Vulnerable plaque overview
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Vulnerable plaque refers to dangerous forms of atherosclerotic plaques that can rupture or induce thrombosis, disrupting blood flow. The document discusses the history and research around vulnerable plaque, including pioneers in the field and emerging techniques to detect vulnerable plaque such as intravascular ultrasound, optical coherence tomography, and magnetic resonance imaging. It summarizes that vulnerable plaques are typically characterized by a thin fibrous cap, large lipid core, and presence of macrophages.
Vulnerable plaque overview
- 1. #1 killer of human beingsin the21st century?
- 6. Dangerous forms of atherosclerotic plaques that can rupture or induce thrombosis and lead to critical disruption of blood flow. Theshort answer is:
- 7. Everybody has atherosclerosis, the question is who has vulnerable plaque Sudden Cardiac Death Acute MI
- 8. What Do We Know About Vulnerable Plaque? Morteza Naghavi, MD Center for Vulnerable Plaque Research University of Texas at Houston Texas Heart Institute October 2001 Mohammad Madjid, MD Silvio Litovsky, MD Alireza Zarrabi, MD MaziarAzadpour, MD Parsa Mirhaji, MD Cornelius Nwora, MD Ward Casscells, MD JamesWillerson, MD
- 10. Carl von Rokitansky (1804-1878) Rokitansky gaveearly detailed descriptionsof arterial disease. Heis alleged to haveperformed 30,000 autopsies. Rokitansky in 1841 championed theThrombogenic Theory. Heproposed that the depositsobserved in theinner layer of thearterial wall derived primarily from fibrin and other blood elementsrather than being theresult of apurulent process. Subsequently, theatheroma resulted from thedegeneration of thefibrin and other blood proteinsasaresult of apreexisting crasisof theblood, and finally thesedepositsweremodified toward apulpy masscontaining cholesterol crystalsand fatty globules. Thistheory cameunder attack by Virchow
- 11. 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.
- 12. 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
- 13. 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.
- 14. James T. Willerson 1981 N Engl J Med 1981 Mar 19;304(12):685-91 Plaque Thrombosis
- 15. Erling Falk Michael Davies Autopsy Series Thin Fibrous Cap + Large Lipid Core + Dense Macrophage A culprit ruptured plaque 1981-1990
- 17. 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 IEL is destructed and occupied by plaque Coronary artery disease is a disease of arterial wall disease not lumen.
- 18. 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
- 19. Falk E., Shak P.K., Fuster V. Circulation 1995 Non-stenotic (<75%) plaques cause about 80% of deadly MI
- 20. Macrophage- driven MMPs soften plaquecap and prompt it to rupture P.K. Shah Peter Libby Atherosclerosis and its thrombotic complication is governed by immunecells. Goran Hansson … Allard van derWal
- 21. 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!
- 22. •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.
- 23. “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:
- 24. Natural History of Vulnerable Plaques Illustrated:
- 25. ~65% 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 ~70% <5% ~20% ~55% ~20% <5% <5% ~20% Rupture Prone Eroded Calcified NoduleHemorrhage Positive Remodeling Fissured /Healed Natural History of Vulnerable Atherosclerotic Plaques
- 26. 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:
- 27. Culprit Plaque; a retrospective terminology Vulnerable Plaque; a prospective terminology Vulnerable Plaque = Future Culprit Plaque Clarification of Terminologies
- 28. Rupture-Prone Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Macrophage Necrotic Lipid Core Thin Fibrous Cap
- 29. Eroded Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
- 30. Fissured / Healed Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
- 31. Plaque with a Subluminal Calcified Nodule Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
- 32. Intra-Plaque Hemorrhage with Intact Cap Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
- 33. Critically Stenotic but Asymptomatic Plaque Naghavi et al, Cur Ath Rep 2001Vulnerable Plaque
- 34. 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. Emerging Diagnostic Techniques Angioscopy Intravascular Ultrasound (IVUS) Intravascular Thermography Intravascular Optical Coherence Tomography (OCT) Intravascular Elastography Intravascular and Transesophageal MRI Intravascular Nuclear Imaging Intravascular Electrical Impedance Imaging Intravascular Tissue Doppler Intravascular Shear Stress Imaging Intravascular (Photonic) Spectroscopy A. Invasive Techniques
- 37. - 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
- 38. 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)
- 39. Emerging Diagnostic Techniques C. Blood Tests / Serum Markers - CRP - ICAM-1, VCAM, p-Selectin - 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
- 40. 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
- 41. 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
- 42. Intravascular Thermography Advantages: Simplicity in theory; hot plaque Gives information about plaque inflammation Disadvantages: Plaque temperature is affected by blood flow Volcano Therapeutics Inc.
