Docstoc

P Abd lK MD Prof Samir Abdul Kader MD Prof Samir

Document Sample
P Abd lK MD Prof Samir Abdul Kader MD Prof Samir Powered By Docstoc
					 Prof. S i Abd l Kader
 P f Samir Abdul K d (MD)
       Cardiology Department,
    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
CHD.
CHD.
                                    25%
The risk for MI increased by about 25%
        y       g
for every 5 mg/dL decrease in serum
HDL
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
  ith     to
with a 2 t 3% d            in the i k f
                  decrease i th risk of
CHD.
CHD.
     Framingham Heart Study




                          are:
The major proteins of HDL are:
  ApoA- ApoA-
  ApoA-I, ApoA-II and other minor
                      as:
 protein constituents as:
                   (SAA).
  Serum amyloid A (SAA).
                (PON1
  Paraoxonase I (PON1) and
                        phospho-
 Lipoprotein associated phospho-
 lipase A2 that help in reversing
             transport.
 cholesterol transport.
A polipoproteins are involved in
  p binding.g
lipid binding.
SAA      is    involved  in   the
inflammatory response.
i fl      t    response.
Paraoxonase I is an antioxidant
that prevents the accumulation of
                   LDL.
lipid peroxides in LDL.




  HDL is composed of many
           particles:
α1-HDL: contain ApoA-I.
   HDL:         ApoA-
α2 and α3 HDL: contain ApoA-I
            HDL:        ApoA-
    II.
and II.
α4 HDL contain ApoA-I.
               ApoA-
                  HDL.
Pre B1 and pre B2 HDL.
  Both pre B1 and α2 HDL are
  correlated with macrophage free
              efflux.
  cholesterol efflux.
  α1 and α2 HDL correlate with liver cell
  scavenger receptor B1 which mediate
                                cells.
  cholesterol efflux from liver cells.
  Cholesterol ester transferase protein
  (CETP) forms a hydrobic tube
  between lipoprotein particles and
        inhibitors.
  CETP inhibitors.




               HDL Metabolism




ATP-binding cassette
ATP-
            (ABCA1
protein A1 (ABCA1) G1
and G4. Scavenger
      t class-
          l        (SR-
receptor class-B1 (SR-
B1).      Phospholipid
transfer        p
                protein
(PLTP).
(PLTP).
             HDL Functions
1. Reverse cholesterol transport mediated
                     ABCA1
  by Apo A-1 via ABCA1 receptors in
             tissue.
  peripheral tissue.
 Scavenger receptor class B1 in the liver
                     diffusion.
 and through Passive diffusion.
               function:
2. Endothelial function:
 Enhanced            endothelium- p
                     endothelium-dependent
 vasodilatation    and inhibits endothelin
 production.
 production.
                                apoptosis.
 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
            components.
  LDL lipid components.
  HDL also inhibits the infiltration of oxidized
                                      al. 2001)
  LDL into the vessel wall (Navab et al., 2001).
  Anti-
4.Anti-inflammatory        effects:
                           effects:      through
  inhibition of production of E-selectin,
  interleukin-8,1 and expression of MCP-1,
  interleukin-                            MCP-
  ICAM-         VCAM-                 al. 2001)
  ICAM-1, and VCAM-1 (Cockerill et al., 2001).
                                HDL:
5. Anticoagulant properties of HDL:
  HDL significantly increases lysis of
  fibrin and inhibits tissue factor
  expression.
  expression.
       l   inhibits l t l t   ti ti     d
  It also i hibit platelet activation and
  aggregation by binding to HDL
                            surface.
  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
  al. 1999)
  al., 1999).




        Causes of Low HDL
1- In certain populations with type 2 DM or
  MS,
                  yp      gy
2- Patients with hypertriglyceridemia, ,
3- Patients with sedentary lifestyle, smokers,
  and people taking certain medications
           anti-          drugs.
  such as anti-retroviral drugs.
                 LCAT,         polymorphisms,
4- Mutations in LCAT CETP polymorphisms
  ABCA1, apo A-I, lipoprotem in lipase, and
  ABCA1
                       lipase.
  hepatic triglyceride lipase.
                 deficiency.
5- Familial HDL deficiency.
 Therapies to Increase HDL

  Nonpharmacologic mechanisms
 increase HDL l
 i                  l by 10-15%
                levels b 10-15%,
 but many individuals may require
 pharmacologic intervention to
                         function.
 optimize HDL levels and function.




     p         g        py
  Nonpharmacologic Therapy
   g Control:
       C
Weight Control:
          meta-
 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
   mg/dL.
 2 mg/dL.
 Patients    treated  with    a    high
 monosaturated fatty acid diet reduces
                apo- however, HDL-
 apo A-I and apo-B however HDL-2
     HDL-                  decreased.
 and HDL-3 were relatively decreased.
                 trans-
 Diets high in trans-fatty acids raise
          g                 y
                       levels.
 LDL and lower HDL levels.
 Low-     diets,
 Low-fat diets in addition to reducing
                    HDL.
 LDL levels, lower HDL.
 Diets high in saturated fats increase
       levels,
 HDL levels but at the expense of
                 well.
 raising LDL as well.
                               (>6
 Fish oil at high doses (>6 g/d)
               gy
 reduces s. triglycerides and increases
 HDL.
 HDL.



