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Atherosclerosis3

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Atherosclerosis3

  1. 1. PATHOGENESIS OFATHEROSCLEROSIS
  2. 2. History This disease has a venerable history, having left traces in the arteries of Egyptian mummies. Apparently uncommon in antiquity, atherosclerosis became epidemic as populations increasingly survived early mortality caused by communicable diseases and malnutrition.
  3. 3.  Virchow- viewed atherosclerosis as a proliferative disease. Rokitansky- believed that atheroma derived from healing and resorption of thrombi.
  4. 4.  Experiments performed in the early part of the 20th century used dietary modulation to produce fatty lesions in the arteries of rabbits and ultimately identified cholesterol as the culprit. These observations, followed by the characterization of human lipoprotein particles at mid-century, promoted the concept of insudation of lipids as a cause for atherosclerosis
  5. 5. ATHEROSCLEROSIS:Pathology, Pathogenesis, Complications, Natural History
  6. 6. ? ? - Affects certain regions of the arterial tree preferentially. ? - Clinical manifestations occur only at certain times. ? - Its role in causing narrowing, or stenosis, of some vessels and ectasia of others.
  7. 7. STRUCTURE OF THE NORMAL ARTERY
  8. 8.  Endothelial cells have a common origin but acquire bed-specific characteristics during development. Arise during embryogenesis from regions known as the blood islands, located on the embryos periphery. ?- postnatal life-The endothelial progenitor cells (EPCs).
  9. 9.  Circulating numbers of EPCs, as assayed in vitro, vary among individuals. Those with a higher burden of risk factors for atherosclerosis have fewer EPCs. EPC number may correlate with prognosis in atherosclerotic patients. More aged individuals may have impaired EPC numbers and hence less ability to repair
  10. 10.  Differential expression of endothelial genes in various types of blood vessels depends on transcriptional regulation by the local environment. Members of the EPH family of tyrosine kinase receptors and their ligands, known as ephrins, display heterogeneous expressions in arterial versus venous endothelial cells during development.
  11. 11. Arterial Smooth Muscle Cells These cells contract and relax and thus control blood flow through the various arterial beds. Abnormal smooth muscle contraction causes vasospasm, a complication of atherosclerosis . SMCs synthesize the bulk of the complex arterial ECM that plays a key role in normal vascular homeostasis as well as the formation and complication of atherosclerotic lesions.
  12. 12.  These cells also can migrate and proliferate, contributing to the formation of intimal hyperplastic lesions. Death of SMC may promote destabilization of atheromatous plaques or favor ectatic remodeling and ultimately aneurysm formation.
  13. 13.  In the descending aorta and arteries of the lower body, the regional mesoderm serves as the source of smooth muscle precursors. In arteries of the upper body, SMCs can actually derive from a completely different germ layer, neurectoderm rather than mesoderm
  14. 14.  SMCs in the coronary arteries derive from mesoderm, but in a special way[from pro epicardial organ]. SMCs show molecular heterogeneity early during development. the promoter of a characteristic smooth muscle gene, known as SM22, drives gene expression in venous, but not arterial.
  15. 15.  Differential dependence on CArG elements in the control of SMC gene transcription furnishes a molecular basis for SMC heterogeneity in different arterial beds.
  16. 16. Normal Artery
  17. 17. Response to injury hypothesis* Injury to the endothelium (dysfunctional endothelium)* Chronic imflammatory response* Migration of SMC from media to intima* Proliferation of SMC in intima• Excess production of ECM• Enhanced lipid accumulation
  18. 18. Response to injury hypothesis (I)1. Chronic EC injury (subtle?)  EC dysfunction  Increased permeability  Leukocyte adhesion (via VCAM-1)  Thrombotic potential
  19. 19. Response to injury hypothesis (II)2. Accumulation of LDL (cholesterol)3. Oxidation of lesional LDL4. Adhesion & migration of blood monocytes; transformation into macrophages and foam cells5. Adhesion of platelets6. Release of factors from platelets, macrophages and ECs
  20. 20. Response to injury hypothesis (III)7. Migration of SMC from media to intima8. Proliferation of SMC9. ECM production by SMC10. Enhanced lipid accumulation Intracellular (SMC and macrophages) Extracellular
  21. 21. Response to Injury
  22. 22. ATHEROSCLEROSIS INITIATION
  23. 23. Endothelial Dysfunction
  24. 24. Initiation of Fatty Streak
  25. 25. Fatty Streak
  26. 26. Fatty Streak-Aorta
  27. 27. Fibro-fatty Atheroma
  28. 28. Evolution of atheroma
  29. 29.  Smooth Muscle Cell Death During Atherogenesis. The Arterial Extracellular Matrix. Angiogenesis in Plaques. Plaque Mineralization
  30. 30. The Focality of Lesion Formation
  31. 31. Lesion progression
  32. 32. COMPLICATIONS OF ATHEROSCLEROSIS Plaque Rupture and Thrombosis. Thrombosis Caused by Superficial Erosion of Plaques.
