acute coronary syndromes unstable angina

1. Acute Coronary SyndromesUnstable Angina/Non Q-Wave MI Current Management Concepts David Putnam, MD Albany Medical College

2. Spectrum of Acute Coronary Syndromes

3. Acute Coronary Syndromes Acute Coronary Syndromes (ACS) are the leading cause of morbidity and mortality in the US. These syndromes are a clinical expression of myocardial ischemia that is most frequently caused by total or subtotal thrombotic occlusion of coronary arteries. Acute coronary syndromes represent a spectrum of clinical conditions, ranging from unstable angina and non-Q-wave myocardial infarction (generally characterized by ST-segment depression or T-wave inversion on ECG) to acute (ST-segment elevation on ECG) myocardial infarction. Each can progress to sudden cardiac death.Acute Coronary Syndromes Acute Coronary Syndromes (ACS) are the leading cause of morbidity and mortality in the US. These syndromes are a clinical expression of myocardial ischemia that is most frequently caused by total or subtotal thrombotic occlusion of coronary arteries. Acute coronary syndromes represent a spectrum of clinical conditions, ranging from unstable angina and non-Q-wave myocardial infarction (generally characterized by ST-segment depression or T-wave inversion on ECG) to acute (ST-segment elevation on ECG) myocardial infarction. Each can progress to sudden cardiac death.

4. Presentation for Acute Coronary Syndromes in US Emergency Departments Acute Coronary Syndromes (ACS), common presenting conditions in US Emergency Departments, are the leading cause of morbidity and mortality in the US. These syndromes are a clinical expression of myocardial ischemia that is most frequently caused by total or subtotal thrombotic occlusion of coronary arteries. Acute coronary syndromes represent a spectrum of clinical conditions, ranging from unstable angina and non-Q-wave myocardial infarction (generally characterized on the ECG as ST-segment depression or T-wave inversion) to acute myocardial infarction (generally characterized by ST-segment elevation). Each can progress to sudden cardiac death.Presentation for Acute Coronary Syndromes in US Emergency Departments Acute Coronary Syndromes (ACS), common presenting conditions in US Emergency Departments, are the leading cause of morbidity and mortality in the US. These syndromes are a clinical expression of myocardial ischemia that is most frequently caused by total or subtotal thrombotic occlusion of coronary arteries. Acute coronary syndromes represent a spectrum of clinical conditions, ranging from unstable angina and non-Q-wave myocardial infarction (generally characterized on the ECG as ST-segment depression or T-wave inversion) to acute myocardial infarction (generally characterized by ST-segment elevation). Each can progress to sudden cardiac death.

5. Acute Coronary Syndromes Unstable angina is a clinical syndrome falling between chronic angina pectoris and myocardial infarction in the spectrum of patients with coronary artery disease (CAD) Non Q-wave MI is a clinical syndrome falling between unstable angina and Q-wave MI

6. Unstable Angina Chest pain syndrome, either new onset or progressive angina Transient ST-segment depression on the electrocardiogram (ECG) Without evidence of myocardial infarction by CK, CK-MB, or Troponin

7. Non Q-Wave MI Chest pain syndrome, either new onset or progressive angina Transient or persistent ST-segment depression on the electrocardiogram (ECG) With evidence of myocardial infarction by CK, CK-MB, or Troponin

8. Unstable Angina/NQWMI Significant likelihood of occurrence of major cardiac events A. Incidence of MI: 8 to 10% B. Mortality: 2 to 5%

