Pathology: Ischemic Heart Disease

Front 1

What is Ischemia?

Back 1

*Deficiency of blood flow in a part, due to functional constriction or actual obstruction of a vessel.

*An imbalance between supply and demand for oxygen.

Front 2

What are the 4 Ischemic Cardiac Syndromes?

Back 2

1. Angina Pectoris:
-Stable (Typical)
-Unstable (Crescendo...much more serious)
-Variant (Prinzmetal--includes spasm of vessels)

2. Myocardial infarction.

3. Chronic IHD with CHF.

4. Sudden cardiac death.

Front 3

Discuss Atherosclerotic IHD:

Back 3

*There is fixed narrowing:
-In 90% of patients with IHD.
-Most lesions are PROXIMAL and epicardial.

*There are acute plaque changes.
*There is thrombosis.
*There is vasospasm.

Front 4

Diagram of CORONARY ARTERY DISTRIBUTION:

Back 4

A, anterior; AL, anterolateral; AS, anteroseptal; I, inferior; IL, inferolateral; P, posterior; PL, posterolateral; PS, posteroseptal; S, septal.

Front 5

Back 5

*This is an autopsy specimen of a left main coronary artery with severe occlusion due to atherosclerosis.
*Yellow = plaque.

Front 6

Back 6

ATHEROMATOUS PLAQUE and its features.

Front 7

Back 7

*ATHEROSCLEROSIS
*Note that the intima is NOT the only layer involved in atherosclerosis.
*Fibrous cap (F).
*Necrotic (lipid) core (C) --soft, prone to rupture.

Front 8

What is the meaning of vascular narrowing?

Back 8

AREA = πr2

REDUCING THE DIAMETER BY 50% = REDUCTION OF AREA BY 75%

Front 9

Discuss Fixed Lesions in CAD.
significant--
critical--

which ones are associated with angina?

Back 9

*A significant lesion has at least 50% reduction in diameter (75% x-s area).

*A critical lesion has at least 75% reduction in diameter (90% x-s area).

*Stable angina pectoris is associated with fixed lesions (50 and 75%).

*The demand is met at rest.
*Symptoms develop with exertion.

Front 10

Discuss Erosion as related to Unstable Angina:

Back 10

*Without penetration into the lipid core, partial occlusion secondary to PLATELET AGGREGATION may occur. *Microthrombi with microemboli to more peripheral coronary artery branches may also occur.

*Ischemia is exacerbated by vasoconstriction if endothelium secretes more vasoconstricting than vasodilating factors.

Front 11

How do Acute Plaque Changes develop? What do they result in?

Back 11

1) Erosion of endothelium.
2) Plaque rupture.
3) Hemorrhage into necrotic core.
4) Thrombosis of blood in lumen.
--> Thrombosis.

Front 12

Discuss Rupture vs. Erosion:

Back 12

*When rupture occurs through the fibrous cap, blood is exposed to the contents of the highly thrombogenic core.

*Significant thrombosis is much more likely in rupture than in erosion.

Front 13

Why Do Plaques Rupture?

Back 13

*In the atherosclerotic lesion, macrophages releasing metallo-proteinases contribute to destabilization and rupture. The released enzymes digest collagen in the fibrous cap.

*More likely if there's a greater than 40% core, a thin fibrous cap, many macrophages, few smooth muscle cells in fibrous cap – “vulnerable plaques.”

Front 14

Pathogenesis of Coronary Thrombosis:

Back 14

1) Plaque rupture exposes blood to thrombogenic core and damaged endothelium.

2) Increase in thromboxane A and other platelet contents.

3) Platelets are activated.

4) Tissue thromboplastin is released.

Front 15

What happens when you have an occlusive thrombus?

Back 15

*If there's penetration of blood into the lipid core, thrombosis results with partial or total occlusion.
*You see this in unstable/crescendo angina.

Front 16

Back 16

CORONARY ARTERY THROMBOSIS. Lumen of the coronary vessel is totally occluded. Pt died of acute MI.

