Prof. S i Abd l Kader
P f Samir Abdul K d (MD)
Assiut i i A i
A i University, Assiut, Egypt
Numerous studies have identified HDL
t b an independent risk f t
to be i d d t i k factor f for
The risk for MI increased by about 25%
for every 5 mg/dL decrease in serum
Analysis of four large prospective
studies the FHS, the MRFIT, the LRC
and the CPPT has indicated that each 1
mg/dL increase in HDL is associated
with a 2 t 3% d in the i k f
decrease i th risk of
Framingham Heart Study
The major proteins of HDL are:
ApoA-I, ApoA-II and other minor
protein constituents as:
Serum amyloid A (SAA).
Paraoxonase I (PON1) and
Lipoprotein associated phospho-
lipase A2 that help in reversing
A polipoproteins are involved in
SAA is involved in the
i fl t response.
Paraoxonase I is an antioxidant
that prevents the accumulation of
lipid peroxides in LDL.
HDL is composed of many
α1-HDL: contain ApoA-I.
α2 and α3 HDL: contain ApoA-I
α4 HDL contain ApoA-I.
Pre B1 and pre B2 HDL.
Both pre B1 and α2 HDL are
correlated with macrophage free
α1 and α2 HDL correlate with liver cell
scavenger receptor B1 which mediate
cholesterol efflux from liver cells.
Cholesterol ester transferase protein
(CETP) forms a hydrobic tube
between lipoprotein particles and
protein A1 (ABCA1) G1
and G4. Scavenger
receptor class-B1 (SR-
1. Reverse cholesterol transport mediated
by Apo A-1 via ABCA1 receptors in
Scavenger receptor class B1 in the liver
and through Passive diffusion.
2. Endothelial function:
Enhanced endothelium- p
vasodilatation and inhibits endothelin
Prevention of endothelial cell apoptosis.
3. Antioxidant Properties through inhibition of
oxidative modification of LDL and
numerous antioxidative enzymes such as
glutathione and paraoxonase 1 that
inactivate lipid peroxides and other oxidized
LDL lipid components.
HDL also inhibits the infiltration of oxidized
LDL into the vessel wall (Navab et al., 2001).
inhibition of production of E-selectin,
interleukin-8,1 and expression of MCP-1,
ICAM- VCAM- al. 2001)
ICAM-1, and VCAM-1 (Cockerill et al., 2001).
5. Anticoagulant properties of HDL:
HDL significantly increases lysis of
fibrin and inhibits tissue factor
l inhibits l t l t ti ti d
It also i hibit platelet activation and
aggregation by binding to HDL
receptors on the platelet surface.
It has a role in enhancement of Protein
C and Protein S activity and may help
prevent thrombin generation (Griffin et
Causes of Low HDL
1- In certain populations with type 2 DM or
2- Patients with hypertriglyceridemia, ,
3- Patients with sedentary lifestyle, smokers,
and people taking certain medications
such as anti-retroviral drugs.
4- Mutations in LCAT CETP polymorphisms
ABCA1, apo A-I, lipoprotem in lipase, and
hepatic triglyceride lipase.
5- Familial HDL deficiency.
Therapies to Increase HDL
increase HDL l
i l by 10-15%
levels b 10-15%,
but many individuals may require
pharmacologic intervention to
optimize HDL levels and function.
p g py
A large meta-analysis of >70 studies
f d th t for f t i d
found that f every 4.5 k of sustained
weight loss, serum HDL increased by
Patients treated with a high
monosaturated fatty acid diet reduces
apo- however, HDL-
apo A-I and apo-B however HDL-2
and HDL-3 were relatively decreased.
Diets high in trans-fatty acids raise
LDL and lower HDL levels.
Low-fat diets in addition to reducing
LDL levels, lower HDL.
Diets high in saturated fats increase
HDL levels but at the expense of
raising LDL as well.
Fish oil at high doses (>6 g/d)
reduces s. triglycerides and increases
The mechanism is not fully understood
but is likely related to increased
expression of LPL or decreased apo A-l
clearance leading to statistically
significant improvement in apo A-I, apo-
HDL1 al. 1998)
B and HDL1 (Zinuda et al., 1998).
Moderate alcohol consumption
increases HDL levels and reduces rates
of CVD disease and increases TGs.
Smoking leads to significant
reductions in HDL due to cigarette
related increase in CETP, reduced
LCAT activity, and decreased apo A-I
A recent meta-analysis of smoking
i 2008 h
significantly increased HDL levels (4
mg/dL) after smoking cessation.
Influence of lifestyle changes on HDL cholesterol
Nicotinic Acid (Niacin):
Through unknown mechanisms it
increases HDL by 15-35%.
Niacin selectively decreases hepatic
l f from HDL i
removal of apo A-I f i
the amount of available HDL.
ER niacin increased HDL by 8 mg/dL
and decreased progression of carotid
IMT (Kashyap et al., 2003).
The HDL Atherosclerosis Treatment
Study (HATS) demonstrated that a
combination of low-dose simvastatin
(10 to 20 mg per day) and high-dose
niacin (2 to 4 g per day) significantly
increased HDL by 26% and modestly
regressed coronary stenoses.
Fibric Acid Derivatives:
PPAR-alpha binds fibric acid
derivatives gemfibrozil bezafibrate
They increase synthesis of apoA-I,
e a c g t e o at o o e
enhancing the formation of new HDL
particles and raise HDL by 5 to 20%20%
(Rubins et al., 1999).