  33. 33. Plaque Rupture and Thrombosis
  34. 34. Thrombosis Caused by Superficial Erosion of Plaques
  35. 35. Fibrous Plaques Complicated Lesions
  36. 36.  ? small atheroma cause most myocardial infarctions .
  37. 37. AHA Classification of atherosclerosis Fig. 11.7
  38. 38. Novel Invasive Imaging Modalities
  39. 39. OPTICAL COHERENCE TOMOGRAPHY
  40. 40. INTEGRATED BACKSCATTER ANALYSIS (“VIRTUAL HISTOLOGY”).
  41. 41.  INTRACORONARY THERMOGRAPHY. PALPOGRAPHY. COMPUTATIONAL FLOW DYNAMICS.
  42. 42. SPECIAL CASES OF ARTERIOSCLEROSIS Restenosis After Arterial Intervention. Accelerated Arteriosclerosis Following Transplantation.
  43. 43. Restenosis After Arterial Intervention After balloon angioplasty, luminal narrowing recurs in approximately one- third of cases within 6 months. These observations renewed interest in adventitial inflammation with scar formation and wound contraction as a mechanism of arterial constriction following balloon angioplasty[negative remodeling].
  44. 44. Restenosis After Arterial Intervention The widespread introduction of stents has changed the face of the restenosis problem. The process of in-stent stenosis, in contrast with restenosis after balloon angioplasty, depends uniquely on intimal thickening.
  45. 45.  Histological analyses reveal that a great deal of the volume of the in-stent restenotic lesion is made up of myxomatous tissue. It comprises occasional stellate SMCs embedded in a loose and highly hydrated extracellular matrix.
  46. 46.  The introduction of stents has reduced the clinical impact of restenosis because of the very effective increase in luminal diameter achieved by this technique. stents that elaborate antiproliferative and antiinflammatory substances have shown great benefit in terms of preventing in-stent stenosis.
  47. 47. Accelerated Arteriosclerosis Following Transplantation
  48. 48. Aneurysmal Disease Atherosclerosis produces not only stenoses but also aneurysmal disease . Data from the Pathobiological Determinants of Atherosclerosis in Youth Study (PDAY) show that the dorsal surface of the infrarenal abdominal aorta has a particular predilection .
  49. 49.  Absence of vasa vasorum. The relative lack of blood supply to the tunica media in this portion of the abdominal aorta. the lumbar lordosis of the biped human may alter the hydrodynamics of blood flow in the distal aorta, yielding flow disturbances
  50. 50.  Transmural destruction of the arterial architecture occurs in aneurysmal disease. Many studies have documented overexpression of matrix-degrading proteinases, including matrix metalloproteinases in human aortic aneurysm specimens. Current clinical trials are testing the hypothesis that MMP inhibitors can reduce the expansion of aneurysms
  51. 51. Consequences ofAtherosclerosis
  52. 52. Altered Vessel Function Vessel change  Consequence  Plaque narrows  Ischemia, turbulence lumen  Aneurysms, vessel  Wall weakened rupture  Narrowing, ischemia,  Thrombosis embolization  Athero-embolization  Breaking loose of plaque  Loss of elasticity  Increase systolic blood pressure
  53. 53. Common Consequences ofAtherosclerosis in Specific Vessels
  54. 54. Aorta Aneurysm  Pulsatile abdominal mass  Abdominal pain  Bleeding Atheroembolization Narrowing of lumen  Usually not a problem
  55. 55. Aortic Aneurysm
  56. 56. Carotids and Cerebral Circulation Atherosclerosis with thrombosis can lead to brain infarction Red or white Coagulative or liquefactive Can lead to transient ischemic attacks (TIA), if narrowing is aggravated by mural thrombus or vasospasm
  57. 57. Celiac and Mesenteric Arteries Narrowing primarily at aorta bifurcation Ischemia uncommon because of collateral circulation Ischemia can occur if more than 1 artery severely affected - ischemic entercolitis
  58. 58. Renal Artery Progressive ischemic atrophy of kidney leads to gradual kidney failure (nephrosclerosis) Renal hypertension due to decreased perfusion
  59. 59. Iliac and Femoral Arteries Aneurysms Vessel occlusion by plaque and thrombus  Ischemia of leg muscles, especially during exercise (intermittent claudication)  Ulcers of skin of legs and feet  Gangrene of feet
  60. 60. Non-Modifiable Risk Factors Age  A dominant influence  Atherosclerosis begins in the young, but does not precipitate organ injury until later in life Gender  Men more prone than women, but by age 60-70 about equal frequency Family History  Familial cluster of risk factors  Genetic differences
  61. 61. Modifiable Risk Factors (potentially controllable) Hyperlipidemia Hypertension Cigarette smoking Diabetes Mellitus Elevated Homocysteine Factors that affect hemostasis and thrombosis Infections: Herpes virus; Chlamydia pneumoniae Obesity, sedentary lifestyle, stress
  62. 62. NOVEL ATHEROSCLEROTIC RISK FACTORS.
