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061 a nano mega initiative

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061 a nano mega initiative

  1. 1. First Meeting of UT-THI and Rice Coalition A Nano-Mega Initiative! Friday, June 07, 2002 Denton A. Cooley Building Texas Medical Center Houston, Texas
  2. 2. How the World Dies Today?
  3. 3. Atherosclerotic Diseases Are Not Diseases of Affluence! • Only 2.7 millions of 6.3 million of who died by IHD were in the developed country. • Cerebrovascular disease (stroke) killed 4.4 million people, of whom only 1.4 million were in the developed world.
  4. 4. Leading cause of death in the United States since the beginning of the 20th century? Except for one year (1924)!
  5. 5. Fatal Heart Attack!
  6. 6. What causesheart attack?
  7. 7. Vulnerable Plaque Theshort answer is:
  8. 8. What is vulnerable plaque?
  9. 9. Dangerous forms of fat buildup (atherosclerotic plaques) in the arterial wall that can rupture or induce thrombosis and lead to critical disruption of blood flow. Theshort answer is:
  10. 10. VulnerablePlaque Ruptured Plaque
  11. 11. Everybody has atherosclerosis, the question is who has vulnerable plaque Sudden Cardiac Death Acute MI Vulnerable Plaque(s)
  12. 12. Vulnerable Plaque and Vulnerable Patient, The Challenge of Cardiovascular Medicine in 21st Century An introductory tutorial from The Center for Vulnerable Plaque Research University of Texas Houston and Texas Heart Institute
  13. 13. What Do We Know About Vulnerable Plaque? Center for Vulnerable Plaque Research University of Texas at Houston Texas Heart Institute October 2001 Morteza Naghavi, MD Mohammad Madjid, MD Silvio Litovsky, MD AlirezaZarrabi, MD Maziar Azadpour, MD ParsaMirhaji, MD CorneliusNwora, MD Ward Casscells, MD James Willerson, MD
  14. 14. Salute to Pioneers
  15. 15. First studies on inflammation of vessels, particularly phlebitis, Started at a time when Cruveilhier2had just stated: La phlebite domine toute la pathologie.3 First a great number of preparatory studies on fibrin, leukocytes, meta-morphosis of blood, published separately. … Rudolf Virchow 1821-1902 The Father of Cellular Pathology Virchow appreciates prior works. Virchow presented hisinflammatory theory. Heutilized thenameof "endarteritisdeformans." By thishe meant that theatheromawasaproduct of an inflammatory processwithin theintimawith thefibrous thickening evolved asaconsequenceof areactivefibrosisinduced by proliferating connectivetissuecells within theintima.
  16. 16. Olcott 1931 “plaque rupture” Leary 1934 “rupture of atheromatous abscess” Wartman 1938 “rupture-induced occlusion” Horn 1940 “plaque fissure” Helpern 1957 “plaque erosion” Crawford 1961 “plaque thrombosis” Gore 1963 “plaque ulceration” Friedman 1964 “macrophage accumulation” Byers 1964 “thrombogenic gruel” Chapman 1966 “plaque rupture” Plaque Fissure in Human Coronary Thrombosis (Abstract) Fed. Proc. 1964, 23, 443 Paris Constantinidis “Thedestruction of thehyalinized wall separating lumen from theatheromawas almost alwaysobserved to bepreceded by or associated with itsinvasion by lipid containing macrophages.” Friedman and van den Bovenkamp 1965 Unheralded Pioneers
  17. 17. N Engl J Med 1999 “Atherosclerosis; an inflammatory disease” Ross R. Russell Ross Atherosclerosis; arterial “Response to Injury” N Engl J Med 1976 Aug 12;295(7):369-77 The pathogenesis of atherosclerosis (first of two parts). Ross R, Glomset JA.
  18. 18. James T. Willerson 1981 N Engl J Med 1981 Mar 19;304(12):685-91 Plaque Thrombosis
  19. 19. Erling Falk Michael Davies Autopsy Series Thin Fibrous Cap + Large Lipid Core + Dense Macrophage A culprit ruptured plaque 1981-1990
  20. 20. PlaqueEruption (Volcano!)
  21. 21. Seymour Glagov Compensatory Enlargement of Human Atherosclerotic Coronary Arteries N Engl J Med 1987 May 28;316(22):1371-5 <50% stenosis Luminal area is not endangered until more than 40% of internal elastic lamina is destructed and occupied by plaque Coronary artery disease is a disease of arterial wall disease not lumen. PositiveRemodeling <80% stenosis
  22. 22. Angiographic progression of coronary artery disease and the development of myocardial infarction. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Department of Medicine, New York Cardiac Center, Mount Sinai Medical Center, New York 10029. Simultaneously, Little et al, Haft et al reported that majority of culprit lesions are found on previously non-critical stenosis plaques. Conclusion: “Myocardial infarction frequently develops from non-severe lesions.” J Am Coll Cardiol 1988 Jul;12(1):56-62 Ambrose, Fuster, and colleagues Angiographically Invisible Plaques
  23. 23. Falk E., Shak P.K., Fuster V. Circulation 1995 Non-stenotic (<75%) plaques cause about 80% of deadly MI
  24. 24. Macrophage- driven MMPs soften plaquecap and prompt it to rupture P.K. Shah Peter Libby Thefateof atherosclerosisand itsthrombotic complication are governed by immunesystem. Goran Hansson and others Allard van der Wal and others
  25. 25. •Eroded Plaque Rupture-prone plaques are not the only type of vulnerable plaque •Calcium Nodule van der Wal - Netherlands Renu Virmani -USA Thiene - Italy Kolodgie F., Burk A.P., Farb A., and Virmani R.