In the Helsinki Heart Study
gemfibrozil increased HDL by 11%.
St ti increase
ti A A-I
production and HDL by 10 to 15%.
They increase the expression of LDL
receptors and dramatically increases the
ability of the liver to uptake CE via CETP
mechanisms by 50%.50%
Treatment with atorvastatin, fluvastatin,
pravastatin and simvastatin results in an
elevation in HDL, but significantly higher
results were reported with rosuvastatin
(Schaefer et al., 1999).
Ezetimibe, through its action on the
brush border, it selectively inhibits
small intestinal absorption of
lowers LDL b 15 t 20% and h a
It l by to 20% d has
trivial effect on HDL even when
combined with statin (Sudhof et al.,
TZDs increase serum adiponectin
levels, which positively correlate with
l l hi h iti l l t ith
Compared to rosiglitazone, pioglita-
zone have greater PPAR-α effects
upregulates ABCA-1 and enhance
reverse cholesterol transport, thus
significantly raises HDL (Szapary et
g y ( p y
Hormone Replacement Therapy
Estrogens increase apo A-I
production and inhibit hepatic
lipase, leading to increased
production of mature HDL-C by 5
p HDL- y
to 15%, but without CV benefit.
Endocannabinoid Receptor Blockers:
The favorable effects of rimonabant on
p , g ,
lipids, including HDL, have been
confirmed in many trials.
The mechanism of these agents in
raising HDL is unknown.
It may b an i di t consequence of f
improving insulin sensitization and
decreased triglyceride levels (Pi-sunyer
et al., 2006).
Apo A-I Milano:
Apo A-I Mil
A is i t f
Milano i variant of apo A-l l,
identified in individuals in rural Italy who
exhibit very low levels of HDL, elevated
plasma LDL, moderate hypertriglycerid-
emia and less atherosclerosis than
predicted for such low HDL level.
It is more effective in promoting
cholesterol efflux from cells, promoting
reverse cholesterol transport, and has
more antioxidative effect than "normal"
apo- al. 1999)
apo-A-I (Franceschini et al., 1999).
Infusion of recombinant apo-A-I
apoA-I mimetic peptide synthesized
from D-amino acids (D-4F), promoted
reverse cholesterol efflux from
p g vivo.
macrophages in vivo. Currently, y,
human studies are underway to
determine tolerability and efficacy
(Navab et al., 2004).
Cholesteryl Ester Transfer Protein
In Rabbit models, JTT-705 and torcetrapib
improve HDL l l d ti
levels and aortic arch l ih lesions
(Morehouse et al., 2004).
The CETi- Vaccine i d
Th CETi-1 V i t tib d
produc-tion against CETP.
JTT-705 is a partial inhibitor of CETP.
High doses decrease CETP activity by
37%, raise HDL by 34%, and decrease
LDL by 7%. The drug was tolerated well
with no adverse events or laboratory
abnormalities (Degrooth et al., 2005).
Recent clinical trials question its
therapeutic value which was
demonstrated to increase HDL
significantly and reduce LDL
Torcetrapib increased risk for CV
morbidity and mortality, and have no
effect on rates of coronary and
carotid atherosclerosis disease
progression (Nissen et al., 2007).
y, p py
Unfortunately, torcetrapib therapy
was associated with significant
l ti in bl d hi h
elevations i blood pressure, which
likely confounded the benefit
associated with raising HDL and
o eo e ,
Moreover, e cess
CHF a d
revascularization procedures were
A recent large clinical trial included
15.000 patients with CAD were
prematurely terminated b th D t
t l t i t d by the Data
and Safety Monitoring Committee in
early December 2006 because of a
statistically significant (
t ti ti ll i ifi t (p <0.01) 01)
excess mortality rate in the active
arm using Torcetrapib (Schacfer
and Asztalos 2007).
IVUS and carotid IMT by ultrasound
h d b fit f the torcetrapib-
showed no benefit of th t t ib
atorvastatin combina-tion over
atorvastatin alone (Kastelein et al.,al.
While CETP inhibition with torcetrapib
has not proved efficacious, the concept
of CETP inhibition may represent a
possible area of continued focus to
raise HDL cholesterol and to lower rates
of atherogenesis (Davidson and TothToth,
E t l delipidation t h l
Extracorporeal d li id ti technology
removes lipids from lipoproteins such as
in the bloodstream and th
HDL i th bl d t t
d then return
the delipidated HDL particles back to the
body d i k lipids from th
b d and picks up excess li id f the
arterial walls and transport them to the
The lipids are then processed and
excreted naturally from the body causing
regression of atherosclerosis and
mobilization of adipose tissue (Chan and
CO C US O
is dynamic molecule involved
HDL i a d i l l i l d
in reverse cholesterol transport,
improvement of endothelial function,
anti-thrombotic activity, inhibition of
LDL oxidation, promotion of atheroma
regression as well as possess ing
C l h id
Currently, the evidence supports lif l
modification plus niacin, fibrates, or
t ti l in bi ti
statins, alone or i combination, t raise to i
HDL, although it is unclear whether HDL
f ti lit is t d in
functionality i augmented i concert with t ith
the numeric level.
Other emerging approaches to increase
HDL include CETP inhibition, infusion of
native and mutant f f
forms of apo A-I such as
apo A-I Milano, infusion of delipidated
HDL oral apo A-I mimetics (i ti F),
(eg, D4F) and d
apo A-I Milano gene transfer.
Effects of lipid-modifying drugs on
% Increase in HDL-C
Fib t 10-