Ischemic Heart disease slide show pathology course

ISCHEMIC HEART DISEASE

1. Ischemic heart disease(IHD)

2. Definition IHD represents a group of related entities resulting from myocardial ischemia — An imbalance between myocardial supply (perfusion) and cardiac demand for oxygenated blood .

3. IHD is due to a reduction in coronary blood flow caused by obstructive atherosclerotic disease I schemia can result from increased demand (e.g., increased heart rate or hypertension), or diminished oxygen-carrying capacity (e.g., anemia, carbon monoxide poisoning), in the vast majority of cases

4. The clinical manifestations of IHD are a direct consequence of insufficient blood supply to the heart. There are four basic clinical syndromes of IHD: Angina pectoris (literally chest pain ), wherein the ischemia causes pain but is insufficient to lead to death of myocardium stable variant angina or Prinzmetal angina unstable

5. Acute myocardial infarction (MI), wherein the severity or duration of ischemia is enough to cause cardiac muscle death Chronic IHD refers to progressive cardiac decompensation (heart failure) following MI. Sudden cardiac death (SCD), can result from a lethal arrhythmia following myocardial ischemia.

6. Epidemiology Nearly 500,000 Americans die of IHD annually But has improvement Risk reduction

7. Pathogenesis IHD occurs because of inadequate coronary perfusion relative to myocardial demand This may result from a combination of pre-existing ("fixed") atherosclerotic occlusion of coronary arteries and new superimposed thrombosis and/or vasospasm A lesion obstructing 70% to 75% or more of a vessel lumen-critical stenosis-generally causes symptomatic ischemia (angina) only in the setting of increased demand

8. A fixed 90% stenosis can lead to inadequate coronary blood flow even at rest . If a coronary artery develops atherosclerotic occlusion at a sufficiently slow rate- collateral perfusion can then protect against MI even in the setting of a complete vascular occlusion. Unfortunately, acute coronary occlusions cannot spontaneously recruit collateral flow and will result in infarction

9. Single major coronary epicardial artery or two or all three arteries- (LAD), (LCX), and (RCA)-can be concurrently involved. Clinically significant plaques can be located anywhere but tend to predominate within the first several centimeters of the LAD and LCX, and along the entire length of the RCA, secondary branches are also involved S ymptom onset depends not only on the extent and severity of fixed atherosclerotic disease but also critically on dynamic changes in coronary plaque morphology

10. Atherosclerosis “response to injury” hypothesis A chronic inflammatory and healing response of the arterial wall to endothelial injury . Lesion progression occurs through interaction of modified lipoproteins, macrophages, and T lymphocytes with ECs and SMCs of the arterial wall

11. Endothelial injury and dysfunction Accumulation of lipoproteins in the vessel wall Monocyte adhesion to the endothelium Platelet adhesion Factor release from activated platelets macrophages , and vascular wall cells SMC proliferation, ECM production, and recruitment of T cells . Lipid accumulation Calcification of ECM and necrotic debris late in the pathogenesis .

12. Role of Acute Plaque Change Unstable angina, infarction occur because of abrupt plaque change followed by thrombosis Rupture, fissuring, or ulceration of plaques exposing highly thrombogenic plaque constituents or underlying subendothelial basement membrane. Hemorrhage into the core of plaques with expansion of plaque volume and worsening of the luminal occlusion.

13. The events that trigger the abrupt plaque changes are complex. They may be intrinsic to the structure of the plaque or extrinsic to it. Basically, rupture reflects the inability of a plaque to withstand mechanical stresses.

14. Plaques that contain a large atheromatous core or those in which the overlying fibrous caps are thin are more likely to rupture and are therefore denoted as "vulnerable." Fissures frequently occur at the junction of the fibrous cap and the adjacent normal plaque-free arterial segment, a location at which the mechanical stresses are highest and the fibrous cap is thinnest

15. Fibrous caps are also continuously remodeling; the balance of collagen synthesis and degradation determines its mechanical strength and thus plaque stability. Collagen is produced by smooth muscle cells and degraded by the action of metalloproteinases elaborated by macrophages in the plaque. a paucity of smooth muscle cells or an increase in inflammatory cell activity in atherosclerotic lesions is associated with plaque vulnerability.

