Apo A-I

Apo A-II

HDL composition is complex:Protein and phospholipid components

Could HDL become “dysfunctional”?

http://www.lipidsonline.org/slides/slide01.cfm?tk=19&pg=1

0

1

2

3

CH

D R

ISK

100 160 220 LDL- cholesterol

(mg/dL)

* Men aged 50-70

85 65

45 25

HDL-C (mg/dL)

Plasma HDL Predicts Events in Population Studies

Structure of HDL

Surface monolayer ofphospholipidsand free cholesterol

Hydrophobic core of triglycerideand cholesteryl esters

apoA-I

apoA-II

Note: LFA1 denotes Lipid Free Apo Lipoprotein A1 r HDL denotes Reconstituted HDL

Non-occlusive Silastic Peri-arterial Carotid Collar in Male NZ White Rabbits

Carotid arteryCollar

Treated Artery Post Two Infusions of LFA1

BA C

CD 18

Apo A1 Milano Infusions Lead to Significant Regression of Coronary

Atherosclerosis (IVUS Study)

.

Nissen, S. E. et al. JAMA 2003;290:2292-2300

Cases

Mr A.M.

• Mr A.M. Is a 34 year old man of aboriginal descent who lives in rural NSW. His BP is 135 / 85. He was started on Rosuvastatin 20 mg because he has a very strong family history of premature cardiovascular disease (father, paternal aunt, 2 maternal uncles and older brother suffered onset of cardiovascular disease before age 45). Waistline is prominent and measures 98cms, but he is thin elsewhere. He had recurrent otitis media as a child and his dentition is poor. Follow-up lipids include TC=4.1, TG=2.9, HDL=0.5, LDL=2.3

Questions about Mr A.M.

• Is Mr A.M. eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule Guidelines? Yes / No

• Mr A.M’s very low HDL-C is mainly due to A) Racial factorsB) Intercurrent infection C) Central Obesity / Lifestyle D) Mendelian genetic factors E) Lack of exercise

• Which other racial groups have been documented to have relatively low HDL levels (2 correct). A) Kiwis B) Indians C) Finns

D) Turkish E) Sub-Saharan Africans

• In rural NSW, the most feasible treatment to improve this man’s HDL-C is A) Fish oil B) An exercise programme C) NiacinD) Fibrate E) Antibiotic

• Mr A.M’s very low HDL-C is mainly due to A) Racial factors B) Intercurrent infection C) Central Obesity / Lifestyle D) Mendelian genetic factors E) Lack of exercise

• Is he eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule Guidelines? Yes / No

• In rural NSW, the most feasible treatment to improve this man’s HDL-C is A) Fish oil B) An exercise programme C) Niacin

D) Fibrate E) Antibiotic

Mr A.M. is a 34 year old man of aboriginal descent who lives in rural NSW. His BP is 135/85. He was started on Rosuvastatin 20 mg because he has a very strong family history of premature cardiovascular disease (father, paternal aunt, 2 maternal uncles and older brother suffered onset of cardiovascular disease before age 45). Waistline is prominent and measures 98cms, but he is thin elsewhere. He had recurrent otitis media as a child and his dentition is poor. Follow-up lipids include TC=4.1, TG=2.9, HDL=0.5, LDL=2.3

Is Mr A.M. eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule

Guidelines?

• Yes

• / No

Is Mr A.M. eligible for Rosuvastatin according to Pharmaceutical Benefits Schedule

Guidelines?Was “yes”, now “no”

•Family history of symptomatic CHD:before age 60 years in one or more first-degree relatives•before age 50 years in one or more second-degree relatives

≤ 18 years at treatment initiationLDL-C > 4 mmol/L> 18 years at treatment initiationLDL-C > 5 mmol/L or total-C

> 6.5 mmol/Lor total-C > 5.5 mmol/L and HDL-C

< 1 mmol/L

Close the Gap scheme

• In Nov 2008 COAG agreed to $1.6 billion for CTG• Benefit: Lower or nil payment for PBS medicines• Eligible: Aboriginal/ Torres Strait Islander of any age who

present with chronic disease or at risk of chronic disease AND would have significant setback from disease if they did not have Rx or unlikely to comply with out such assistance

• Register: at GP in the Indigenous Health Incentive under PIP or Indigenous Health services.

• Prescriber: Any in a practice participating in IHI under PIP or any in HIS or any specialist in any location if the patient is registered and the patient has been referred a doctor in IHI program.

• Script: CTG

• For more informationEmail: PBS-Indigenous@health.gov.au

Mr A.M’s very low HDL-C is mainly due to

• A) Racial factors

• B) Intercurrent infection

• C) Central Obesity / Lifestyle

• D) Mendelian genetic factors

• E) Lack of exercise

Mr A.M’s very low HDL-C is mainly due to..Reasons for a preference for “A”, “B” or “C”

Which other racial groups have been documented to have relatively low HDL

levels ?• A) Kiwis

• B) Indians

• C) Finns

• D) Turkish

• E) Sub-Saharan Africans

Which other racial groups have been documented to have relatively low HDL levels “B” supported by INTERHEART, but difficult

to compare, eg “D”.

