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					  Stents Are Not Enough:

             Statins

           Keith Channon

Department of Cardiovascular Medicine
        University of Oxford
   John Radcliffe Hospital, Oxford
Plaque Remodelling in Angiographically Normal Artery
           Preservation of Lumen Area

                               5.07 mm2




                                5.18 mm2
               Stable Plaque




 Unstable Plaque               Plaque Growth
(Erosion, Rupture)
          Plaque Biology = Clinical Events

“Vulnerable” plaque


              Lumen
                                    Lipid
                                    core
                  area of
                  detail




                  Lumen                     – T lymphocyte
                            Lipid
                            core
                                            – Macrophage
                                              foam cell (tissue factor+)
                                            – “Activated” intimal SMC (HLA-DR+)
“Stable” plaque                             – Normal medial SMC
Cellular Mechanisms of Plaque Stability
IVUS Assessment of Plaque Stability

 Thick Fibrous Cap   Thin Fibrous Cap
     Acute vs. Chronic Coronary Syndromes:
               Plaque Composition


Lipid Content >40%    Macrophages (%)   Smooth Muscle (%)




Stable Unstable      Stable Unstable    Stable Unstable
Angiographic Stenosis in Infarct-Related Artery
       Most are not severely stenosed
Additional Unstable Plaques Beyond the Culprit Lesion
27 patients with ACS. Angio + 3 vessel IVUS
Plaque Biology, Stenosis and Risk:
      The Paradox for PCI
        Plaque Biology, Stenosis and Risk
            Stents are Not Enough ?



• Using current technology, Stenting alone
cannot treat all high risk lesions

• Stenting alone does nothing to alter disease
biology or natural history


               …….Statins ?
LDL Cholesterol Lowering by Statins
Cholesterol Metabolism – Regulation by HMG CoA Reductase




      VLDL                           LDL
                           LDL
                                                 LDL




             Cholesterol                   Acetyl-CoA


                                 HMG-CoA


             Mevalonic Acid



                       HMG CoA Reductase
Cholesterol Metabolism – Regulation by HMG CoA Reductase




      VLDL                           LDL
                           LDL
                                                 LDL




             Cholesterol                   Acetyl-CoA


                                 HMG-CoA


             Mevalonic Acid



                                 Statins
Cholesterol Metabolism – Regulation by HMG CoA Reductase




      VLDL                             LDL   LDL
                                 LDL
                                             LDL         LDL
                                                         LDL

             LDL
                   Cholesterol
                                                   Acetyl-CoA


         LDL                           HMG-CoA


                   Mevalonic Acid




                                        Statins
                 Statins and Cholesterol Synthesis:
            Effects on Cell Signalling through Isoprenoids

     Acetyl CoA
                                                Modification of
      HMG CoA                              Cell Signalling Proteins

          HMG CoA                         e.g. G-Proteins Rho, Rac
Statins   Reductase

                                          ‘Pleiotrophic’ Effects on
     Mevalonate                           Vascular Cells:

                       Isoprenoid         •Gene Regulation
                       Derivatives        •Cell Proliferation
                                          •eNOS Expression
     Cholesterol
                                          •Inflammation
                                          •Apoptosis
                                          •Stem & Progenitor Cells
STATINS




          • CRP

          • Endothelial Function

          • Cytokines
  REVERSAL : Reductions in LDL, Plaque Volume and CRP

18 Months N=522 paired IVUS



                     LDL-C (%)      Change in 15.47Vol (%)2
                                       TVA Plaque mm             CRP (%)

                                 -1.0   0     1.0    2.0   3.0




 PRAVASTATIN          - 25 %            Lumen                     -5%
    40 mg                               5.51 mm2
                                            P=0.02


 ATORVASTATIN         - 46 %                                      - 36 %
    80 mg                        Plaque = 9.96 mm2
Heart Protection Study – Major Vascular Events
LIPS : Benefits of Statin Following PCI




                                   80 mg
Statin Therapy and Outcome after PCI: Cleveland Clinic




    n=5052                         n=1552




     Circulation 2002; 105;691-6            Circulation 2003; 107;1750-6
AVERT : Atorvastatin Versus Revascularization Treatments




   Randomised to Atorvastatin 80 mg vs. PCI + Usual Care


                                     Pitt B et al. N Engl J Med 1999;341:170-6
AVERT : Time to First Ischaemic Event
AVERT : Major Exclusion Criteria
AVERT : Baseline Characteristics
AVERT : Ischaemic Events at 18 Months
           Why are Stents not Enough ?

Stents treat lesions that are selected on luminal stenosis
Plaque events are determined more by plaque biology, rather
than stenosis




Coronary disease is diffuse and progressive
PCI at discrete sites does not alter disease burden or
progression
                       Why Statins ?

Statins directly alter CAD natural history through lipid lowering
and other direct cellular effects


Effects on mortality and morbidity in very large studies in
primary and secondary prevention, including PCI


High Dose, more potent newer statins can achieve plaque
regression and stabilisation


Stenting symptomatic stenoses combined with high-dose
statin therapy is currently best CAD management strategy

				
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