Front 17

Back 17

*Recent Coronary Thrombosis With Total Occlusion.
*Huge core in the plaque (~70% of plaque is core).
*Note the irregularly shaped lumen, filled with thrombus.

Front 18

Back 18

L: Ruptured vulnerable plaque: note large lipid core, thin fibrous cap and thrombosis containing crystals from lipid core.

Middle: Plaque erosion with superficial thrombus. Note many SM cells and no lipid core.

R: Large complicated atherosclerotic plaque with narrowed lumen. Note calcifications (blue areas).

*Imaging techniques are being developed to identify vulnerable plaques in vivo.

Front 19

Back 19

*Recanalized Atherosclerotic Coronary Artery.
*Irregular space on right had had calcium deposition; the Ca fell out during specimen prep.
*The smaller space on the left is the recanalization that the body achieved on its own.

Front 20

Evidence For Thrombosis As Cause of Myocardial Infarction:

Back 20

*Wasn't recognized until about 100 years ago.

*Pathological studies helped point the finger.

*Clinical studies of coronary arteriography in patients with acute MI before and after thrombolytic agents also pointed to thrombosis.

*We now know it's the cause.

Front 21

Summary of Coronary Artery Pathology In Two Ischemic Syndromes:
angina, both forms--
MI--

Back 21

*Angina:
-Chronic stable: you see fixed lesions with at least one having > 75% reduction.
-Unstable: you see plaque erosion or rupture, mural thrombi (arterial), and possibly microemboli.

*Myocardial infarction: you see plaque rupture followed by thrombosis with complete occlusion.

Front 22

Infarcts: Transmural vs Subendocardial:

Back 22

*Transmural:
-Involves entire wall.
-Caused by plaque rupture and coronary thrombosis.
-Q waves (usually).
-Usually begin in sub-endocardial region.

*Subendocardial:
-Usually involves inner 1/3 to 1/2 of wall.
-Not limited to a coronary branch zone. More spotty.
-Non-Q wave.
-Related to global reduction in coronary blood flow.

*In the case of total occlusion, if reperfusion is timely, necrosis can be limited to a localized subendocardial infarct.

Front 23

DISTRIBUTION OF MYOCARDIAL NECROSIS in different types of infarcts: 6

Back 23

Red dots= occluded vessels.
*Transmural:
-Involves entire wall.
-Caused by plaque rupture and coronary thrombosis.
-Q waves (usually).
-Usually begin in sub-endocardial region.

*Subendocardial:
-Usually involves inner 1/3 to 1/2 of wall.
-Not limited to a coronary branch zone. More spotty.
-Non-Q wave.
-Related to global reduction in coronary blood flow.

Front 24

WHAT ARE THE EARLY BIOCHEMICAL FINDINGS IN MI?

Back 24

Front 25

What happens to MYOCARDIAL VIABILITY after an MI?

Back 25

*Reversible phase is very limited.

Front 26

Ischemic Myocardium: what is the Timecourse of injury to about 6 hours?

Back 26

*In a few minutes cell swelling, mitochondrial swelling, glycogen depletion.

*20-40 minutes for irreversibility; EM defects in sarcolemmal membranes.

*Myocytes die in a wavefront from sub-endocardium to subepicardium in about 6 hours; effectiveness of thrombolytic agents is therefore limited to this period.

Front 27

PROGRESSION OF MYOCARDIAL NECROSIS diagram:

Back 27

Front 28

What are the Determining Factors of severity of Myocardial Infarction?

Back 28

*Location, severity, and rate of occlusion.
*Size of vascular bed, e.g. left main CA.
*Duration of survival.
*Metabolic demands.
*Presence of collateral vessels.
*Spasm.
*Heart rate, rhythm, BP.

Front 29

MI: What do we see on Gross Pathology?

Back 29

*Source of frustration in forensic path--if person dies immediately, there's nothing to see!
*Nothing in 1st 12 hours.
*With special dyes after 2-3 hours.
*Pallor or red blood hue @ 12-24 hours.
*Yellow with red-tan border @ 3-10 days.
*Yellow area rimmed by granulation tissue appearing hyperemic.
*A white scar after a few weeks.

