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Ischaemia lecture

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Ihd Presentation V4

  1. 1. Ischaemic Heart Disease CPC Dec 09 Dr John O’Connor Consultant Biochemist RDE
  2. 2. Ischaemic Heart Disease (IHD) Overview <ul><li>Epidemiology </li></ul><ul><li>Definition and causes </li></ul><ul><li>Cardiac markers </li></ul><ul><li>Chest pain cases </li></ul><ul><li>Risk Factors </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Few words about the endothelium </li></ul>
  3. 3. Epidemiology <ul><li>Commonest cause of death in the Western world ( about 1/3 of total mortality). </li></ul><ul><li>117,000 deaths in 2002 in the UK, more than any other single disease process at an enormous cost to the NHS - £1.73 billion in 1999. </li></ul><ul><li>Death rates falling 44% over last 10 years but less than other western countries. </li></ul><ul><li>Over 20% males < 60 years may have evidence of early IHD. </li></ul>
  4. 4. Atherothrombosis * is a Leading Cause of Death Worldwide †1 1. The World Health Report 2001. Geneva: WHO; 2001. Mortality (%) *Cardiovascular disease, ischemic heart disease and cerebrovascular disease † Worldwide defined as Member States by WHO Region (African, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific)
  5. 5. What is Ischaemic Heart Disease? <ul><li>An imbalance between supply of oxygen and myocardial demand resulting in myocardial ischaemia. </li></ul><ul><li>Anaerobic glycolysis occurs and lactate and H + ion concentration increase. </li></ul><ul><li>This in turn impairs the ability of cardiac muscle to contract, resulting in ischaemia and angina. </li></ul>
  6. 8. What are the causes of IHD? <ul><li>Restricted passageway - atheroma, thrombosis, embolus, spasm. </li></ul><ul><li>Reduce oxygen in the blood - hypoxia. </li></ul><ul><li>Reduced blood cells/haemodynamic problem - anaemia/ hypotension. </li></ul><ul><li>Increased oxygen demand - tachycardia - thyrotoxicosis, myocardial hypertrophy. </li></ul><ul><li>Several of above may be present as contributing or precipitating factors. </li></ul>
  7. 9. What are the manifestations of IHD? <ul><li>Asymptomatic </li></ul><ul><li>Stable angina pectoris (chronic IHD) </li></ul><ul><li>Acute coronary syndrome(ACS) </li></ul><ul><li>Arrhythmias - may be fatal </li></ul><ul><li>Heart failure - rising incidence, difficult to assess clinically </li></ul><ul><li>Sudden death </li></ul>
  8. 10. What are the current cardiac biomarkers? Myoglobin Actin, Myosin Troponin LDH CK, AST BNP
  9. 11. Creatine Kinase (CK) <ul><li>Not cardiospecific as present in skeletal muscle as well as cardiac muscle. </li></ul><ul><li>3 isoenzymes - CK-MB (heart), CK-MM (heart & skeletal), CK-BB. </li></ul><ul><li>In health serum CK circulates as CK-MM, level in health reflects muscle mass and activity. </li></ul><ul><li>In AMI level starts rising by 6-8 hours , peaks around 18 - 24 hours and returns to normal by 72 hours. </li></ul><ul><li>Assay is simple, cheap and readily available. </li></ul>
  10. 12. Cardiac Troponin T (cTnT) <ul><li>cTnT is a regulatory protein, within a complex on the myosin fibril. </li></ul><ul><li>specific to heart. </li></ul><ul><li>NOT specific for ACS but released in any form of myocardial damage. </li></ul><ul><li>very sensitive, can detect 3 -5 mg of cardiac damage. </li></ul><ul><li>Troponin measurements are now the “gold standard” biochemical marker of ACS. </li></ul>
  11. 13. <ul><li>MYOFIBRE STRUCTURE </li></ul>TnI Actin Tropomyosin TnC TnT
  12. 14. Case 1 I Presentation <ul><li>55 year old man, smoker, FH of IHD, presents at A & E with severe chest pain which had been present for the past 2 hours. </li></ul><ul><li>Admission ECG showed ST segment elevation. </li></ul><ul><li>Admission CK 95 IU/L ( Reference: 55 - 196). </li></ul><ul><li>At 12 hours CK 1500 IU/L, Troponin T 3.5 ug/L (Ref: < 0.01). </li></ul><ul><li>What is the diagnosis? </li></ul><ul><li>Myocardial Infarction </li></ul><ul><li>What treatment should be given? </li></ul>