  26. 26. Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994 Mar 1;23(3):809-13 James E. Muller 1994 Muller coined the term of “Vulnerable” Plaque Muller likened Vulnerable Plaques to American nuclear missiles stored underground in Nevada desert where they could be vulnerable to Russians’ long-range missile attack!
  27. 27. “Who is Who” on www.VP.org Thefield of vulnerableplaqueisbest owed to many known and unknown scientistswho have worked hard to shed light on our way to prevent and eradicateheart attacksin thefuture. To seeamorecompletelist pleasevisit:
  28. 28. Natural History of Vulnerable Plaques Illustrated:
  29. 29. ~70% Percent of stenosis Frequency of plaques “Risk” per each plaque Culprit Risk per each type of Vulnerable Plaque (Log) Culprit lesions found in autopsy series of acute MI Different Types of Plaque Vulnerable to Thrombosis All Male Female ~10% <5% ~20% 50% Angiography ~80% <5% ~20% ~55% ~20% <5% <5% ~20% Rupture Prone Eroded Calcified NoduleHemorrhage Positive Remodeling Fissured /Healed Natural History of Vulnerable Atherosclerotic Plaques
  30. 30. Ruptured Plaques (~70%) 1. Stenotic (~20%) 2. Non-stenotic (~50%) Non-ruptured Plaques (~ 30%) 1. Erosion (~20%) 2. Calcified Nodule (~5%) Plaque Pathology Responsible for Coronary Thrombotic Death In summary:
  31. 31. Rupture-Prone Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Macrophage Necrotic lipid core Thin fibrouscap
  32. 32. Eroded Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Endothelial denudation Proteoglycans
  33. 33. Fissured / Healed Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Mural thrombi Wounded plaque
  34. 34. Intra-Plaque Hemorrhage with Intact Cap Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Leaking angiogenesisor ruptureof vasa vaserum
  35. 35. Different Types of Vulnerable Plaques Major Underlying Cause of Acute Coronary Events Normal Rupture-prone Fissured Eroded Critical Stenosis Hemorrhage Naghavi et al, Cur Ath Rep 2001
  36. 36. Emerging Techniques for Detection of Vulnerable Plaque
  37. 37. Emerging Diagnostic Techniques A. Invasive Techniques Angioscopy IntravascularUltrasound (IVUS) IntravascularThermography IntravascularOptical Coherence Tomography (OCT) IntravascularElastography Intravascularand Transesophageal MRI IntravascularNuclearImaging IntravascularElectrical Impedance Imaging IntravascularTissue Doppler IntravascularShearStress Imaging Intravascular(Photonic) Spectroscopy
  38. 38. - Raman Spectroscopy - Near-Infrared Diffuse Reflectance Spectroscopy -Fibrousis and lipid measurement -pH and lactate measurement - Fluorescence Emission Spectroscopy - Spectroscopy with contrast media … Invasive Techniques Intravascular (Photonic) Spectroscopy Intra-coronary assessment of endothelial function Intra-coronary measurement of MMPs and cytokines
  39. 39. Emerging Diagnostic Techniques B. Non-Invasive Techniques: A. MRI 1- MRI without contrast media 2- MRI with contrast media: Gadolinium-DPTA 2- MR Imaging of Inflammation: Super Paramagnetic Iron Oxide (SPIO and USPIO) 3- MR Imaging of Thrombosis using monoclonal Ab B. Electron Beam Tomography (EBT) C. Multi-Slice Fast Spiral / Helical Computed Tomography D. Nuclear Imaging (18-FDG, MCP-1, Annexin V, CD40)
  40. 40. Emerging Diagnostic Techniques C. Blood Tests / Serum Markers - CRP - ICAM-1, VCAM, p-Selectin, sCD40-L - Proinflamatory cytokines - Lp-PLA2 - Ox-LDL Ab - PAPP-A D. Endothelial Function Test -Intra coronary acethylcholine test -Noninvasive flow mediated dilatation of brachial artery - Anti-body against endothelial cells
  41. 41. Angioscopy Advantages: Intuitive (anatomic) Simple (easy to understand) Disadvantages: Visualizes only the surface of the plaque Requires a proximal occluding balloon The spatial resolution is limited Glistening yellow plaque Uchida et al, Japan
  42. 42. Intravascular Ultrasound (IVUS): Advantage: Reveals the morphology of the plaque Differs between soft (hypo-echoic) and Hard (hyper-echoic) plaques Disadvantages: Doesn’t give information about plaque inflammation Low spatial resolution (~ 200 µm) Nissen, Yock, and Fitzgerald
  43. 43. Optical Coherence Tomography (OCT) Advantage: Very high-resolution Disadvantages: Needs continuous saline wash / proximal occlusion Limited penetration Does not give information about plaque inflammation Light Lab Inc.Mark Brezinski, James Fujimoto, Eric Swanson
  44. 44. Intravascular Thermography Advantages: Simplicity in theory; hot plaque Gives information about plaque inflammation Disadvantages: Plaque temperature is affected by blood flow Volcano Therapeutics Inc.
