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Treatment of Coronary Artery Disease

VIEWS: 11 PAGES: 50

									Treatment of Myocardial Infarction

• Epidemiology
• Pathogenesis
   – Where do lesions form
   – How lesions grow
• Treatment of the sequelae of myocardial infarction
  (MI)
   – Ventricular arrhythmias
   – Congestive heart failure (CHF)
   – Stem cells
                   Myocardial infarction
     • 700,000 new and 500,000 recurrent heart attacks
       in U.S. in 2007.
     • 653,000 deaths/yr in U.S. due to coronary artery
       disease
     • Estimated cost (2007): $150 billion.
          – Cholesterol-lowering medications: $14 billion.
          – 1.28 million PTCA/coronary angioplasties/stents
          – 427,000 coronary artery bypass surgeries



Circulation. 2007;115:e69-e171.
                   Economic costs of heart disease




Circulation. 2007;115:e69-e171.
http://www.who.int/cardiovascular_diseases/en/cvd_atlas_14_deathHD.pdf
Crude Death Rates for Leading Causes of Death in the United States from 1900 to 1950




            Braunwald, E. N Engl J Med 1997;337:1360-1369
Changes in Age-Adjusted Death Rates from Coronary Heart Disease (CHD), Stroke, and
    Noncardiovascular Disease (Non-CVD) in the United States from 1950 to 1995

          Hypertension and hypercholesterolemia linked to CHD




                             …..
                                x




          Surgeon General’s report on smoking.

       Braunwald, E. N Engl J Med 1997;337:1360-1369
  Traditional risk factors for MI
• Hypertension (Borderline 120-139/80-89)
• Hypercholesterolemia
   – LDL (Borderline 100-159 mg/dl)
   – HDL (Borderline 40-59 mg/dl)
• Diabetes mellitus (Borderline fasting glucose 110-
  125 mg/dl)
• Cigarette smoking

 ~ only 10% of all patients with CAD will not
    have any of these known risk factors.
Ann Intern Med 142:393-402, 2005
Proposed Mechanism for Fatty Streak Formation




                               Andrew Watson, M.D., Ph.D.
           Where do lesions form?

                             Predilection
                             sites occur at
                             areas of low
                             shear stress and
                             oscillatory flow.




Circ Res 53:502-514, 1983
                   How do lesions grow?
                                                          *
                                               40%




          Outward remodeling                        Inward remodeling

 • Plaques initially grow outward within the
   vessel wall (“outward remodeling”) instead
   of inward toward the lumen
 • Inward remodeling* is associated with
   vulnerability to rupture.

Naghavi, M. et al. Circulation 2003;108:1664-1672; NEJM 316:1371-5, 1987
 Episodic plaque growth by intraplaque hemorrhage from vasa
                          vasorum




                                                                RBC

Arterioscl Thromb Vasc Biol 25:2054-2061, 2005; N Engl J Med 349:2316-25, 2003
Modeling to calculate effect of calcification on plaque stress distribution




                                          J Am Coll Cardiol 46;1507-15, 2005
         The clinical event: Myocardial infarction

  • Formation of plaque
    (decades, no symptoms)



  • Plaque rupture (60-70%)
    or erosion (30-40%)




Lusis, A. J. et al. Circulation 2004;110:1868-1873
Animation of thrombus
          Acute sequelae of MI

• Unstable cardiac rhythms (Ventricular
  tachycardia or fibrillation: VT/VF)
• Loss of pump function (Congestive heart failure:
  CHF)
  Immediate Sequelae of MI
Unstable electrical rhythm (ventricular
tachycardia and fibrillation – VT or VF)




Approximately 1/3 of patients with MI die
before reaching the hospital or in the ER,
probably from VF.
   Immediate Sequelae of AMI

Poor pump function or congestive heart failure
(CHF) can result if too much of the myocardium is
damaged.