  13. 17. Case 1 II <ul><li>Management is aimed at opening the occluded artery by percutaneous coronary intervention(PCI) or by thrombolytic therapy. </li></ul><ul><li>Further episode of chest pain 3 days later with a CK 125 IU/L and 12 hours later 1730 IU/L. </li></ul><ul><li>Why is a TnT level not normally measured to assess re-infarction? </li></ul><ul><li>TnT remains abnormal for up to 7-8 days, better to use CK as marker for re-infarction. </li></ul>
  14. 19. Case 1 III <ul><li>Patient dies and has a Post Mortem. </li></ul>
  15. 20. <ul><li>This is an image of a coronary artery </li></ul><ul><li>What does it show? </li></ul><ul><li>What do the labels identify? </li></ul><ul><li>Adventitia </li></ul><ul><li>Atheroma </li></ul><ul><li>Media </li></ul><ul><li>Thrombus </li></ul><ul><li>Intima </li></ul>What is the aetiopathogenesis of this complication? IMAGES IN PATHOLOGY Media Intima Atheroma Advetitia Thrombus
  16. 21. Myocardial Injury <ul><li>Irreversible injury typically requires 30 minutes of ischaemia. </li></ul><ul><li>Chronic O 2 deficiency makes cells more resistant. </li></ul><ul><li>Cell death occurs after 30 - 60 minutes. </li></ul><ul><li>80% of cells at risk die within 3 hours. </li></ul><ul><li>Rising to almost 100% by 6 hours of ischaemia. </li></ul><ul><li>With cell death there is release of cardiac markers, dependent on size and solubility eg CK and Troponins. </li></ul>
  17. 22. Case 1 IV Comments <ul><li>Classical MI, cardiac markers play no role in determining treatment, only possibly give an idea of size of infarct. </li></ul><ul><li>TnT > 1.1 ug/L can predict Left Ventricular Ejection Fraction( LVEF) of < 40%. </li></ul>
  18. 23. Case 2 I Presentation <ul><li>46 year old woman presenting with atypical chest pain within 4 hours to the A & E department. At 9:00 pm ECG non-diagnostic, non-ST elevation. </li></ul><ul><li>Admission CK = 50 IU/L (Ref: 50 -180). </li></ul><ul><li>9:00 am next day CK = 250 IU/L TnT = 0.15 ug/L (Ref: <0.01). </li></ul><ul><li>What are possible differential diagnoses? </li></ul><ul><li>NSTEMI , pulmonary embolus, myocarditis. </li></ul>
  19. 24. What are the main cardiovascular risk factors? <ul><li>Fixed - age, male, post menopausal female, positive family history. </li></ul><ul><li>Modifiable - smoking, diet, obesity, hypertension, hyperlipidaemia(oxidised LDL), diabetes mellitus. </li></ul><ul><li>Other - lack of exercise, high EtOH, raised homocysteine. </li></ul>
  20. 25. Modern Diet <ul><li>Fast food culture : - high in saturated fat - high in sugar - high in salt - low in fresh fruit and vegetables </li></ul>
  21. 28. Case 2 II Comments <ul><li>ECG fails to diagnose 30 –35% cases of MI. </li></ul><ul><li>Troponins are very sensitive and cardiospecific markers but can be raised in cardiac damage due to other causes. eg PE, myocarditis. </li></ul><ul><li>Troponin levels are not an early marker of cardiac damage and although levels in some patient rise at 3-4 hours the test is most diagnostically useful at 12 hours post symptoms, particular for ruling out cardiac damage. </li></ul>
  22. 29. 10 Size of Myocardial Infarction (grams) 0.01 100 0.001 1 0.1 ECHO CK, AST CK- MB TROPONIN ECG
  23. 30. Case 3 I Presentation <ul><ul><ul><li>71 yr old man presenting with episodes of increasing chest pain on exertion. </li></ul></ul></ul><ul><ul><ul><li>Admission ECG showed ischaemic pattern. </li></ul></ul></ul><ul><ul><ul><li>Admission CK = 50 IU/L. </li></ul></ul></ul><ul><ul><ul><li>12 hours later CK =65 IU/L, TnT = 0.03 ug/L. </li></ul></ul></ul>
  24. 31. Case 3 II <ul><li>What is the likely diagnosis? </li></ul><ul><li>Unstable angina with minimal evidence of myocardial damage. </li></ul><ul><li>Comment: Troponin level here is used a prognostic indicator, as increased risk risk of MI or death over next 6 months. </li></ul>
  25. 32. Myocardial Ischaemia <ul><li>Spectrum of presentation </li></ul><ul><ul><li>silent ischemia </li></ul></ul><ul><ul><li>exertion-induced angina </li></ul></ul><ul><ul><li>unstable angina </li></ul></ul><ul><ul><li>acute myocardial infarction </li></ul></ul>