  45. 45. Casscells W, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet. 1996 May 25;347(9013):1447-51. Vulnerable plaques are hot and acidic! Ward Casscells and James Willerson showed ex-vivo that human carotid atherosclerotic plaques have temperature heterogeneity and plaques with thinner cap and higher macrophage infiltration give off more heat. Two years later Morteza Naghavi invented Thermosensor Basket catheter and showed invivo temperature heterogeneity in Hypercholestrolemic Dogs and Watanabe Rabbits. Coincidentally Stefanadis et al in 1999 confirmed significant temperature heterogeneity invivo in patients with unstable angina and acute MI. Stefanadis C, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation. 1999 Apr 20;99(15):1965-71.
  46. 46. Photonic Spectroscopy Advantage:  Chemical compounds Disadvantage: Based on statistical analysis and calibration is always an issue S/N is a serious problem Still not proven to be able to distinguish vulnerable plaques from stable ones Near Infrared Reflectance Spectroscopy InfraReDx Inc. NIR Spectroscopy Robert Lodder, James Muller, and Pedro Moreno
  47. 47. Intravascular Elastography Advantages: Provides novel information, showing stiffness Small added cost to IVUS Disadvantage: Does not give any chemical – compositional data, nor shows inflammation de Korte et al. Thorax Center, Erasmus University Rotterdam
  48. 48. Intravascular Nuclear Imaging Immuno-scintigraphy Advantage: One may use radio-labeled antibodies to detect specific antigens in plaque like MCP-1 Disadvantages: Radiation and safety problems Poor resolution and flow artifacts Lack of specificity ImetrX Inc.William Strauss and Vartan Ghazarossian
  49. 49. Magnetic Resonance Imaging Plaque Characterization and Angiography Advantages: Lack of ionizing radiation Non-invasive Provides enormous information about flow as well as plaque Enhancement by contrast agents and NMR spectroscopy Disadvantages: Ineligibility of patients with metal prostheses High cost Longer time for adoption by cardiologists
  50. 50. Human Carotid Plaque CCA Carotid bifurcation ICA stenosis & plaque Courtesy of Dr. Chun Yuan University of Washington Seattle
  51. 51. Human Carotid Plaque Courtesy of Dr. Chun Yuan University of Washington
  52. 52. Fuster and Fayad and colleagues reinforced earlier MRI investigation of plaque for invivo non-invasive detection of vulnerable plaque with large lipid pool and thin fibrous caps.
  53. 53. Noninvasive Coronary Vessel Wall and Plaque Imaging With Magnetic Resonance Imaging René M. Botnar; Matthias Stuber; Kraig V. Kissinger; Won Y. Kim; Elmar Spuentrup; Warren J. Manning. Circulation. 2000;102:2582
  54. 54. Intravascular MRI Advantages: Lack of ionizing radiation High resolution Potential for NMR spectroscopy Disadvantages: Invasive and slower than fluoroscopy Needs open/short bore high field magnet Longer time for adoption by cardiologists Surgi-Vision Inc.Ergin Atalar IVUS
  55. 55. Coronary Calcium Imaging EBT and MSCT Advantages: Quick and easy Provide information about total burden of atherosclerosis Disadvantages: Cannot distinguish vulnerable from stable plaque (poor plaque characterization) Inadequate specificity, may not accurately predict near future event May not be suitable for monitoring treatment Calcium Score Imatron Inc.Rumberger, Aard, Raggi, and others
  56. 56. Race for Non-Invasive Coronary Angiography • Multi-Slice Fast Computed Tomography (MSCT) • Magnetic Resonance Angiography (MRA)
  57. 57. Plaque Morphology vs. Plaque Activity Why do we need both?
  58. 58. Morphology vs. Activity Imaging Inactive and non-inflamed plaque Active and inflamed plaque Appear Similar in IVUS OCT MRI w/o CM Morphology Show Different Activity Thermography, Spectroscopy, immunoscientigraphy, MRI with targeted contrast media…
  59. 59. 2001 2050 Genomic Proteomic 2010 2020 2030 2040 VP Treatment Home-based VP Screening Test Heart Attack Eradicated Annual Death of MI <10,000 Cloning Heart VP Rx as OTC or Vaccine? Eradication of Heart Attack VP Detection Mission:
  60. 60. Center for Vulnerable Plaque Research Ongoing Projects Non-invasive Invasive Diagnostic • MRI SPIO • CT Detection of Inflammation • NanoScan • MR Guide Wire & Catheter • Intravascular Magnetometer Therapy • Coronary Dialysis • Vaccine
  61. 61. Association for Eradication of Heart Attack www.VP.org