Exercise:
Exercise:
 The mechanism is not fully understood
                y
 but is likely related to increased
 expression of LPL or decreased apo A-l
 clearance     leading to     statistically
                                      apo-
 significant improvement in apo A-I, apo-
        HDL1           al. 1998)
 B and HDL1 (Zinuda et al., 1998).
        Consumption:
Alcohol Consumption:
 Moderate      alcohol     consumption
 increases HDL levels and reduces rates
                              TGs.
 of CVD disease and increases TGs.
        Cessation:
Smoking Cessation:
 Smoking       leads   to   significant
 reductions in HDL due to cigarette
 related increase in CETP, reduced
 LCAT activity, and decreased apo A-I
 synthesis.
  y
 synthesis.
             meta-
 A recent meta-analysis of smoking
 cessation
       ti        in
                 i    2008      h
                               showed d
 significantly increased HDL levels (4
                       cessation.
 mg/dL) after smoking cessation.




                                      cholesterol.
Influence of lifestyle changes on HDL cholesterol
    Pharmacologic Therapies
               (Niacin):
Nicotinic Acid (Niacin):
 Through unknown mechanisms it
                   15-35%
 increases HDL by 15-35%.
 Niacin selectively decreases hepatic
        l f         from HDL i
 removal of apo A-I f                 i
                          HDL, increasing
                         HDL.
 the amount of available HDL.
 ER niacin increased HDL by 8 mg/dL
 and decreased progression of carotid
                 al. 2003)
 IMT (Kashyap et al., 2003).




 The HDL Atherosclerosis Treatment
Study (HATS) demonstrated that a
                 low-
combination of low-dose simvastatin
                            high-
(10 to 20 mg per day) and high-dose
niacin (2 to 4 g per day) significantly
                    26%
increased HDL by 26% and modestly
                      stenoses.
regressed coronary stenoses.
            Derivatives:
Fibric Acid Derivatives:
 PPAR-
 PPAR-alpha        binds   fibric   acid
               gemfibrozil, bezafibrate,
 derivatives gemfibrozil bezafibrate
      fenofibrate.
 and fenofibrate.
                                  apoA-
 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%
             al. 1999)
 (Rubins et al., 1999).
 In    the    Helsinki   Heart     Study
                                 11%
 gemfibrozil increased HDL by 11%.



Statins:
Statins:
 Statins
 St ti      increase
            i           h
                        hepatic
                             ti     A A-I
                                    ApoA-
                                    ApoA
                             15%
 production and HDL by 10 to 15%.
 They increase the expression of LDL
      p                      y
 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
              al. 1999)
 (Schaefer et al., 1999).
Ezetimibe:
Ezetimibe:
 Ezetimibe, through its action on the
 brush border, it selectively inhibits
 small    intestinal  absorption    of
 cholesterol.
 cholesterol.
    lowers LDL b 15 t 20% and h a
 It l           by   to 20%   d has
 trivial effect on HDL even when
                                   al.
 combined with statin (Sudhof et al.,
 2002).
 2002)




                   (
                   (TZDs):
                        )
Thiazolidinediones (TZDs):
  TZDs increase serum adiponectin
 levels, which positively correlate with
 l     l     hi h   iti l      l t    ith
         levels.
 HDL levels.
                                pioglita-
  Compared to rosiglitazone, pioglita-
 zone have greater PPAR-α effects
                        PPAR- effects,
                  ABCA-
 upregulates ABCA-1 and enhance
 reverse cholesterol transport, thus
 significantly raises HDL (Szapary et
   g            y           (   p y
 al. 2006)
 al., 2006).
Hormone Replacement Therapy
 (
 (HRT):
     )
 (HRT):
  Estrogens increase apo A-I
 production and inhibit hepatic
 lipase, leading to increased
 lipase
 production of mature HDL-C by 5
 p                     HDL-      y
    15%                 benefit.
 to 15%, but without CV benefit.




