Ischaemia lecture

1. Ischaemic Heart Disease CPC Dec 09 Dr John O’Connor Consultant Biochemist RDE

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)

10. What are the current cardiac biomarkers? Myoglobin Actin, Myosin Troponin LDH CK, AST BNP

29. 10 Size of Myocardial Infarction (grams) 0.01 100 0.001 1 0.1 ECHO CK, AST CK- MB TROPONIN ECG

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

38. The Vascular endothelium

40. The endothelium maintains vascular health Dilatation Growth inhibition Antithrombotic Anti-inflammatory Antioxidant Constriction Growth promotion Prothrombotic Proinflammatory Pro-oxidant

41. Risk factors and endothelial dysfunction: Mediator role of oxidative stress and NO Hypertension Hypercholesterol- aemia Diabetes Smoking Oxidative stress Reduced NO Endothelial dysfunction

47. Cost economics

48. Standard management

49. BNP based management

52. Pathogenesis of IHD

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

58. The Role of Platelets in Atherothrombotic Disease

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

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

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

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