  26. 33. What are the consequences of ischaemia? <ul><li>Decreased supply of O2 and nutrients, inadequate phosphorlyation, accumulation of metabolites. </li></ul><ul><li>Severity of ischaemic damage depends on; - extent of decrease in blood flow - duration of ischaemia </li></ul><ul><li>previous ischaemic episodes - preconditioning </li></ul>
  27. 34. Acute Coronary Syndrome Ischemic Discomfort Unstable Symptoms No ST-segment elevation ST-segment elevation Unstable Non-Q Q-Wave angina AMI AMI ECG Acute Reperfusion History Physical Exam
  28. 35. Major Clinical Manifestations of Atherothrombosis Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Transient ischaemic attack <ul><li>Angina: </li></ul><ul><li>Stable </li></ul><ul><li>Unstable </li></ul>Ischaemic stroke Myocardial infarction <ul><li>Peripheral arterial </li></ul><ul><li>disease: </li></ul><ul><li>Intermittent claudication </li></ul><ul><li>Rest Pain </li></ul><ul><li>Gangrene </li></ul><ul><li>Necrosis </li></ul>
  29. 36. Cardiac Troponin T <ul><li>Will detect non-Q wave MI not detected by other means. </li></ul><ul><li>Slightly raised levels in UA indicates patients who have a high incidence of cardiac events in next 6 months. </li></ul><ul><li>Important to rule out cardiac damage 12 hours post symptoms. </li></ul>
  30. 37. What is the endothelium and why is so important? <ul><li>Endothelium is a single layer of cells, lining all blood vessels conferring a number of protective functions. </li></ul><ul><li>Pivotal role in regulating vascular tone, vascular growth and haemostasis. </li></ul><ul><li>Endothelial cells(EC) produce nitric oxide (NO), a vasodilator, inhibits platelet aggregation, blocks adhesion molecules and inhibits growth vascular smooth muscle cells. </li></ul>
  31. 38. The Vascular endothelium
  32. 39. What happens when there is endothelial dysfunction? <ul><li>Imbalance between - relaxing and contracting factors - procoagulant and anticoagulant factors pro-inflammatory and anti-inflammatory mediators </li></ul><ul><li>EC dysfunction plays a key role in pathogenesis of atherosclerosis and IHD. </li></ul><ul><li>Most likely mediated by increased oxidative stress leading to reduced bioavailability of NO. </li></ul>
  33. 40. The endothelium maintains vascular health Dilatation Growth inhibition Antithrombotic Anti-inflammatory Antioxidant Constriction Growth promotion Prothrombotic Proinflammatory Pro-oxidant
  34. 41. Risk factors and endothelial dysfunction: Mediator role of oxidative stress and NO Hypertension Hypercholesterol- aemia Diabetes Smoking Oxidative stress Reduced NO Endothelial dysfunction
  35. 42. Oxidative Stress <ul><li>Term used to describe conditions where excessive levels of Reactive Oxygen Species(ROS) prevails with subsequent cellular damage. </li></ul><ul><li>It occurs when the capacity of the cell to detoxify these potentially injurious oxidants using endogenous antioxidant defence systems is exceeded. </li></ul>
  36. 43. IHD Summary <ul><li>Causes of IHD have a common pathway </li></ul><ul><li>Damage to the vascular endothelium is a key step in development of atherosclerosis </li></ul><ul><li>Troponins are important biomarkers of cardiac damage in acute coronary syndromes particularly when ECG & clinical history are equivocal </li></ul>
  37. 44. Congestive Cardiac Failure <ul><li>Biochemical markers have a role </li></ul><ul><li>Currently ANP (Atrial Naturetic Peptide) </li></ul><ul><li>BNP (Brain Naturetic Peptide) </li></ul>
  38. 46. Current diagnostic tools <ul><li>Clinical symptoms </li></ul><ul><ul><li>poor sensitivity - 55% </li></ul></ul><ul><li>3rd heart sound pathognomonic </li></ul><ul><ul><li>In the real world </li></ul></ul><ul><ul><li>“ I am grateful if I can hear any heart sounds” </li></ul></ul><ul><li>ECG </li></ul><ul><ul><li>sensitivity 55-60% </li></ul></ul><ul><li>CXR </li></ul><ul><ul><li>sensitivity 55-60% </li></ul></ul>
  39. 47. Cost economics