9. 6-month mortality for UA/NQMI and ST ? MI When patients presenting with UA/NQMI are treated with aspirin plus heparin, myocardial injury can occur due to the inadequacy of these therapies in preventing platelet aggregation. Patients who have experienced myocardial injury are at high risk of cardiac morbidity and mortality over time. The inadequacy of acute treatment with aspirin and heparin is highlighted by the fact that at 6 months patients who presented initially with ST-segment depression UA/NQMI and who were managed with aspirin plus heparin during initial hospitalization experience higher incidence of death than patients who presented with ST ? MI and were treated with fibrinolytics. This indicates the need for more potent therapies for UA/NQMI to prevent early MI and resultant long-term mortality.6-month mortality for UA/NQMI and ST ? MI When patients presenting with UA/NQMI are treated with aspirin plus heparin, myocardial injury can occur due to the inadequacy of these therapies in preventing platelet aggregation. Patients who have experienced myocardial injury are at high risk of cardiac morbidity and mortality over time. The inadequacy of acute treatment with aspirin and heparin is highlighted by the fact that at 6 months patients who presented initially with ST-segment depression UA/NQMI and who were managed with aspirin plus heparin during initial hospitalization experience higher incidence of death than patients who presented with ST ? MI and were treated with fibrinolytics. This indicates the need for more potent therapies for UA/NQMI to prevent early MI and resultant long-term mortality.

10. Unstable Angina/NQWMI:Pathophysiology Acute plaque fissuring and rupture Superimposed thrombus Transient occlusion Mediator-induced vasospasm may be present

11. Histologic studies have characterized the progression of atherosclerotic lesion types. The earliest lesions (from the first decade on) are characterized histologically by isolated foam cells or fatty streaks in the vessel wall. Lesion growth at this stage occurs mainly by lipid accumulation. Intermediate lesions, which may be associated with small extracellular lipid pools, progress to atheroma, which has a core of extracellular lipid. These lesions may be seen starting in the third decade. Starting in the fourth decade, lesions may progress to the fibrous plaque stage, which is characterized by accelerated increases in smooth muscle and collagen. Complicated lesions are characterized by thrombosis, fissure, and hematoma formation.2 Histologic studies have characterized the progression of atherosclerotic lesion types. The earliest lesions (from the first decade on) are characterized histologically by isolated foam cells or fatty streaks in the vessel wall. Lesion growth at this stage occurs mainly by lipid accumulation. Intermediate lesions, which may be associated with small extracellular lipid pools, progress to atheroma, which has a core of extracellular lipid. These lesions may be seen starting in the third decade. Starting in the fourth decade, lesions may progress to the fibrous plaque stage, which is characterized by accelerated increases in smooth muscle and collagen. Complicated lesions are characterized by thrombosis, fissure, and hematoma formation.2

13. Pathophysiology of UA/NQMI Unstable angina and non-Q-wave MI are generally the result of a platelet aggregate partially occluding the coronary artery. The adhesion of platelets to exposed subendothelial surfaces is mediated mainly by von Willebrand factor, a protein that is both present in the subendothelium and recruited there upon endothelial injury. Adhered platelets are exposed to a number of subendothelial proteins, including collagen and thrombin, that promote platelet activation. Platelets can also be activated by shear stress at the site of adhesion. Activated platelets release additional platelet agonists, resulting in amplification of activation and further recruitment of platelets to the nascent thrombus. The most important consequence of platelet activation is the expression of platelet receptor GP IIb-IIIa on the surface of the platelet that allows binding to fibrinogen. Fibrinogen can bind to two GP IIb-IIIa molecules at the same time; it therefore cross-links receptors on adjacent platelets and initiates platelet aggregation. Left untreated, the platelet aggregate will be stabilized by the deposition of a mesh of fibrin strands. This stabilized thrombus can continue to grow and completely occlude the artery, resulting in myocardial infarction or death.Pathophysiology of UA/NQMI Unstable angina and non-Q-wave MI are generally the result of a platelet aggregate partially occluding the coronary artery. The adhesion of platelets to exposed subendothelial surfaces is mediated mainly by von Willebrand factor, a protein that is both present in the subendothelium and recruited there upon endothelial injury. Adhered platelets are exposed to a number of subendothelial proteins, including collagen and thrombin, that promote platelet activation. Platelets can also be activated by shear stress at the site of adhesion. Activated platelets release additional platelet agonists, resulting in amplification of activation and further recruitment of platelets to the nascent thrombus. The most important consequence of platelet activation is the expression of platelet receptor GP IIb-IIIa on the surface of the platelet that allows binding to fibrinogen. Fibrinogen can bind to two GP IIb-IIIa molecules at the same time; it therefore cross-links receptors on adjacent platelets and initiates platelet aggregation. Left untreated, the platelet aggregate will be stabilized by the deposition of a mesh of fibrin strands. This stabilized thrombus can continue to grow and completely occlude the artery, resulting in myocardial infarction or death.