Acta Cardiol. 2007 Oct;62:453-9. Do Turkish adults really have lower serum levels of high-density lipoprotein cholesterol?Duran S, Memisogullari R, Coskun A, Yavuz O, Yuksel H.

CONCLUSIONS:Our finding that the HDL-C level in this population was higher than the previously reported levels in Turkey indicates that HDL-C levels may not be as low as previously thought. We believe that lower HDL-C levels that were previously reported might be due to the difference between techniques of analysis, nutritional status, and percent of subjects who were fasting in the day of analysis or improper subject inclusion which did not reflect the Turkish population causing selection bias.

In rural NSW, the most feasible treatment to improve this man’s HDL-C is...

• A) Fish oil

• B) An exercise programme

• C) Niacin

• D) Fibrate

• E) Antibiotic

In rural NSW, the most feasible treatment to improve this man’s HDL-C is...

The case for “D”

Acyl-CoASynthase

Acetyl CoA

FFA

apo A-Iapo A-IIABCA1

apo C-IIIApo A-V

TG

Liver Circulation

… by controlling

the expressio

nof PPAR

target genes

Results

LPLDecreased small and

dense LDLParticles

LDL

Increased VLDL

Clearance

Decreased VLDL

ProductionVLDL

Increased HDLProductionHDL

ABCG1

Decreased TGlevels

More questions about Mr A.M.

• Mr A.M. has mild albuminuria. Would you add an antihypertensive, and if so, which of the following: A) Nil B) Diuretic C) CCB D) ACEI E) Moxonidine

• His lipids remain unaltered but his eGFR declines slightly to 55mls / min. Would you add A) Fenofibrate 48mg B) Fenofibrate 145 mg , but cease if creatinine increased by 25 umol/l C) Fenofibrate 145mg, but continue if creatinine increased by < 25umol/l) D) Fenofibrate 145 mg no matter what E) More rosuvastatin

• CVD risk can’t be calculated because low HDL makes TC:HDL too high for risk calculators. To further assess risk in this rural setting, would you A) Test ABI and hs-CRP locally B) Refer for regional exercise stress test C) Refer to a more distant regional centre for imaging (IMT)

D) Refer to capital city for CT angio or coronary calcium scoreE) Not perform any of these investigations

Mr A.M. has mild albuminuria. Would you add an antihypertensive, and if so, which of the

following:

• A) Nil

• B) Diuretic

• C) CCB

• D) ACEI

• E) Moxonidine

Mr A.M. has mild albuminuria. Would you add an antihypertensive, and if so, which of the

following:The case for “D”

ease

Mr A.M’s lipids remain unaltered but his eGFR declines slightly to 55mls / min. Would you

add

• A) Fenofibrate 48mg

• B) Fenofibrate 145 mg , but cease if creatinine increased by 25 umol/l

• C) Fenofibrate 145mg, but continue if creatinine increased by < 25umol/l)

• D) Fenofibrate 145 mg no matter what

• E) More rosuvastatin

Mr A.M’s lipids remain unaltered but his eGFR declines slightly to 55mls / min. Would you

add...The case for “C”

CVD risk can’t be calculated because low HDL makes TC:HDL too high for risk

calculators. To further assess risk in this rural setting, would you...

• A) Test ABI and hs-CRP locally

• B) Refer for regional exercise stress test

• C) Refer to a more distant regional centre for imaging (IMT)

• D) Refer to capital city for CT angio or coronary calcium score

• E) Not perform any of these investigations

CVD risk can’t be calculated because low HDL makes TC:HDL too high for risk

calculators. To further assess risk in this rural setting, would you...

A survey of opinions

Mr S.K.

• This 37 year old man of Greek descent had routine tests in his 20’s that revealed a very low HDL-C (<0.2 mmol/l). He is a smoker who drinks 20 gms alcohol per week. He trains regularly as a body-builder. A cardiologist was sufficiently concerned to arrange angiography at age 33, which was normal. On examination there are no relevant physical findings and lipids are TC=2.2, TG=2.2, HDL-C =0.08, LDL-C=1.0mmol/l.

Questions concerning Mr S.K.

Is his lipid disorder..... Primary / Secondary

Are there any simple tests that would provide a diagnosis? Yes/No

Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible) A) Diuretics B) Danazol C) Beta blockers C) Probocol E) Highly Active Antiretrovirals

Your treatment would include A) Quit smoking advice onlyB) Niacin C) Statin D) Fibrate E)

More alcohol

Is his lipid disorder..... Primary / Secondary

Are there any simple tests that would provide a diagnosis? Yes/No

Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible) A) Diuretics B) Danazole C) Beta blockers

C) Anabolic steroids E) Highly Active Antiretrovirals

Your treatment would include A) Quit smoking advice only B) Niacin C) Statin D) Fibrate E) More alcohol

This 37 year old man of Greek descent had routine tests in his 20’s that revealed a very low HDL-C (<0.2 mmol/l). He is a smoker who drinks 20 gms alcohol per week. He trains regularly as a body-builder. A cardiologist was sufficiently concerned to arrange angiography at age 33, which was normal. On examination there are no relevant physical findings and lipids are TC=2.2, TG=2.2, HDL-C =0.08, LDL-C=1.0mmol/l.