16. Influences extrinsic to the plaque are also important. Adrenergic stimulation can elevate physical stresses on the plaque through systemic hypertension or local vasospasm. Intense emotional stress can also contribute to plaque disruption. Such acute changes often develop in plaques not initially critically stenotic or even symptomatic before rupture.. Pathologic and clinical studies show that two-thirds of ruptured plaques are ≤50% stenotic before plaque rupture, and 85% have initial stenosis ≤70%.

17. It is presently impossible to reliably predict plaque rupture in any given patient. Plaque disruption with ensuing platelet aggregation and thrombosis are common, repetitive, and often clinically silent complications of atherosclerosis. Healing of subclinical plaque disruptions and overlying thrombosis is an important mechanism by which atherosclerotic lesions progressively enlarge.

18. Role of Inflammation Inflammation plays an essential role at all stages of atherosclerosis, from inception to plaque rupture. A therosclerosis begins with the interaction of endothelial cells and circulating leukocytes, resulting in T-cell and macrophage recruitment and activation.

19. These cells subsequently drive smooth muscle cell proliferation, with variable amounts of extracellular matrix (ECM) accumulating over an atheromatous core of lipid, cholesterol, calcification, and necrotic debris. At later stages, destabilization of atherosclerotic plaque occurs through metalloproteinase secretion.

20. Role of Thrombus Thrombosis associated with a disrupted plaque is critical to the pathogenesis of acute coronary syndromes. Partial vascular occlusion by a newly formed thrombus on a disrupted atherosclerotic plaque can wax and wane with time and lead to unstable angina or sudden death;

21. Partial luminal occlusion by thrombus can compromise blood flow ( subendocardial infarct). Mural thrombus in a coronary artery can also embolize In the most serious extreme, completely obstructive thrombus over a disrupted plaque can cause a massive MI. Organizing thrombi produce potent activators of smooth muscle proliferation, which can contribute to the growth of atherosclerotic lesions

22. Role of Vasoconstriction Vasoconstriction directly compromises lumen diameter by increasing local mechanical shear forces, it can potentiate plaque disruption. In atherosclerotic plaques can be stimulated by (1) circulating adrenergic agonists, (2) locally released platelet contents, (3) an imbalance between endothelial cell relaxing factors (e.g., nitric oxide) versus contracting factors (e.g., endothelin) (4) mediators released from perivascular inflammatory cells

23. Other Pathologic Processes Rarely, processes other than atherosclerosis and superimposed thrombi can compromise coronary perfusion. Emboli originating from valve vegetations, coronary vasculitis, and systemic hypotension. Myocardial hypertrophy (e.g., hypertrophic cardiomyopathy, can also increase myocardial demand beyond what even relatively normal coronaries can provide.

24. Angina Pectoris Angina pectoris is intermittent chest pain caused by transient(15sec-15min), reversible myocardial ischemia, insufficient to cause myocyte necrosis. There are three variants: Typical or stable angina E pisodic chest pain associated with exertion or some other form of increased myocardial oxygen demand Stable angina pectoris is usually associated with a fixed atherosclerotic narrowing (≥70%) of one or more coronary arteries.

25. With this degree of critical stenosis, the myocardial oxygen supply may be sufficient under basal conditions but cannot be adequately augmented to meet any increased requirements. The pain is usually relieved by rest (reducing demand) or by administering agents such as nitroglycerin; In larger doses, nitroglycerin also increases blood supply to the myocardium by direct coronary vasodilation.

