Important or Imposter?
HDL - Cholesterol
The wider roles of HDL
HDL and Reverse Cholesterol Transport
Membrane rafts are small (10–200 nm), heterogeneous cholesterol & sphingolipid-enriched domains.
Phospholipid
Cholesterol
Glycosphingolipid
Normal Cell Membrane
Lipid Raft
ABCA1
Lipid-poor
apoAI
Diffusion ABCG1
SR-B1
Diffusion
SR-B1
Nascent,
discoidal HDL
LCAT
CE
Mature,
spherical HDL
Pharmacologic Inhibition of CETP:
A Novel HDL-raising Strategy
Feces
Bile
A-I
FC
CE
SR-BI
Liver
FC
CE
A-I
LCAT
CE
FC
FC ABCA1
Macrophage
Pharmacologic Inhibition of CETP:
A Novel HDL-raising Strategy
Feces
Bile
A-I
FC
CE
FC
CE
A-I
LCAT
SR-BI
CE
FC
FC ABCA1
Macrophage
Liver
LDLR
CETP
B
CE
TG
VLDL/LDL
Liver receptor X (LXR) Promotes
Reverse Cholesterol Transport:
LXR
Feces
Bile
LXR
ABCG1
A-I
BA
FC
FC
LXR
ABCA1
CE
SR-BI
A-I
LCAT
FC
LXR
FC
ABCA1
Macrophage
ABCA1
FC
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 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)
PCSK9
Mild increase uncertain
Mild increase
HDL Evidence: Epidemiology and trials
STUDY or TRIAL
HDL observation CVD effect
Observational (eg Framingham)
inverse relation
protective
Angiographic (Niacin, eg CLASS)
(CETP, eg ILLUSTRATE)
large increase
large increase
regression
neutral
RCT (Niacin, eg AIM-HIGH)
(Fibrate, eg VA-HIT)
(Fibrate in MS, eg FIELD)
(Torcetrapib, eg ILLUMINATE)
(Dalcetrapib, eg DALOUTCOMES)
large increase
small increase
small increase
very large increase
large increase
flawed neutral
protective
protective
detrimental
neutral
Potential Antiatherogenic Actions of HDL
Vasodilatory
Activity
Antithrombotic
Activity
Anti-infectious
Activity
Reverse
Cholesterol
Transport
Cellular
Cholesterol
Efflux
Anti-inflammatory
Activity
HDL
Antiapoptotic
Activity
Antioxidative
Activity
Endothelial
Repair
Apo A-I
Apo A-II
Chapman MJ, et al. Curr Med Res Opin. 2004;20:1253-1268.
Assmann G, et al. Annu Rev Med. 2003;53:321-341.
HDL composition is complex:
Protein and phospholipid components
Could HDL become “dysfunctional”?
Plasma HDL Predicts Events in
Population Studies
* Men aged 50-70
CHD RISK
3
2
1
25
45
65
0
85
100
160
220
LDL- cholesterol
(mg/dL)
Structure of HDL
Surface monolayer of
phospholipids
and free cholesterol
apoA-I
apoA-II
Hydrophobic core
of triglyceride
and cholesteryl esters
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
Collar
Carotid artery
Treated Artery Post Two Infusions of LFA1
CD 18
A
B
C
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 factors
B) 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) 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
• 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
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 firstdegree relatives
•before age 50 years in one or
more second-degree relatives
≤ 18 years at treatment initiation
LDL-C > 4 mmol/L
> 18 years at treatment initiation
LDL-C > 5 mmol/L
or
total-C
> 6.5 mmol/L
or
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”
Liver
… by
controlling
the
expressio
n
of PPAR
target
genes
Circulation
apo A-I
apo A-II
ABCA1
ABCG1
Results
HDL
VLDL
apo C-III
Apo A-V
TG
FFA
Acyl-CoA
Synthase
Acetyl CoA
LPL
LDL
Increased HDL
Production
Decreased
VLDL
Production
Increased
VLDL
Clearance
Decreased TG
levels
Decreased
small and
dense LDL
Particles
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 score
E) 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
ease
Mr A.M. has mild albuminuria. Would you add
an antihypertensive, and if so, which of the
following:
The case for “D”
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
Niacin
C) Statin
A) Quit smoking advice only
B)
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,
LDLC=1.0mmol/l.
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
B) Niacin
C) Statin
A) Quit smoking advice only
D) Fibrate
E) More alcohol
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
HDL
absent
Tangiers disease (ABC A1 defect)
very low
LCAT deficiency (& fish eye disease)
very low
Apo A1 Milano (dimer formation)
very low
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
Nascent
HDL
apoA-I
No effect on increasing Apo A1 synthesis
Inhibits hepatic lipase activity which
reduces lipolysis of large HDL
HDL3
CE A-I
HDL2
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
C) Nothing else
D) Aspirin
E) Seek Trial access to a CETP Inhibitor
B) Fibrate
Glagov Phenomenon
Varnava AM et al. Circulation 2002;105:939-43
Plaque severity and events
Severity of Coronary Plaques before MI
70
60
50
68%
40
Percent
30
20
10
14%
18%
>70%
50-70%
0
Lesion Severity
Ambrose et al. J Am Coll Cardiol 1988;12:56-62
Little et al. Circulation 1988;78:1157-66
Nobuyoshi et al. J Am Coll Cardiol 1991;18:904-10
Giroud et al. Am J Cardiol 1992;62:729-32
<50%
Atherosclerosis is a chronic
inflammatory disorder
Monocytes
CAMs
Tissue
Factor
ECs
Foam
cells
Clotting
Matrix
T-lymphocytes
Cytokines
SMCs
Normal
MMPs
Growth
Factors
Activated
Macrophages Matrix
Degradation
Adhesion
Infiltration
Rupture
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/l
Would 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/l
Would 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