  40. 48. Standard management
  41. 49. BNP based management
  42. 50. Cost economics <ul><li>Echocardiography as the “Gold standard” for diagnosis </li></ul><ul><ul><li>Echo cost £50-200 </li></ul></ul><ul><ul><li>Waiting list 1-6 months </li></ul></ul><ul><ul><li>OPD £100-500 </li></ul></ul><ul><li>Total cost £250-1200 </li></ul><ul><li>BNP £15-20 </li></ul>
  43. 52. Pathogenesis of IHD
  44. 53. What is Atherothrombosis? <ul><li>Atherothrombosis is characterized by a sudden (unpredictable) atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation </li></ul><ul><li>Atherothrombosis is the underlying condition that results in events leading to myocardial infarction, ischemic stroke, and vascular death </li></ul>Plaque rupture 1 Plaque erosion 2 1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al . Heart 1999; 82: 269–72. Shows a disrupted coronary plaque with occlusive thrombosis superimposed Shows plaque erosion with acute coronary thrombosis
  45. 54. The Development of Atherothrombosis – a Generalized and Progressive Process Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Plaque rupture acts as the stimulus for thrombus formation If non occlusive, ischaemic symptoms are temporary Thrombosis can contribute to plaque growth through the formation and resolution of subclinical platelet thrombi Plaque rupture Platelet activation and aggregation Non-occlusive thrombus <ul><li>Acute syndrome: </li></ul><ul><li>coronary </li></ul><ul><li>cerebrovascular </li></ul><ul><li>peripheral </li></ul>Occlusive thrombus Healing and resolution Plaque growth
  46. 55. Atherothrombosis and Microcirculation Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: 570–80, and Falk E et al . Circulation 1995; 92: 657–71. Thrombus formation on a plaque is a dynamic process in which platelets aggregate then dis-aggregate This leads to embolization of platelet aggregates from evolving thrombus. These can be occlusive and are pro-inlammatory Particulate matter is also shed, this can cause block in the microvasculature leading to cardiac insufficiency or vascular dementia Plaque rupture Microvascular obstruction Embolization
  47. 56. Identifying Those at Risk of Atherothrombosis 1,2 1. Yusuf S et al . Circulation 2001; 104: 2746–53. 2. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. <ul><li>Lifestyle </li></ul><ul><li>Smoking </li></ul><ul><li>Diet </li></ul><ul><li>Lack of exercise </li></ul><ul><li>Genetic </li></ul><ul><li>Genetic traits </li></ul><ul><li>Gender </li></ul><ul><li>Age </li></ul><ul><li>Generalised </li></ul><ul><li>disorders </li></ul><ul><li>Obesity </li></ul><ul><li>Diabetes </li></ul><ul><li>Systemic </li></ul><ul><li>conditions </li></ul><ul><li>History of vascular events </li></ul><ul><li>Hypertension </li></ul><ul><li>Hyperlipidemia </li></ul><ul><li>Hypercoagulable states </li></ul><ul><li>Homocystinemia </li></ul><ul><li>Local factors: </li></ul><ul><li>Elevated prothrombotic factors: fibrinogen, CRP, PAI-1 </li></ul><ul><li>Blood flow patterns, vessel diameter, arterial wall structure </li></ul>Atherothrombosis manifestations (myocardial infarction, stroke, vascular death)
  48. 57. Summary <ul><li>Atherothrombosis is characterized by a sudden plaque disruption leading to platelet activation and thrombus formation 1 </li></ul><ul><li>Atherothrombosis is the common pathological link between all major clinical manifestations of vascular disease: myocardial infarction, ischemic stroke and peripheral arterial disease 2 </li></ul><ul><li>Patients with clinical manifestations of atherothrombosis in one vascular bed are not only at risk of a recurrent event in the same arterial distribution, but also at risk of developing ischemic events in other vascular beds 3 </li></ul><ul><li>Atherothrombosis is one of the leading causes of death worldwide 4 </li></ul>1. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. 2. Nenci GG. Eur Heart J 1999; 1(suppl A): A27–A30. 3. Lichtman JH et al. Circulation 2002; 105: 1082–7. 4. The World Health Report 2001. Geneva: WHO; 2001.