26. Prinzmetal, or variant angina is angina occurring at rest due to coronary artery spasm. Although such spasms typically occur on or near an existing atherosclerotic plaque, completely normal vessels can be affected. T he anginal attacks are unrelated to physical activity, heart rate, or blood pressure, and can occur at rest. The etiology is not clear, but Prinzmetal angina typically responds promptly to the administration of vasodilators such as nitroglycerin or calcium channel blockers

27. Unstable angina (also called crescendo angina ) is characterized by increasing frequency of pain, precipitated by progressively less exertion; the episodes also tend to be more intense and longer lasting(>20min) than stable angina. unstable angina is associated with plaque disruption and superimposed partial thrombosis, distal embolization of the thrombus, and/or vasospasm. Unstable angina is the harbinger of more serious, potentially irreversible ischemia (due to complete luminal occlusion by thrombus) and called pre-infarction angina.

28. Myocardial Infarction MI, popularly called heart attack, is necrosis of heart muscle resulting from ischemia. . The major underlying cause of IHD is atherosclerosis and therefore the frequency of MIs rises progressively with increasing age and presence of other risk factors such as hypertension, smoking, and diabetes.

29. Approximately 10% of MIs occur in people younger than 40 years, and 45% occur in people younger than age 65. Blacks and whites are equally affected. Men are at significantly greater risk than women, although the gap progressively narrows with age. women are remarkably protected against MI during their reproductive years. menopause-and presumably declining estrogen production-is associated with exacerbation of coronary atherosclerosis.

30. Pathogenesis M ost MIs are caused by acute coronary artery thrombosis. In most cases, disruption of an atherosclerotic plaque results in the formation of thrombus. Vasospasm and/or platelet aggregation can contribute but are infrequently the sole cause of an occlusion. S evere diffuse coronary atherosclerosis significantly limits coronary vessel perfusion, and a prolonged period of increased demand (e.g., due to tachycardia or hypertension) may be sufficient to cause necrosis of myocytes most distal to the epicardial vessels.

31. Coronary Artery Occlusion In a typical MI, the following sequence of events transpires: There is a sudden disruption of an atheromatous plaque-for example, intraplaque hemorrhage, erosion or ulceration, or rupture or fissuring E xposing subendothelial collagen and necrotic plaque contents. Platelets adhere , aggregate, become activated, and release potent secondary aggregators including thromboxane A 2 , adenosine diphosphate, and serotonin.

32. Vasospasm is stimulated by platelet aggregation and mediator release. Other mediators activate the extrinsic pathway of coagulation, adding to the bulk of the thrombus. Within minutes the thrombus can evolve to completely occlude the coronary lumen of the coronary vessel.

33. The evidence for this series of events derives from (1) A utopsy studies of patients dying with acute MI (2) Angiographic studies demonstrating a high frequency of thrombotic occlusion early after MI (3) The high success rate of therapeutic thrombolysis and primary angioplasty (4) The demonstration of residual disrupted atherosclerotic lesions by angiography after thrombolysis.

34. Coronary angiography performed within 4 hours of the onset of MI shows a thrombosed coronary artery in almost 90% of cases. When angiography is delayed until 12 to 24 hours after onset of symptoms, occlusions are observed in only 60% of patients, even without intervention. At least some occlusions seem to clear spontaneously as a result of lysis of the thrombus and/or relaxation of spasm Any residual thrombus is likely to be incorporated into the growing atherosclerotic plaque

35. Myocardial Response to Ischemia Coronary artery obstruction blocks the myocardial blood supply, leading to profound functional, biochemical, and morphologic consequences. Within seconds of vascular obstruction, cardiac myocyte aerobic glycolysis ceases, leading to inadequate production of adenosine triphosphate (ATP) and accumulation of potentially noxious breakdown products (e.g., lactic acid).

