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Important or Imposter? HDL - Cholesterol. The wider roles of HDL. Phospholipid. Glycosphingolipid. HDL and Reverse Cholesterol Transport. Membrane rafts are small (10–200 nm), heterogeneous cholesterol & sphingolipid -enriched domains. Cholesterol. Normal Cell Membrane. Lipid Raft. - PowerPoint PPT Presentation
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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”?
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: [email protected]
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