14. Small, vulnerable plaques are responsible for causing MI Up until the 1990�s, it was assumed that MIs resulted from the buildup of plaque in coronary arteries until it reduced circulation to the point where thrombosis would occur. This analysis of autopsy data by Faulk demonstrated that the majority of MIs result from smaller plaques that are less than 50% stenosed. This lead to the concept that many of the smaller plaques were more unstable and more likely to rupture than the high-grade lesions.Up until the 1990�s, it was assumed that MIs resulted from the buildup of plaque in coronary arteries until it reduced circulation to the point where thrombosis would occur. This analysis of autopsy data by Faulk demonstrated that the majority of MIs result from smaller plaques that are less than 50% stenosed. This lead to the concept that many of the smaller plaques were more unstable and more likely to rupture than the high-grade lesions.

15. Determinants of Plaque Vulnerability Lipid-rich core size Cap thickness Cap inflammation and repair

16. Atherosclerotic plaques typically consist of a lipid-rich core, which is found in the central portion of the eccentrically thickened intima. The lipid core is bounded on the luminal surface by a fibrous cap. The integrity of the fibrous cap determines the stability of the plaque. The vulnerable plaque typically has a substantial lipid core and a thin, friable fibrous cap. Shear stress is increased at sites of plaques prone to rupture. When there is plaque rupture, the antigen HLA-DR? is expressed by smooth muscle cells (SMCs) and leukocytes. The expression of HLA-DR? is felt to be a marker for activation of SMCs.4 In contrast, the stable atherosclerotic plaque typically has a relatively thick fibrous cap, which is more resistant to shear stress and less prone to rupture.Atherosclerotic plaques typically consist of a lipid-rich core, which is found in the central portion of the eccentrically thickened intima. The lipid core is bounded on the luminal surface by a fibrous cap. The integrity of the fibrous cap determines the stability of the plaque. The vulnerable plaque typically has a substantial lipid core and a thin, friable fibrous cap. Shear stress is increased at sites of plaques prone to rupture. When there is plaque rupture, the antigen HLA-DR? is expressed by smooth muscle cells (SMCs) and leukocytes. The expression of HLA-DR? is felt to be a marker for activation of SMCs.4 In contrast, the stable atherosclerotic plaque typically has a relatively thick fibrous cap, which is more resistant to shear stress and less prone to rupture.

17. Unstable AnginaClinical Presentation Rest angina within 1 week of presentation New onset angina of CCSC (Canadian) Class III or IV within 2 months of presentation Angina increasing in CCSC Class to at least Class III or IV Non-Q-wave myocardial infarction Post-MI angina (>24 hours)

18. AnginaCanadian Cardiovascular Classification Class I Class II Class III Class IV Prolonged exertion Walking >2 blocks Walking >1 block Minimal or rest

19. Unstable Angina/NQWMIInitial Evaluation Should take place in a medical facility, not by telephone Careful clinical history Physical examination Assessment of likelihood of coronary artery disease Assessment of risk of adverse outcomes