36. The functional consequence A striking loss of contractility Ultrastructural changes including M yofibrillar relaxation G lycogen depletion Cell and mitochondrial swelling However, these early changes are potentially reversible, and myocardial cell death is not immediate

37. Only severe ischemia lasting at least 20 to 40 minutes causes irreversible injury and myocyte death; C oagulation necrosis

38. If myocardial blood flow is restored anywhere along this timeline ( reperfusion ), cell viability may be preserved. Irreversible injury of ischemic myocytes first occurs in the subendocardial zone Not only is this region the last area to receive blood delivered by the epicardial vessels, the relatively higher intramural pressures there further compromise blood inflow.

39. With more prolonged ischemia, a wavefront of cell death moves through the myocardium to involve progressively more of the transmural thickness of the ischemic zone, so that an infarct usually reaches its full size within 3 to 6 hours . Any intervention in this time frame can potentially limit the final extent of necrosis.

40. The final location, size, and specific morphologic features of an acute MI depend on Size of the vascular bed perfused by the obstructed vessels Duration of the occlusion Metabolic demands of the myocardium (affected, e.g., by blood pressure and heart rate) Extent of collateral supply

41. Morphologic feature Typical features of coagulative necrosis become detectable within 4 to 12 hours of infarction. Necrotic myocardium elicits acute inflammation (typically most prominent 1-3 days after MI), followed by a wave of macrophages to remove necrotic myocytes and neutrophil fragments (most pronounced 5-10 days after MI). The infarcted zone is progressively replaced by granulation tissue (most prominent 2-3 weeks after MI), which in turn forms the provisional scaffolding upon which dense collagenous scar is formed. an MI heals from its borders toward the center, and a large infarct may not heal as readily or as completely as a small one.

42. Clinical Features An MI is usually heralded by severe, crushing substernal chest pain or discomfort that can radiate to the neck, jaw, epigastrium, or left arm. The pain of an MI typically lasts from 20 minutes to several hours and is not significantly relieved by nitroglycerin or rest. 10% to 15% MIs can be entirely asymptomatic. Such "silent" infarcts common in P atients with underlying diabetes mellitus (with peripheral neuropathies) Elderly population

43. With MIs the pulse is generally rapid and weak, and patients can be diaphoretic and nauseated particularly with posterior-wall MIs. Dyspnea is common and is caused by impaired myocardial contractility and dysfunction of the mitral valve apparatus Arrhythmias caused by electrical abnormalities of the ischemic myocardium and conduction system are common, and indeed, SCD due to a lethal arrhythmia accounts for the vast majority of deaths occurring before hospitalization.

44. Diagnosis Laboratory evaluation of MI is based on measuring the blood levels of intracellular macromolecules that leak out of injured myocardial cells through damaged cell membranes; these molecules include Myoglobin, cardiac troponins T and I (TnT, TnI), Creatine kinase (CK, and more specifically the myocardial-specific isoform, CK-MB), L actate dehydrogenase

45. Troponins and CK-MB have high specificity and sensitivity for myocardial damage TnI and TnT are not normally detectable in the circulation, but after acute MI both troponins become detectable after 2 to 4 hours and peak at 48 hours; their levels remain elevated for 7 to 10 days.

46. CK-MB is the second best marker after the cardiac-specific troponins. Total CK activity is not a reliable marker of cardiac injury (i.e., it could come from skeletal muscle injury). CK-MB activity begins to rise within 2 to 4 hours of MI, peaks at 24 to 48 hours, and returns to normal within approximately 72 hours.. With reperfusion, both troponin and CK-MB peaks occur earlier as a result of washout of the enzyme from the necrotic tissue

47. Diagnostic Tests Blood tests include serum lipids, fasting blood sugar, Hematocrit, thyroid (anemias and hyperthyroidism can exacerbate myocardial ischemia Resting Electrocardiogram: CAD patients have normal baseline ECGs P athologic Q waves = previous infarction minor ST and T waves abnormalities not specific for CAD

48. Consequences and Complications of MI S ince the 1960s the in-hospital death rate has declined from approximately 30% to an overall rate of between 10% and 13% today (and to ∼7% for patients receiving aggressive reperfusion therapy). H alf of the deaths associated with acute MI occur in individuals who never reach the hospital; such patients generally die within 1 hour of symptom onset-usually as a result of arrhythmias. The variables associated with a poor prognosis include advanced age, female gender, diabetes mellitus, and previous MI.