Front 30

Back 30

*Lateral MI; Several Days post MI. Yellow lesion at left.
*Also note significant LVH.

Front 31

Back 31

*4 days post MI with TTC stain.
*Red=dye oxidation (good tissue)
*Tan= dead tissue.
*Firm, white areas are fibrosis/scarring. Prior MI!
*Significant LVH; pressure overload pattern.

Front 32

Back 32

*Extensive anteroseptal MI (ASMI).
*Several Days post MI.

Front 33

MI: what do we see on Histopathology?

Back 33

*Wavy fibers as early as 1-3 hours.
*Coagulation necrosis: hypereosinophilia, then loss of striations in 4-12 hours.
*Nuclear changes as early as 5 hours.
*Nuclear disappearance @ 24-48 hours.
*Polys as early as 6-8 hours; Peak @ 48 hrs.
*Macrophages 4 days; Peak 6 days.
*Proliferation of vessels as early as 3 days.
*Fibroblasts as early as 4 days.
*Collagen fibers as early as 9 days.
*Early granulation tissue 7-10 days.
*Granulation tissue peaks 2-4 weeks.
*Advanced scarring 6 weeks.

Front 34

Back 34

*MYOCARDIAL INFARCT (1 DAY).
*Right is normal.
*Left are wavy fibers. Some are anucleate. EARLIEST SIGN OF MI ON HISTOLOGY.

Front 35

Back 35

*MYOCARDIAL INFARCT (3-4 DAYS).
*Anucleate fibers= dead cells.
*Loss of striations; fibers look eosinophilic.
*Background cells are neutrophils.

Front 36

Back 36

*MYOCARDIAL INFARCT (7-10 DAYS).
*Increasing number of macrophages.
*This correlates with highest risk of spontaneous cardiac RUPTURE post MI; high amount of tissue removal by macrophages.

Front 37

Back 37

*MYOCARDIAL INFARCT (10-14 DAYS)
*Red = capillaries
*Blue = collagen
*This is granulation tissue; this is healing.

Front 38

Back 38

*MYOCARDIAL INFARCTION (HEALED).
*Bottom right part is scarred. Mostly collagen.
*"Replacement Fibrosis."
*There's compensatory hypertrophy adjacent to the area of necrosis.

Front 39

Back 39

*HEALED MYOCARDIAL INFARCT on trichrome stain showing abundant collagen (blue).

Front 40

Discuss Myocytolysis:

Back 40

*Vacuolar degeneration or colliquative myocytolysis.

*Appears as a nucleus in an empty sarcolemmal tube.

*Seen in LV subendocardium and at perimeter of MIs.

*These cells are thought to be still viable.

*Unlike fibers in coagulation necrosis, stain for creatine kinase and lactic dehydrogenase.

Front 41

Back 41

*Subendocardial myocytolysis.
*Cells on left half have a central nucleus with a halo around them. This is myocytolysis.

Front 42

What happens to cardiac function with reperfusion after occlusion of a vessel?

Back 42

*Salvage can occur if caught in time. Still loss of function.
*But injuries in reperfusion can occur.

Front 43

Discuss Myocardial Reperfusion:
what do experiments show?

Back 43

*Occlude proximal LCX in dogs

*Reperfuse:
-At 40 minutes – infarct size was reduced by 60-70%.
-At 3 hours – less reduction.
-At 6 hours – NO REDUCTION.

*When present, reduction was in subepicardial region.

Front 44

Discuss Thrombolysis for Acute MI:

Back 44

*Streptokinase or tissue-type plasminogen activator (tPA).

*Resulting patency in about 70%.

*Reperfusion injury and STUNNED myocardium can follow.

*Hemorrhage in the infarct is more common but not clinically important.

Front 45

Diagram of REPERFUSION:

Back 45

Front 46

Back 46

*MI (S/P REPERFUSION).
*Triphenyl tetrazolium stain
*Pt died after reperfusion.
*You can see the dark infarction (think hemorrhage).
*LVH.

Front 47

Discuss Reperfusion Injury:

Back 47

*Can cause lethal injury to cells which might have survived.