      Emerging Therapies
                         Blockers:
Endocannabinoid Receptor Blockers:
 The favorable effects of rimonabant on
   p ,            g          ,
 lipids, including HDL, have been
                     trials.
 confirmed in many trials.
 The mechanism of these agents in
                unknown.
 raising HDL is unknown.
           be   indirect
 It may b an i di t consequence of      f
 improving insulin sensitization and
                               (Pi-
 decreased triglyceride levels (Pi-sunyer
    al. 2006)
 et al., 2006).
        Milano:
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
                             hypertriglycerid-
 plasma LDL, moderate hypertriglycerid-
 emia and less atherosclerosis than
                              level.
 predicted for such low HDL level.
 It is more effective in promoting
 cholesterol efflux from cells, promoting
 reverse cholesterol transport, and has
                                      normal
 more antioxidative effect than "normal"
 apo-                     al. 1999)
 apo-A-I (Franceschini et al., 1999).




                              apo-
 Infusion of recombinant apo-A-I
 Milano-phospholipid
 Milano-                  complexes
 p
 produces       p
              rapid    g
                     regression    of
 atherosclerosis.
 atherosclerosis.
 apoA-
 apoA-I mimetic peptide synthesized
                       (D-
 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
           al. 2004)
 (Navab et al., 2004).
Cholesteryl Ester         Transfer      Protein
        Inhibitors:
 (CETP) Inhibitors:
                        JTT-
 In Rabbit models, JTT-705 and torcetrapib
 i
 improve HDL l        l     d   ti
               levels and aortic arch l ih lesions
                 al. 2004)
 (Morehouse et al., 2004).
 The CETi- Vaccine i d
 Th CETi-1 V        i                  t    tib d
                          induces autoantibody
                         CETP.
 produc-tion against CETP.
 JTT-                                CETP.
 JTT-705 is a partial inhibitor of CETP.
   High doses decrease CETP activity by
   37%                      34%
   37%, raise HDL by 34%, and decrease
   LDL by 7%. The drug was tolerated well
   with no adverse events or laboratory
                                   al. 2005)
   abnormalities (Degrooth et al., 2005).




Torcetrapib:
Torcetrapib:
 Recent clinical trials question its
 therapeutic      value    which    was
 demonstrated       to  increase    HDL
 significantly     and    reduce    LDL
 cholesterol.
 cholesterol.
 Torcetrapib increased risk for CV
          y              y
 morbidity and mortality, and have no
 effect on rates of coronary and
 carotid       atherosclerosis disease
                          al. 2007)
 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
     y
likely confounded the benefit
associated with raising HDL and
          LDL.
reducing LDL.
  o eo e ,
Moreover,    e cess
             excess    C
                       CHF    a d
                              and
revascularization procedures were
 l noted.
       t d
also noted.




A recent large clinical trial included
15.000 patients with CAD were
15.
prematurely terminated b th D t
       t    l t    i t d by the Data
           y          g
and Safety Monitoring Committee in
early December 2006 because of a
statistically significant (
 t ti ti ll     i ifi   t (p <0.01) 01)
                 y
excess mortality rate in the active
arm using Torcetrapib (Schacfer
     Asztalos, 2007)
and Asztalos 2007).
 IVUS and carotid IMT by ultrasound
  h     d     b   fit f the torcetrapib-
 showed no benefit of th t        t    ib
                             torcetrapib-
 atorvastatin    combina-tion        over
 atorvastatin alone (Kastelein et al.,al.
 2007).
 2007)
 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,
 2007)
 2007).



       Delipidation:
Plasma Delipidation:
 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
 liver
 liver.
 li .
 The lipids are then processed and
 excreted naturally from the body causing
 regression       of  atherosclerosis     and
 mobilization of adipose tissue (Chan and
            2005)
 Kostner, 2005).
             CO C US O
             CONCLUSION

       is dynamic molecule involved
  HDL i a d        i    l    l i    l d
 in reverse cholesterol transport,
 improvement of endothelial function,
 anti-
 anti-thrombotic activity, inhibition of
 LDL oxidation, promotion of atheroma
 regression,                possess-ing
 regression as well as possess ing
 various     anti-
             anti-inflammatory       and
               properties.
 antioxidative properties.



CONCLUSION

 C         l     h      id
 Currently, the evidence supports lif              l
                                            lifestyle
 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
                  level.
 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,        l
 HDL oral apo A-I mimetics (i ti             F),
                                      (eg, D4F) and d
                            transfer.
 apo A-I Milano gene transfer.
           lipid-
Effects of lipid-modifying drugs on
             HDL- levels.
             HDL-C levels
      Drug                   HDL-
               % Increase in HDL-C
 Niacin              15-
                     15-35%
 Fibrates
 Fib t               10-
                     10-15%
 Estrogens           10-
                     10-15%
 Statins              5-10%
 Ezetimibe            3-5%
 Rimonabant           5-10%
          p
 Torcetrapib         50-
                     50-100%
 Glitazones           5-20%

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:3
posted:4/2/2011
language:English
pages:19