Is Mr S.K’s his lipid disorder.....

Primary

Secondary

Is Mr S.K’s his lipid disorder.....The case for “primary”

Apo A1 deficiency absent

Tangiers disease (ABC A1 defect) very low

LCAT deficiency (& fish eye disease) very low

Apo A1 Milano (dimer formation) very low

HDL

Most secondary causes > 0.4 mmol/l

Are there any simple tests that would provide a diagnosis?

Yes

No

Are there any simple tests that would provide a diagnosis?

The case for “no”

Apo A1 deficiency absent Western or IEF if sufficient

Tangiers disease (ABC A1 defect) very low Macrophge CE efflux

LCAT deficiency (& fish eye disease)very low Plasma activity if sufficient

Apo A1 Milano (dimer formation) very low IEF (Iso-electric focussing)

Alternative proteomic and genetic techniques, but highly specialised

Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible)

A) Diuretics

B) Danazol

C) Beta blockers

D) Probocol

E) Highly Active Antiretrovirals

Which drugs can DRASTICALLY reduce HDL-C? (More than 1 possible

The case for “B” and D”

J Allergy Clin Immunol. 2005 115:864-9.Adverse effects of danazol prophylaxis on the lipid profiles of patients with hereditary angioedema.Széplaki G, Varga L, Valentin S, Kleiber M, Karádi I, Romics L, Füst G, Farkas H.

Probucol, a powerful antioxidant, is a CETP and SR-B1inducer that dramatically reduces HDL-C (by 20-30%). Dayspring T et al

Your treatment for Mr S.K. would include..

A) Quit smoking advice only

B) Niacin

C) Statin

D) Fibrate

E) More alcohol

Your treatment for Mr S.K. would include..All feasible, but “B” the most effective

and “E” inappropriate?

Hepatocyte

Inhibits hepatic lipase activity which reduces lipolysis of large HDL

No effect on increasing Apo A1 synthesis

A-ICE

HDL2

apoA-IHDL3

Nascent HDL

More questions concerning Mr S.K.• Mr S.T’s plasma Testosterone was normal. Does this surprise you? Yes / No

Mr S.T. Has managed to stop smoking. An exercise stress test was normal 2 years previously. On this review, the cardiologist repeated the CT coronary angiogram, which now shows a 25% RCA lesion composed of soft plaque. LDL-C remains 1.0 mmol/l

• Would you commence statin therapy? Yes / No

• Would you add any other agent? A) Niacin B) FibrateC) Nothing else D) Aspirin

E) Seek Trial access to a CETP Inhibitor

Varnava AM et al. Circulation 2002;105:939-43

Glagov Phenomenon

14% 18%

68%

0

10

20

30

40

50

60

70

Percent

>70% 50-70% <50%

Lesion Severity

Severity of Coronary Plaques before MI

Ambrose et al. J Am Coll Cardiol 1988;12:56-62Little et al. Circulation 1988;78:1157-66Nobuyoshi et al. J Am Coll Cardiol 1991;18:904-10Giroud et al. Am J Cardiol 1992;62:729-32

Plaque severity and events

ECs

SMCs

Monocytes

CAMs

Matrix

Foamcells

CytokinesGrowthFactors

T-lymphocytes

ActivatedMacrophages

TissueFactor

Clotting

MMPs

MatrixDegradation

Normal Adhesion Infiltration Rupture

Atherosclerosis is a chronic inflammatory disorder

Mr S.T’s plasma Testosterone was normal. Does this surprise you?

• Yes

• No

Mr S.T’s plasma Testosterone was normal. Does this surprise you?

The case for “no”

Mr S.T. has managed to stop smoking. An exercise stress test was normal 2 years previously. On this review, the cardiologist repeated the CT coronary angiogram, which now shows a 25% RCA lesion

composed of soft plaque. LDL-C remains 1.0 mmol/lWould you commence statin therapy?

Yes

No

Mr S.T. has managed to stop smoking. An exercise stress test was normal 2 years previously. On this review, the cardiologist repeated the CT coronary angiogram, which now shows a 25% RCA lesion

composed of soft plaque. LDL-C remains 1.0 mmol/lWould you commence statin therapy?

The case for “yes”

HDL remains unchanged. Would you add any other agent?

• A) Niacin

• B) Fibrate

• C) Nothing else

• D) Aspirin

• E) Seek Trial access to a CETP Inhibitor

HDL remains unchanged. Would you add any other agent?

Each could be argued for and against