20. Evaluation in Emergency Department History Physical ECG ( serial ECG�s if indicated ) CK-MB, Troponin

21. Evaluation in Emergency Dept Time goal of initial assessment and triage to be completed is 10 minutes

22. Common Symptom History in Acute Coronary Syndromes Chest Pain Usually substernal Crushing or squeezing in quality Can resemble �indigestion� May radiate to either arm, neck, jaw, epigastrium, or between scapulae Generally under 20 minutes in duration with unstable angina but may be longer with NQWMI

23. Associated Symptoms inUnstable Angina/NQWMI Dyspnea Diaphoresis Weakness Nausea Vomiting Feeling of impending doom

24. Common Cardiac Causes of Chest Pain Angina Myocardial Infarction Aortic valve disease Hypertrophic or congestive cardiomyopathy Aortic dissection Pericarditis Mitral valve prolapse

25. Noncardiovascular Causes of Chest Pain Abnormalities of the cervicodorsal spine Costochondral separation Nonspecific chest wall pain Gastrointestinal disease: indigestion, hiatal hernia, GERD, esophagitis Dyspnea Pleuritic pain secondary to pleural effusion/pneumonia

26. Physical Examinaton Not that helpful May have evidence of CHF: JVD, rales, edema May have S4 May have murmur of mitral regurgitation from papillary muscle dysfunction

27. Electrocardiogram One of the most important tests that can be performed is the twelve-lead ECG taken during chest pain In the absence of ECG changes during chest pain, the diagnosis of myocardial ischemia is unlikely

29. Coronary Markers

30. CK-MB Levels 9461 patients in the PURSUIT Trial CK-MB elevation directly correlated with mortality Increased risk begins with CK-MB elevations just above normal levels JAMA 2000;283:347-353

31. Troponin T and Troponin I 773 patients with chest pain less than 12 hours and without ST elevation Testing on arrival and six hours after onset of pain Event rates in patients with negative tests were 1.1% for Troponin T and 0.3% for Troponin I NEJM 1997;337:1648-53

32. Moving to the 14 day events, we find that again cTnI is a strong indicator of higher risk for the composite outcome of death/MI or urgent revascularization with an absolute risk difference of nearly 14% between the troponin I positive and negative groups. Further, we see that an elevated baseline cTnI was predictive of increased risk of each component of the composite endpoint including both death and myocardial infarction. Similar to results from TIMI 3B, troponin I positive patients were at an over 3 fold higher risk of death than those with a normal baseline troponin.Moving to the 14 day events, we find that again cTnI is a strong indicator of higher risk for the composite outcome of death/MI or urgent revascularization with an absolute risk difference of nearly 14% between the troponin I positive and negative groups. Further, we see that an elevated baseline cTnI was predictive of increased risk of each component of the composite endpoint including both death and myocardial infarction. Similar to results from TIMI 3B, troponin I positive patients were at an over 3 fold higher risk of death than those with a normal baseline troponin.

33. Acute Coronary Syndrome

34. Likelihood of CAD

35. Likelihood of Adverse Events

36. Practical Point of ViewPatients to Admit Patients with symptoms within 24 hours of presentation Angina with increased frequency, severity, and/or duration New onset of prolonged rest angina Recurrent angina after a recent MI

37. Unstable Angina Outpatient Care Patients at low risk for adverse outcomes Onset or worsening of symptoms within preceeding two weeks but without severe, prolonged, or rest episodes Follow-up evaluation within 72 hours

38. Unstable AnginaOutpatient Care Medical Management Aspirin 80-324 mg/day Ticlodipine 250 mg bid or Clopidogrel mg qd ( patients unable to take Aspirin ) Sublingual NTG prn Oral beta blockers and/or long-acting topical or oral nitrates

39. Acute Coronary Syndromes

40. Acute Coronary SyndromesPotential First Line Drugs Beta-blocker Nitrates Aspirin 2b3a Inhibitors Heparin

41. Initial Medical Treatment Choice/timing of drugs determined by: Certainty of diagnosis Severity of symptoms Hemodynamic state Medication history