  63. 63. Smoking Other than advanced age, smoking is the single most important risk factor for coronary artery disease. Landmark studies in the early 1950s first reported strong positive associations between cigarette smoke exposure and coronary heart disease. smoking may enhance oxidation of low- density lipoprotein (LDL) cholesterol and impair endothelium-dependent coronary artery vasodilation.
  64. 64.  Smoking has adverse hemostatic and inflammatory effects, including increased levels of CRP, soluble ICAM-1, fibrinogen, and homocysteine. Cessation of cigarette consumption overwhelmingly remains the single most important intervention in preventive cardiology. Smoking predicts better outcome following various reperfusion strategies (the so-called “smokers paradox”) --- smokers are likely to undergo such procedures at a much younger age and hence have on average lower comorbidity
  65. 65. Hypertension Most epidemiological studies now recognize the joint contributions of SBP&DBP to the development of CV risk. ISH has at least as much importance as DBP for the outcomes of total CV &CVA .
  66. 66.  Treatment of systolic hypertension is well supported, even in the elderly. Isolated systolic hypertension thus appears to represent a distinct pathophysiological state. In ISH elevated blood pressure reflects reduced arterial elasticity not necessarily associated with increased peripheral resistance or an elevation in mean arterial pressure.
  67. 67. Hyperlipidemia and Elevated Low-Density Lipoprotein Cholesterol In the 1850s, the German pathologist Virchow recognized in human atheromata “numerous plates of cholesterine…which display themselves even to the naked eye as glistening lamellae. Multiple Risk Factor Intervention Trial (MRFIT). Northwick Park Study and the Prospective Cardiovascular Munster (PROCAM) Cohort . the Atherosclerosis Risk in Communities (ARIC) study.
  68. 68.  REVERSAL trial, which monitored intravascular coronary ultrasound, PROVE-IT, A-to-Z, and TNT trials, all of which support more aggressive use of statin therapy for reduction in hard clinical endpoints.
  69. 69. Metabolic Syndrome, Insulin Resistance, and Diabetes.
  70. 70. Exercise, Weight Loss, and Obesity. Physical exercise reduces myocardial oxygen demand and increases exercise capacity, both of which correlate with lower levels of coronary risk. The cardioprotective effects of exercise include reduced adiposity and diabetes incidence, lowered blood pressure, and improvement of dyslipidemia, as well as vascular inflammation.
  71. 71.  Exercise also enhances endothelial dysfunction, insulin sensitivity, and endogenous fibrinolysis. In the Womens Health Initiative, walking briskly for 30 minutes five times/week was associated with a 30 percent reduction in vascular events over a 3.5-year follow-up. In the Womens Health Study, high BMI was more strongly associated with adverse cardiovascular biomarkers than physical activity
  72. 72. Mental Stress, Depression, and Cardiovascular Risk. In the INTERHEART study,psychosocial stress was found to be associated with vascular risk, with a magnitude of effect similar to that of the major coronary risk factors. In the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) trial, formal psychosocial intervention modestly improved measures of clinical depression but did not significantly improve event-free survival
  73. 73. High-Sensitivity C-Reactive Protein Composed of five 23-kDa subunits, CRP is a circulating member of the pentraxin family that plays a major role in the human innate immune response. Although derived primarily from the liver, studies have found that cells within human coronary arteries, particularly in the atherosclerotic intima, can also elaborate CRP.
  74. 74.  hsCRP levels less than 1, 1 to 3, and higher than 3 mg/liter should be interpreted as lower, moderate, and higher relative vascular risk. Values of hsCRP in excess of 8 mg/liter may represent an acute-phase response caused by an underlying inflammatory disease or intercurrent infection and should lead to repeat testing in approximately 2 to 3 weeks. consistently high values, however, represent very high risk of future cardiovascular disease.
  75. 75. Fibrinogen and Fibrin D-Dimer fibrinogen associates positively with age, obesity, smoking, diabetes, and LDL cholesterol level, and inversely with HDL cholesterol level, alcohol use, physical activity, and exercise level. Fibrinogen, like CRP, is an acute-phase reactant and increases during inflammatory responses.
  76. 76.  Despite the consistency of these data, fibrinogen evaluation has found limited use in clinical practice because of suboptimal assay standardization and consistency across reference laboratories remains poor.
  77. 77. Lipoprotein(a) Lipoprotein(a) (Lp[a]) consists of an LDL particle with its apolipoprotein B-100 (apo B- 100) component linked by a disulfide bridge to apolipoprotein(a) (apo[a]). The close homology between Lp(a) and plasminogen has raised the possibility that this lipoprotein may inhibit endogenous fibrinolysis.
  78. 78.  Many but not all prospective cohort studies have supported a role for Lp(a) as a determinant of vascular risk. Standardization of commercial Lp(a) assays remains problematic and inaccuracy of commercial Lp(a) assays has resulted from the use of techniques sensitive to apo(a) size.
  79. 79.  Womens Health Study have found that extremely high levels of Lp(a) (greater than the 90th percentile, or higher than 65.6 mg/liter) are indeed associated with increased cardiovascular risk, independent of other traditional risk factors.

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