- 43. 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 possibly 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.
- 44. 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
- 45. 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
- 46. 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
- 47. 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
- 48. 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
- 49. Human Carotid Plaque CCA Carotid bifurcation ICA stenosis & plaque Courtesy of Dr. Chun Yuan University of Washington Seattle
- 50. Human Carotid Plaque Courtesy of Dr. Chun Yuan University of Washington
- 51. 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.
- 52. 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
- 53. 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
- 54. 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.John Rumberger, Paolo Raggi, and others
- 55. Race for Non-Invasive Coronary Angiography • Multi-Slice Fast Computed Tomography (MSCT) • Magnetic Resonance Angiography (MRA) • Electron Beam Tomography (EBT)
- 56. Plaque Morphology vs. Plaque Activity Why do we need both?
- 57. Functional vs. Structural Imaging Inactive and non-inflamed plaque Active and inflamed plaque Different Similar IVUS OCT MRI w/o CM Structural: Functional: Thermography, Spectroscopy, MRI w/ CM
- 58. High Level of Sensitivity and Specificity Needed • Knowing the extensive prevalence of atherosclerosis, in order to accurately detect vulnerable plaques, it is imperative to obtain information about both structure and activity of plaque assuring minimum false positive and negative results. NO MORE TREADMILL TEST!
- 59. Potential Intravascular Solutions: • IVUS + Thermography • OCT + Thermography • OCT + NIR Spectroscopy • IVUS + Raman Spectroscopy • …
- 60. … the question is who has vulnerable plaque
- 61. The Question seems to be MORE THAN ONE: 2.Who hasvulnerableblood? 3.Who hasvulnerableheart? 4.Who isvulnerablepatient? 1.Who hasvulnerableplaque?√
- 62. Who Has Vulnerable Blood? • In which patient the blood tends to create an occlusive thrombus on a vulnerable plaque, thereby resulting in an acute clinical syndrome? • In other words: Who has hyper-coagulable or “vulnerable blood”?
- 63. Who Has Vulnerable Heart? • Whose heart is more sensitive to an acute ischemic episode due to sub-occlusive or occlusive thrombi, thereby resulting in fatal arrhythmia and sudden out-of- hospital cardiac arrest? • In other words: Who has “vulnerable heart”?
- 64. Who is Vulnerable Patient? Whoever has more vulnerable plaque, vulnerable blood, and vulnerable heart.
- 65. The Beat Goes On…
- 68. r = -0.63 p = 0.0001
- 70. Basket CatheterBasket Catheter Wires with built-in Thermocouples 0.0014” Flexible Guide wire
- 71. Flexible guide wire Collapsed basket Shaft A penny! 0.014” Diamete r
- 73. In vivo intravascular study showing a significantly higher temperature as well as temperature heterogeneity in femoral artery of 5 Labrador atherosclerotic dogs
- 76. Stefanadis et al, 1999 First in vivo human intra-coronary thermometry study
- 81. of Atherosclerotic Plaques and its Correlation with •Morteza Naghavi MD, •Reji John MD, Said Siadaty MD, •Sameh Naguib MD, Roxana Grasu MD, •KC Kurian MD, Mohammad Madjid MD, •James T. Willerson MD, Ward Casscells MD, The University of Texas-HoustonTexas Heart pH HeterogeneitypH Heterogeneity Temperature HeterogeneityTemperature Heterogeneity
- 82. pH 9.00 8.88 8.75 8.63 8.50 8.38 8.25 8.13 8.00 7.88 7.75 7.63 7.50 7.38 7.25 7.13 7.00 6.88 6.75 6.63 Noofpointswiththesameph 140 120 100 80 60 40 20 0 pH Distribution in 48 Human Carotid Plaques This histogram demonstrates distribution of pH measured in 858 points in 48 carotid plaques of 48 patients. A marked variation ranging from 6.5 to 8.9 is seen.