42. Beta Blockers Decrease frequency and duration of myocardial ischemia Decrease development of refractory angina Decrease mortality and incidence of myocardial infarction Intravenous forms recommended in unstable situations

43. Beta Blockers Remain the mainstay of therapy in patients with acute ischemic syndromes Should be used in all patients unless contraindicated

44. Beta Blockers: Contraindications Acute bronchospasm History of severe COPD or severe asthma Significant bradycardia ( < 60 ) Significant hypotension ( SBP < 90 ) Overt CHF

45. Nitrates Decrease frequency and duration of myocardial ischemia Decrease development of refractory angina No reduction in mortality or incidence of myocardial infarction Intravenous forms recommended in unstable situations Tolerance may develop quickly

46. Unstable AnginaCalcium Channel Blockers Are not first-line therapy May be used as add-on therapy Rate limiting calcium channel blockers may be used as substitute for beta blocker if beta blocker contraindicated

47. Anti-Platelet/Anti-Thrombin Therapy

48. Acute Ischemic SyndromesAspirin Reduces risk of fatal/nonfatal MI A. 71% during acute phase B. 60% at 3 months C. 52% at 2 years Reduces risk of early and late major complications

49. Aspirin--Platelet Inhibition Potent inhibitor of arachidonic acid Weak inhibitor of ADP, thrombin Does not prevent alpha granule release Does not inhibit shear-induced platelet aggregation

50. Outcomes of current management strategies for UA/NQMI Although significant advances have been made with the use of aspirin plus heparin (in addition to IV nitroglycerin and beta blockers) in the management of acute coronary syndromes, the morbidity and mortality associated with these syndromes remains high. In recent studies that enrolled patients with unstable angina or non�Q-wave myocardial infarction, the combined endpoint of death or non-fatal myocardial infarction was between 7.7% and 15.7%, depending on the method of defining myocardial infarction.Outcomes of current management strategies for UA/NQMI Although significant advances have been made with the use of aspirin plus heparin (in addition to IV nitroglycerin and beta blockers) in the management of acute coronary syndromes, the morbidity and mortality associated with these syndromes remains high. In recent studies that enrolled patients with unstable angina or non�Q-wave myocardial infarction, the combined endpoint of death or non-fatal myocardial infarction was between 7.7% and 15.7%, depending on the method of defining myocardial infarction.

51. Unstable Angina: Aspirin Stat Aspirin 324 mg chewed then 162 to 324 mg/day Clopidogrel 75 mg po if Aspirin intolerant or already on aspirin

52. Mechanism of action: GP IIb-IIIa inhibitors GP IIb-IIIa inhibitors prevent aggregation of activated platelets by blocking the binding of fibrinogen to platelet receptors GP IIb-IIIa. By blocking platelet aggregation, GP IIb-IIIa inhibitors prevent progression of thrombosis to full occlusion of the coronary arteries and thus prevent MI. Mechanism of action: GP IIb-IIIa inhibitors GP IIb-IIIa inhibitors prevent aggregation of activated platelets by blocking the binding of fibrinogen to platelet receptors GP IIb-IIIa. By blocking platelet aggregation, GP IIb-IIIa inhibitors prevent progression of thrombosis to full occlusion of the coronary arteries and thus prevent MI.