*Generation of reactive oxygen species, intracellular calcium overload, and inflammation which combine to facilitate cell death.

*Studies underway to find therapies which will block these mediators of injury.

*Contraction bands are a manifestation.

Front 48

What is Contraction Band Necrosis?

Back 48

*Accelerated necrosis of irreversibly injured myocytes.

*Hypercontraction with massive influx of calcium.

*Appear after as little as 2 minutes of reperfusion.

*There are margins of infarcts between dead and viable zones.
*They are more numerous in infarcts after reperfusion.
*You sometimes see them in the myocardium of sudden death cases.

*Perioperative ischemia during cardiac surgery.

Front 49

Back 49

*Contraction band necrosis in a 1 day old myocardial infarct; occasional PMN, nuclear loss, focal myocytolysis.
*Linear areas of horizontal staining are the bands.

Front 50

Discuss Myocardial Stunning:

Back 50

*Reperfused myocytes are viable but temporarily have biochemical changes and are unable to contract.

*May be stunned for hours or days.

*There are NO abnormalities at the level of light microscopy.

*Temporary assist devices may be indicated.

Front 51

Summarize MIs:

Back 51

*A dynamic process that begins with the transition from reversible to irreversible ischemic injury and culminates in replacement of dead myocardium by a fibrous scar.

*Myocytes die in a wavefront from inner to outer layer; a process which takes about 6 hours.

*Reperfusion is more likely to salvage the outer layer.

Front 52

Discuss the RELEASE OF MYOCYTE PROTEINS after MI:

Back 52

Front 53

What are the Complications of MI?

Back 53

*Tachyarrhythmias, AV block with bradycardia, shock, congestive heart failure, rupture, thromboembolism, ventricular aneurysm, pericarditis.

*Pericarditis of 2 types:
1) Acute fibrinous pericarditis with transmural infarct.
2) Post-MI syndrome (Dressler's syndrome) autoimmune.

Front 54

Back 54

*ANTERIOR MYOCARDIAL RUPTURE post MI.

Front 55

Back 55

*VENTRICULAR SEPTAL RUPTURE post MI.
*AV is visible above the rupture.

Front 56

Back 56

*RUPTURE OF PAPILLARY MUSCLE post MI.
*Pt developed MR due to ruptured muscle post MI.
*Same risk profile (time-wise) as rupture of free wall.

Front 57

Back 57

*FIBRINOUS PERICARDITIS post MI. NOT Dressler's.
*Lots of fibrin deposition; Pt would also have a friction rub.

Front 58

Back 58

*MURAL THROMBUS post MI. Can lead to stroke and death, which is what happened here.

Front 59

Back 59

*VENTRICULAR ANEURYSM post MI.
*In the vulnerable spot where the MI occurred.

Front 60

Discuss Chronic Ischemic HD:
findings?

Back 60

*May have been asymptomatic and present with heart failure or have a history of angina/prior MIs.

*Diffuse myocardial atrophy, but more commonly hypertrophy with dilatation; subendocardial vacuolization, replacement fibrosis (healed MIs).

*Insist on objective evidence before making diagnosis of IHD; an elderly person might have another cause of heart failure and cardiomegaly.

Front 61

Discuss Sudden Cardiac Death:

Back 61

*80-90% have severe IHD.

*> 75% stenosis in more than one vessel.

*Usually > 90% in one vessel.

*Acute plaque changes and thrombosis in 75-80% and old MI in 40%.

*A long list of causes other than IHD.

*Fatal arrhythmia due to reduced blood flow is usual cause of death in these patients.

Front 62

PATHWAYS OF PROGRESSION OF ISCHEMIC HEART DISEASE diagram:

Back 62

Front 63

What is Graft Arteriopathy?

Back 63

*Limits the long-term success of cardiac transplants.

*Marked progressive diffuse intimal thickening of coronary arteries with luminal narrowing.

*The denervated heart does not allow the patient to note anginal warning symptoms.

*Similar to accelerated atherosclerosis.

Front 64

Back 64

Graft Arteriopathy. Note elastin (IEM) and thickened intima. You develop this after a transplant.