Therefore the focus of treatment of AMI is
restoration of blood flow within the first six hrs.
               Acute Treatment of MI
   • Plaque rupture or erosion
Aspirin     Heparin      ADP receptor blockers
                                                               Inhibit further
GP IIb/IIIa inhibitors                                         clot formation

                                                              Restore blood
Thrombolytic agents        Angioplasty       Surgery
                                                                  flow.
   • Sequelae of MI
          – Loss of pump function: CHF                   ACEI
          – Loss of stable electrical rhythm             Beta blockers
            Antiarrhythmics
   • Cholesterol and Inflammation                      Statins

                                  ACEI = angiotensin converting enzyme inhibitors
Estimated Short-Term Mortality from Acute Myocardial Infarction in the
                   United States in Different Eras




Braunwald, E. N Engl J Med 1997;337:1360-1369
            Long-term treatment of MI
   • Plaque rupture or erosion
Aspirin     Heparin      ADP receptor blockers
                                                          Inhibit further
GP IIb/IIIa inhibitors                                    clot formation


   • Sequelae of MI
          – Loss of pump function: CHF       ACEI, b-blockers,
                                             aldosterone antag.
          – Loss of stable electrical rhythm
          Antiarrhythmics     Defibrillators     b -blockers
   • Cholesterol and Inflammation                   Statins
What if the patient continues to have
    CHF despite medications?

• Biventricular pacemakers to synchronize
  contraction
• Heart transplantation
• Assist devices
   6000-8000 patients each yr are added to the transplant waiting list.




                                                  2, 125 in 2005
~ 17% of patients on the waiting list die before a new heart is available.
Cardiac Support Devices (CSD)


                    Prevents dilatation.
                    Improves collagen
                    content.
                    Unpublished reports
                    indicate that CSD
                    decreases need for
                    transplant or assist
                    devices.


                     www.paracorsurgical.com
 Components of the Left Ventricular Assist Device
                                                                              Survival 50% at
                                                                              1 yr (cf. 50% 10
                                                                              yr survival with
                                                                              transplantation).


                                                                              Death due to
                                                                              infection (41%),
                                                                              device failure
                                                                              (17%).


                                                                              10-30% may
                                                                              have a stroke or
                                                                              cerebral bleed.
Rose, E. A. et al. N Engl J Med 2001;345:1435-1443; Circulation 2005:112:e111-115.
MicroMed Debakey VAD




                                    1”

   Only moving part at 10000 rpm.
Treatment of Myocardial Infarction
              (MI)
• Scope of the problem
• Pathogenesis
• Treatment of the sequelae of myocardial infarction
  (MI)
   – Ventricular arrhythmias
   – Congestive heart failure (CHF)
• Newer concepts
   – Identifying “vulnerable” lesions
   – Role of inflammation
   – Stem cells

                                              Cotran 6th ed.
Identifying the vulnerable plaque

• Not size
• Neovascularization
• Thin cap with large lipid core
   – Intravascular ultrasound+elastography
   – Optical coherence tomography
   – MRI
• Active inflammation


                                        Circulation 106:804-8, 2002
Detecting only flow-limiting lesions will miss future heart attacks




             2/3 of plaque rupture occur in vessels with <50% stenosis

                                         J Am Coll Cardiol 22;1141-1154, 1993
     Imaging of neovascularization by contrast-enhanced
ultrasound [bubbles coated with echistatin (binds avb1 a5b1)]




                                         Circulation 111:3248-54, 2005
Targeting of neovascularization with nanoparticles (MRI)




                                 Magn. Reson. Med. Vol.53, 3 Pages: 621-627
IVUS elastography: High strain areas correlate with high lipid content




                                             Circulation 102:617-23, 2000
Thin cap with large lipid core as seen by
    Optical Coherence Tomography




              JACC 37:1277-83, 2001; Circulation 107:113-9, 2003
Plaque characterization by MRI




                        Circulation 101:2503-9, 2000
Active inflammation/macrophage infiltration
• Thermography: Increased temperature was
  prognostic for recurrent angina, MI or death
  (41 vs 7%) in patients who are undergoing
  PTCA.
• Diffuse near-infrared reflectance
  spectroscopy (based on the abs of light by
  organic molecules)




JACC 37:1277-83, 2001; Circulation 107:113-9, 2003; Circulation 105:923-7. 2002
 Once we identify the vulnerable
  plaque, can we prevent MI?
          Maybe not.
• In patients with plaque rupture leading to
  symptoms, 80% were shown to have 1-5
  other plaque ruptures that did not cause
  symptoms.
• There is widespread inflammation
  throughout the coronary vascular bed


               Circulation 106:804-8, 2002; NEJM 347:5-12, 2002
      Traditional modifiable risk
            factors for MI
• Diabetes mellitus
• Cigarette smoking
• Hypertension
• Hypercholesterolemia
    The most effective drugs in lowering
    cholesterol levels are Statins
                                Statins
     • Block HMG-CoA reductase, the rate-limiting step
       in cholesterol biosynthesis
     • In patients with a history of angina or MI who
       start statins, it takes about 2 years before a
       decrease in cardiac events is seen.
     • In patients with acute MI, it takes only 4 mo of
       statins to decrease the number of recurrent
       ischemic events.
     • In addition to its cholesterol-lowering properties,
       statins have been shown to be anti-inflammatory.