53. Mechanism of action of GP IIb-IIIa inhibitors Pharmacological inhibitors of specific platelet activation pathways suffer from a common limitation: each agent targets only a subset (usually one) of the activation pathways, leaving alternate routes of platelet activation unchecked to stimulate expression of platelet receptor GP IIb-IIIa. For instance, aspirin, the most commonly used antiplatelet agent, inhibits only generation of TxA2. While TxA2 is utilized by all activation pathways, most platelet agonists can induce platelet activation even in the absence of TxA2 synthesis, and aspirin is therefore considered to be a relatively weak antiplatelet agent. Likewise, heparin, an indirect inhibitor of thrombin generation, only blocks thrombin-induced platelet aggregation. By inhibiting the final common pathway of platelet aggregation, fibrinogen binding to platelet receptor GP IIb-IIIa, GP IIb-IIIa inhibitors block all routes to platelet aggregation and thrombus formation.Mechanism of action of GP IIb-IIIa inhibitors Pharmacological inhibitors of specific platelet activation pathways suffer from a common limitation: each agent targets only a subset (usually one) of the activation pathways, leaving alternate routes of platelet activation unchecked to stimulate expression of platelet receptor GP IIb-IIIa. For instance, aspirin, the most commonly used antiplatelet agent, inhibits only generation of TxA2. While TxA2 is utilized by all activation pathways, most platelet agonists can induce platelet activation even in the absence of TxA2 synthesis, and aspirin is therefore considered to be a relatively weak antiplatelet agent. Likewise, heparin, an indirect inhibitor of thrombin generation, only blocks thrombin-induced platelet aggregation. By inhibiting the final common pathway of platelet aggregation, fibrinogen binding to platelet receptor GP IIb-IIIa, GP IIb-IIIa inhibitors block all routes to platelet aggregation and thrombus formation.

54. Unstable Angina: IIb/IIIa Inhibitors

55. 2b3a InhibitorsSmall Molecular Weight Compounds Tirofiban (Aggrastat) Eptifibatide (Integrilin) No binding to 2b/3a receptor (competative inhibitor) High plasma concentration Short half life

56. 2b3a InhibitorsLarge Molecular Weight Compounds Abciximab (Reopro) Binds to the 2b/3a receptor directly Low plasma concentration Long half life

57. Unstable Angina: IIb/IIIa InhibitorsContraindications History of bleeding diathesis Evidence of active abnormal bleeding within previous 30 days Severe hypertension (SBP>200, DBP>110) Major surgery within past 6 weeks

58. Unstable Angina: IIb/IIIa InhibitorsContraindications History of stroke within 30 days History of hemorrhagic stroke Platelet count < 100,000 Serum creatinine > 2.0 (eptifibatide) Dependency on renal dialysis (eptifibatide)

59. Unstable Angina: IIb/IIIa InhibitorsIndications Positive troponin Marked ST segment depression Status-post recent MI Currently on Aspirin

60. Heparin Reduction in frequency and duration of ischemic episodes Reduction in MI Reduction in MI/mortality when combined with Aspirin Potential to reduce complications and improve survival in PTCA

61. Improvements in treatment have led to reductions in the risk of death, MI, and refractory angina in patients presenting with unstable angina. Combination treatment with aspirin and heparin showed a reduction in event rates in comparison to either treatment alone.Improvements in treatment have led to reductions in the risk of death, MI, and refractory angina in patients presenting with unstable angina. Combination treatment with aspirin and heparin showed a reduction in event rates in comparison to either treatment alone.

62. Unstable AnginaHeparin vs. ASA Double-blind, randomized trial 484 patients A. 240 patients treated with IV heparin B. 244 patients treated with aspirin MI occurrence A. 0.8% of patients treated with heparin B. 3.7% of patients treated with aspirin Theroux P. CIRCULATION 1993;88:2045-8

63. Unstable AnginaHeparin Should be used in intermediate and high risk patients for its antithrombin effect Low molecular weight heparin is probably better than unfractionated heparin How long patients should be treated with heparin is not clear (probably should maintain for at least 48 hours)

64. Unstable AnginaLow Molecular Weight Heparin Meta-analysis of TIMI 11b and ESSENCE Enoxaparin superior to unfractionated heparin Eight day death/cardiac event rate on enoxaparin 18.1% Eight day death/cardiac event rate on heparin 20.2% ACC Meeting Mar/99

65. LMWH vs. Unfractionated Heparin Review of 12 trials No convincing diffeerence in effectiveness between the two drugs. Lancet 2000(Jun);355;1936-42.