49. 1. Contractile dysfunction An MI affects left ventricular pump function approximately proportional to its size. Typically, there is some degree of left ventricular failure, with hypotension, pulmonary vascular congestion, and fluid transudation into the pulmonary interstitial and pulmonary edema

50. 2. Severe "pump failure" (cardiogenic shock) Occurs in 10% to 15% of patients after acute MI, Generally with a large infarct (often >40% of the left ventricle). Cardiogenic shock has a nearly 70% mortality rate and accounts for two-thirds of in-hospital deaths

51. 3. Arrhythmias Following an MI, many patients develop arrhythmias responsible for many of the sudden deaths. MI-associated arrhythmias include sinus radycardia, heart block, tachycardia, ventricular premature contractions or ventricular tachycardia, and ventricular fibrillation

52. 4. Myocardial rupture Complicates somewhere between 1% and 5% of MIs is a frequent cause (7% to 25%) of MI-associated demise Complications R upture of the ventricular free wall, with hemopericardium and cardiac tamponade , usually fatal Rupture of the ventricular septum, leading to a new VSD and left-to-right shunt Papillary muscle rupture, resulting in severe mitral regurgitation

53. 5. Pericarditis 6. Infarct expansion 7. Mural thrombus. With any infarct; C ombination of a local loss of contractility (causing stasis) with endocardial damage (causing a thrombogenic surface) can foster mural thrombosis potentially, thromboembolism

54. prognosis D epends on infarct size, site, and fractional thickness of the myocardial wall that is damaged (subendocardial or transmural infarct). Large transmural infarcts have a higher probability of cardiogenic shock, arrhythmias, and late CHF. Patients with anterior transmural infarcts are at greatest risk for free-wall rupture, expansion, mural thrombi, and aneurysm.

55. P osterior transmural infarcts are more likely to be complicated by serious conduction blocks, right ventricular involvement, or both; Overall, however, patients with anterior infarcts have a substantially worse clinical course than those with posterior infarcts.

56. Chronic Ischemic Heart Disease Called ischemic cardiomyopathy, I s essentially progressive heart failure as a consequence of ischemic myocardial damage. U sually results from postinfarction cardiac decompensation that follows exhaustion of the hypertrophy of the viable myocardium. S evere obstructive CAD may be present without prior infarction, but with diffuse myocardial dysfunction.

57. Morphology Hearts from patients with chronic IHD are usually enlarged and heavy from left ventricular dilation and hypertrophy. Invariably there is moderate to severe atherosclerosis of the coronary arteries, sometimes with total occlusion. The major microscopic findings include myocardial hypertrophy, diffuse subendocardial myocyte vacuolization, and fibrosis from previous infarcts. Arrhythmias are common and, along with CHF and intercurrent MI, account for many deaths.

58. Sudden Cardiac Death (SCD C ommonly defined as unexpected death from cardiac causes either without symptoms or within 1 to 24 hours of symptom onset Coronary artery disease is the most common underlying cause, and in many adults SCD is the first clinical manifestation of IHD. With younger victims other nonatherosclerotic causes are more common:. Only a minority (10% to 20%) of cases of SCD are of nonatherosclerotic origin

59. The ultimate mechanism of SCD is most often a lethal arrhythmia, such as ventricular fibrillation . Morphology Severe coronary atherosclerosis with critical (≥75%) stenosis involving one or more of the three major vessels is present in 80% to 90% of SCD victims; acute plaque disruption is found in only 10% to 20% of these. A healed MI is present in about 40%, but in those who were successfully resuscitated from sudden cardiac arrest.

60. THE END!!!