Lancet 344:1383-9, 1994; JAMA 285:1711-18, 2001; Circ 108:1560-6, 2003
Identifying the vulnerable plaque:
  Can we prevent MI? Yes, with
              statins.
• In patients with plaque rupture leading to
  symptoms, 80% were shown to have 1-5
  other plaque ruptures that did not cause
  symptoms.
• There is widespread inflammation
  throughout the coronary vascular bed


               Circulation 106:804-8, 2002; NEJM 347:5-12, 2002
  Relationship Between Mean Low-Density Lipoprotein Cholesterol Levels and
Median Change in Percent Atheroma Volume for Several Intravascular Ultrasound
                     Trials: The lower the LDL, the better




                                              Nissen, S. E. et al. JAMA 2006;295:1556-1565.
                    News

Return to article
                    Nature
                    Published online: 4
                    January 2006; |
                    doi:10.1038/43900
                    8a
                    Blow follows blow for
                    stem-cell work
Your cells help you back to health
Coronary artery disease (CAD) is the most common form of heart disease or cardiovascular disease,
affecting almost 1.3 million Americans. CAD and its complications, such as heart attack and angina
pectoris, are the leading causes of death in the United States in both men and women. While standard
treatment can help most, the rest still live in pain with little or no hope.



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             Mount Elizabeth Hospital, Singapore                 Phyathai Hospital, Bangkok




              Bangkok Heart Hospital, Bangkok                    Gleneagles Hospital, Singapore
Cardiac cell dogma
• Human cardiac tissue
  cannot regenerate.
• Cardiac cells respond
  to stress or injury by
  hypertrophy, not
  hyperplasia
• ? Loss of regenerative
  capacity related to an
  advanced immune
  system
            Lancet 364:183-92, 2004
Cardiac cell dogma         Cardiac cell biology
• Human cardiac tissue     • Cardiac cells can
  cannot regenerate.         regenerate, albeit
• Cardiac cells respond      limited potential.
  to stress or injury by   • Stem cells present in
  hypertrophy, not           the bone marrow and
  hyperplasia                heart can help improve
• ? Loss of regenerative     cardiac function after
  capacity related to an     myocardial infarction.
  advanced immune
  system
                                     Lancet 364:183-92, 2004
Mechanism: Controversial/unknown




                        Circ 114:339-352, 2006
    Randomized controlled trials of
 stem cell therapy in patients with MI
N=67           N=60           N=100          N=204
(2006)         (2004)         (2006)         (2006)


Infusion 1 d   Infusion ~ 6   Infusion 5-8   Infusion 3-7
after MI       days after     days after     days after
               MI/stent       MI/stent       MI/stent

No change in LVEF          No change in LVEF 
contractility. (52% to 57%) contractility. (50% to 54%)
  Increased glucose metabolism after
stenting and stem cell infusion post-MI
                     Before and after stenting and stem cell infusion




             European J Nuc Med and Mol Imaging 31:1146-51,2004
Molecular imaging of stem cell survival, proliferation and
      migration using bioluminescence and PET




                                      Circulation 113:1005-14, 2006
                     Summary
• Hypertension, LDL, HDL, diabetes and
  smoking account for 90% of cardiac events.
• Myocardial infarctions occur when plaques
  rupture or erode, leading to clot
   – Vulnerable plaques are characterized by new vessels,
     large lipid core, thin cap and inflammation.
   – Therapies are focuses to inhibit clot formation,
     restoration of blood flow (angioplasty, bypass surgery),
     preventing unstable heart rhythms and negative
     remodeling, and decreasing inflammation.
• Current and future biophysical research focused
  on identifying vulnerable plaques, tracing fate of
  stem cells, building drug delivery systems.

								
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