66. LMWH vs. Unfractionated Heparin

67. Thrombolytics Standard treatment regimens have no demonstrated benefit in unstable angina or NQWMI

68. Re-Assessing Persistent Symptoms Most patients are stabilized/improved after 30 minutes of aggressive medical management Patients failing to respond to initial RX A. Consider other diagnosis B. Consider early cardiac catheterization if ongoing ischemia is suspected

69. Nonintensive Medical Management Recurrence of pain and return to intensive management Noninvasive testing Cardiac catheterization Myocardial revascularization Invasive vs. noninvasive approach Hospital discharge

70. Progression to Non-IntensiveMedical Management Serial enzymes to rule out MI Follow up ECG at 24 hours Chest x-ray within 48 hours in stable patients Reassess heparin use Continue Aspirin and oral antianginal agents

71. Non-Invasive TestingGoals Estimate subsequent prognosis Determine additional tests and adjustments in therapy Determine exercise limitations

72. Non-Invasive Risk Stratification Baseline ECG Continuous ECG monitoring/telemetry Exercise testing Myocardial imaging

73. Baseline ECG Development of changes with or without chest pain has important prognostic implications ST depression portends a worse prognosis and is a marker of severe multi-vessel or left main disease

74. Exercise Testing Provides some important prognostic information Large disparities in event rates, clinical classification, and documentation of CAD Patients with a negative test also appear to have a high incidence of adverse events

75. Exercise TestingTesting Modalities Exercise Stress Test Nuclear Stress Test Persantine Nuclear Stress Test Dobutamine Nuclear Stress Test Stress Echocardiogram Dobutamine Stress Echocardiogram

76. Choice of Stress Testing Modality Evaluation of patient�s resting ECG Ability to perform exercise Local expertise and technologies available

77. Cardiac Catheterization Goal of cardiac catheterization in patients with acute coronary syndromes Provide detailed structural information Assess prognosis Select an appropriate long, or short-term management strategy

78. Interventional Therapy Unstable angina often associated with multi-vessel disease Wide variation in apparent need for intervention Most effective role has not been fully defined

79. Early Invasive Strategy vs.Early Conservative Strategy Early Invasive Strategy A. All patients catheterized within 48 hours of admission Early Conservative Strategy A. Only high risk patients and patients with ongoing ischemia receive a cardiac catheterization

80. Early Invasive Strategy vs.Early Conservative Strategy Studies Supporting Invasive Strategy A. FRISCH II B. TACTICS-TIMI 18 Studies Supporting Conservative Strategy A. TIMI IIIB B. VANQWISH

81. FRISCH II

82. Invasive StrategyHigh-Risk Characteristics Ongoing resting pain ECG changes Positive Troponin Provacable ischemia

83. Thus, numerous factors contribute to the development of plaque instability. Once unstable, plaques are prone to rupture, exposing the thrombogenic core to the hemostatic mechanisms. The adhesion, activation, and aggregation of platelets forms the nidus for thrombus development, interfering with blood flow, and ultimately resulting in symptoms which bring the patient to clinical attention. Interference with this platelet process is one step in halting the pathophysiologic mechanisms leading to myocardial damage.3,19Thus, numerous factors contribute to the development of plaque instability. Once unstable, plaques are prone to rupture, exposing the thrombogenic core to the hemostatic mechanisms. The adhesion, activation, and aggregation of platelets forms the nidus for thrombus development, interfering with blood flow, and ultimately resulting in symptoms which bring the patient to clinical attention. Interference with this platelet process is one step in halting the pathophysiologic mechanisms leading to myocardial damage.3,19