  49. 58. The Role of Platelets in Atherothrombotic Disease
  50. 59. Hemostatic Plug Formation Adapted from: Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. Primary hemostasis (termination of bleeding)is the process of platelet plug formation at the site of injury (occurs within seconds) Secodary hemostasis describe the reactions in the coag system that result in a fibrin clot (minutes) fibrin strands strengthen the plug (important in larger vessels to prevent further bleeding Thrombin AGGREGATION Fibrin Hemostatic clot Clotting Platelet Aggregation 0 min 10 min 5 min SECONDARY PRIMARY COAGULATION
  51. 60. Platelet Adhesion and Activation Aggregation of platelets into a thrombus Platelets Endothelial cells Platelets adhering to subendothelial space Platelet thrombus Normal platelets in flowing blood Platelets adhering to damaged endothelium and undergoing activation Subendothelial space Adapted from: Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. Platelet relationship with the vessel wall is crucial. Normally they do not adhere. But an injury like a ruptured plaque will cause them to adhere Adherance is promoted by a platelet collagen receptor. This interaction is stabilised by VWF allows platelets to remain attached despite high shear forces. Fibrinogen then links adjacent platelets There are many things that can cause activation ADP, serotonin, thromboxane. They also activate the coagulation cascade producing thrombin which further stimulates platelets
  52. 61. Platelet Aggregation Adapted from: Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34. VWF makes the platelets change shape, they look like rolling balls. They become “inside out” which release factors that change shape to a hemisphere FIRM, BUT REVERSIBLE ADHESION IRREVERSIBLE ADHESION Scanning electron micrograph of discoid, dormant platelets Activated, aggregating platelets illustrating fibrin strands Flowing disc-shaped platelet Rolling ball-shaped platelet Hemisphere-shaped platelet Spreading platelet
  53. 62. Key Mediators in Platelet Adhesion, Activation and Aggregation Adhesion 1. Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. INJURY <ul><li>vWF </li></ul><ul><li>Thrombin </li></ul><ul><li>Collagen </li></ul><ul><li>Fibronectin </li></ul>Shear Forces vWF ADP-receptor THROMBUS Activation Aggregation <ul><li>Membrane changes </li></ul><ul><li>Granule secretion </li></ul><ul><li>GPIIb/IIIa expression </li></ul><ul><li>Multiple agonists </li></ul><ul><li>Feedback loops </li></ul><ul><li>GPIIb/IIIa-mediated </li></ul><ul><li>Fibrinogen </li></ul><ul><li>vWF </li></ul>
  54. 63. Plaque Disruption Leading to Atherothrombosis Formation Adapted from: Falk E et al. Circulation 1995; 92: 657–71. Size and composition of the clot varies with the site of injury. Thombus formation can cause an acute event (MI) or contribute to long term progression of vascular disease A small fissure can result in a mural thrombus that partially occludes the vessel contributing to plaque growth Macrophage Tissue factor Fibrin Aggregated platelets BLOOD FLOW
  55. 64. Inflammatory Modulators Produced by Platelets 1. Libby P, Simon DI. Circulation 2001; 103: 1718–20. 2. von Hundelshausen P et al . Circulation 2001; 103: 1772–7. 3. Wever RMF et al . Circulation 1998; 97: 108–12. 4. Hermann A et al . Platelets 2001; 12: 74–82. 5. Robbie L, Libby P. Ann N Y Acad Sci 2001; 947: 167–79. <ul><li>Transforming growth </li></ul><ul><li>factor-ß 5 </li></ul><ul><li>Stimulate smooth muscle cell biosynthesis </li></ul><ul><li>Nitric oxide 3 </li></ul><ul><li>Effects on monocyte, leucocyte, endothelium, and smooth muscle cells </li></ul><ul><li>CD154 </li></ul><ul><li>(CD40 ligand) 1,4 </li></ul><ul><li>Regulates macrophage and smooth muscle cell functions </li></ul><ul><li>RANTES 2 </li></ul><ul><li>Influences macrophage adhesion to endothelial cell </li></ul><ul><li>Platelet-factor 4 1 </li></ul><ul><li>Mediates shear-resistant arrest of monocytes to endothelium </li></ul>PLATELET <ul><li>Platelet-derived growth </li></ul><ul><li>factor (PDGF) 1 </li></ul><ul><li>Induces proliferation of smooth muscle cells </li></ul><ul><li>Thrombospondin 1 </li></ul><ul><li>Interacts with cell surface receptors </li></ul>
  56. 65. Role of Platelets Summary <ul><li>Rupture or erosion of an atherosclerotic plaque exposes the thrombogenic core of the lesion and lead to adhesion and aggregation of platelets and thrombus formation 1 </li></ul><ul><li>A large rupture typically results in the formation of a large thrombus that completely occludes the vessel, resulting in an acute vascular event 2 </li></ul><ul><li>A smaller rupture may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and, in the long term, contributing to progression of atherothrombosis 2 </li></ul><ul><li>Platelets produce several inflammatory modulators and may play a significant role in atherosclerotic development 3 </li></ul>1. Ferguson JJ. The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.15–35. 2. Falk E et al. Circulation 1995; 92: 657–71. 3 . Libby P, Simon DI. Circulation 2001; 103: 1718–20.