- 83. 2220231717191026252428N = 11 human umbilical artery pH 9.5 9.3 9.1 8.9 8.7 8.5 8.3 8.1 7.9 7.7 7.5 7.3 7.1 6.9 6.7 6.5 6.3 6.1 5.9 5.7 5.5 pH Heterogeneity in 11 Human Umbilical Arteries
- 84. pH 9.00 8.88 8.75 8.63 8.50 8.38 8.25 8.13 8.00 7.88 7.75 7.63 7.50 7.38 7.25 7.13 7.00 6.88 6.75 6.63 Noofpointswiththesameph 140 120 100 80 60 40 20 0 pH Distribution in 48 Human Carotid Plaques This histogram demonstrates distribution of pH measured in 858 points in 48 carotid plaques of 48 patients. A marked variation ranging from 6.5 to 8.9 is seen.
- 85. Watanabe Rabbit Aorta pH 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 pH Heterogeneity in 9 Watanabe Rabbit Aortas
- 86. 2220231717191026252428N = 11 human umbilical artery pH 9.5 9.3 9.1 8.9 8.7 8.5 8.3 8.1 7.9 7.7 7.5 7.3 7.1 6.9 6.7 6.5 6.3 6.1 5.9 5.7 5.5 pH Heterogeneity in 11 Human Umbilical Arteries
- 87. calcified&thrombosedLipid Rich pH 9.0 8.5 8.0 7.5 7.0 6.5 pH in Lipid Rich Yellow Areas vs. Calcified areas Areas with large lipid core exhibit higher temperature and lower pH p < 0.01
- 88. Correlation of pH and Temperature in Human Carotid Plaques Varied by the Areas We see a marked inverse correlation between temperature and pH of plaques that varies by macroscopic characteristics of plaques. p < 0.01
- 89. Fluorescence Single-Emission Imaging Microscopy of a Predominantly Lipid Rich Plaque Shows Significant Microscopic pH Heterogeneity Mostly Acidic
- 94. Catheter Tipped with a Side Looking Silvered Conical 0.5 mm Mirror cm 0.5mm
- 95. 6.60 6.80 7.00 7.20 7.40 7.60 6.60 6.80 7.00 7.20 7.40 7.60 electrode pH NIRpH R2 = 0.63 RMSD = 0.14 pH units
- 96. Non-invasive Magnetic Resonance Imaging of Vulnerable Plaque Using SPIO Nano- Particles
- 97. SPIO Accumulation in Atherosclerotic Plaque Atherosclerotic plaqueNormal aortic segment Iron staining of Apo E K/O Aorta, 24 hour after SPIO injection Iron particles
- 98. 0 5 10 15 Atherosclerotic Aorta Average number of iron particles per sample P <0.001 Comparison of the Number of the Iron Particles in Apo E Mice Plaque vs. Normal Wall Normal Vessel Wall
- 99. Hypothesis: Because Macrophages Phagocytose Hemoglobin and Store Hemosiderin, Injection of Superparamagnetic Iron Oxide Particles Will Permit MR Imaging of Organizing Hemorrhage, Thrombosis, and Inflammation
- 100. MR Image of Abdominal Aorta After SPIO Injection in Mouse Apo E deficient mouse C57B1 (control) mouse Before injection After injection (5 Days ) Dark (negatively enhanced) aortic wall, full of iron particles Bright aortic lumen and wall without negative enhancement and no significant number of iron particles
- 101. Association of Influenza Vaccination and Reduced Risk of Recurrent Myocardial Infarction Morteza Naghavi, MD., Zeba Barlas, MD., Said Siadaty, MD., Sameh Naquib, MD., Mohammad Madjid, MD., Silvio Litovsky, MD, S. Ward Casscells, MD.
- 105. Prevention of unpredicted acute coronary events by early detection and treatment of vulnerable plaques/patients. The GOAL:
- 106. 2001 2050 Genomic Proteomic 2010 2020 2030 2040 Cellomic?! 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:
- 107. Association for Eradication of Heart Attack www.VP.org
- 114. Mohammad Madjid, MD Reza Mohammadi, MD Parsa Mirhaji, M.D. Mohammed Reza Khan, MD Khawar Gul, M.D.
- 126. Business @theSpeedof Thought William H. Gates Chairman and Chief Software Architect Microsoft Corporation
- 127. Research @ the Speed of Internet Mort Gates!!!