84. Brigham and Women�s HospitalCritical Pathways for ACS

85. Critical Pathways for ACSAcute Ischemia Protocol

86. The End

87. Plaques cannot be classified purely on the basis of their size; other�characteristics are�also important. Classification of coronary plaques was undertaken by the Committee on Vascular Lesions, which identified eight different morphologies of plaques and grouped them into categories designated types I through V. Plaques that have a high lipid content and a high proportion of cholesterol esters are vulnerable to rupture. In some patients, plaque disruption may lead to a labile thrombus with transient or intermittent vessel occlusion and subsequent unstable angina. In other patients, more severe vascular injury may lead to the formation of a fixed thrombus, resulting in acute myocardial infarction (MI).2 Not all disrupted plaques result in clinically detectable thrombosis, and in fact, the rupture and healing cycle may represent an etiology of plaque progression.3Plaques cannot be classified purely on the basis of their size; other�characteristics are�also important. Classification of coronary plaques was undertaken by the Committee on Vascular Lesions, which identified eight different morphologies of plaques and grouped them into categories designated types I through V. Plaques that have a high lipid content and a high proportion of cholesterol esters are vulnerable to rupture. In some patients, plaque disruption may lead to a labile thrombus with transient or intermittent vessel occlusion and subsequent unstable angina. In other patients, more severe vascular injury may lead to the formation of a fixed thrombus, resulting in acute myocardial infarction (MI).2 Not all disrupted plaques result in clinically detectable thrombosis, and in fact, the rupture and healing cycle may represent an etiology of plaque progression.3

88. In the plaque cap, synthesis and breakdown of collagen and elastin are regulated by various mediators. The collagen in the fibrous cap is primarily types I and III and is synthesized by vascular smooth muscle cells. The production of interferon-? (IFN-?) by the activated T cells decreases the production of collagen by smooth muscle cells and also inhibits smooth muscle cell proliferation. At the same time, IFN-? also activates macrophages that produce matrix metalloproteinases (MMPs), such as collagenase, gelatinase, and stromelysin, which degrade the fibrous cap. Plaques contain other macrophage activators besides IFN-?; such as tumor necrosis factor-? (TNF-?), macrophage colony stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1).4In the plaque cap, synthesis and breakdown of collagen and elastin are regulated by various mediators. The collagen in the fibrous cap is primarily types I and III and is synthesized by vascular smooth muscle cells. The production of interferon-? (IFN-?) by the activated T cells decreases the production of collagen by smooth muscle cells and also inhibits smooth muscle cell proliferation. At the same time, IFN-? also activates macrophages that produce matrix metalloproteinases (MMPs), such as collagenase, gelatinase, and stromelysin, which degrade the fibrous cap. Plaques contain other macrophage activators besides IFN-?; such as tumor necrosis factor-? (TNF-?), macrophage colony stimulating factor (M-CSF), and macrophage chemoattractant protein-1 (MCP-1).4

89. Clinical manifestations of arterial thrombosis The clinical manifestation of coronary thrombosis depends on the extent and duration of thrombotic occlusion. Unstable angina and non-Q-wave MI are characterized by mural, platelet-rich thrombi, which do not completely block coronary blood flow and therefore cause ischemia of relatively short duration. The aggregated platelets can serve as a substrate for further thrombus propagation, leading to formation of an occlusive red thrombus formed by entrapment of red blood cells within the fibrin mesh. This complete occlusion results in abrupt and persistent ischemia that clinically manifests as ST-segment elevation MI. Left untreated, occlusion of the coronary arteries can lead to sudden cardiac death.Clinical manifestations of arterial thrombosis The clinical manifestation of coronary thrombosis depends on the extent and duration of thrombotic occlusion. Unstable angina and non-Q-wave MI are characterized by mural, platelet-rich thrombi, which do not completely block coronary blood flow and therefore cause ischemia of relatively short duration. The aggregated platelets can serve as a substrate for further thrombus propagation, leading to formation of an occlusive red thrombus formed by entrapment of red blood cells within the fibrin mesh. This complete occlusion results in abrupt and persistent ischemia that clinically manifests as ST-segment elevation MI. Left untreated, occlusion of the coronary arteries can lead to sudden cardiac death.