Myocardial Infarction and Stroke

Question 1

What are the 3 layers of tissue that constitute the heart?

Answer 1

1. Pericardium:
   - Fibrous (outer layer)
   - Serous (parietal which is fused to the fibrous layer and then visceral which is closer to the heart)
2. Myocardium:
   - Made up of with cardiomyocytes: striated, branching, centrally located nuclei and intercalated discs
3. Endocardium:
   - Lining of heart made up of endothelial cells

Question 2

What is myocardial disease>

Answer 2

• Myocardial disease is coronary insufficiency due to atherosclerosis, where the luminal cross-sectional area of the coronary artery is decreased by more than 75%

Question 3

What are the two manifestations of myocardial disease?

Answer 3

1. Angina pectoris: due to gradual occlusion of the coronary artery
2. Myocardial infarction: due to sudden occlusion of the coronary artery

Question 4

What are some risk factors for IHD?

Answer 4

HARD risk factors:

1. High levels of blood lipids (e.g. LDL)
2. Hypertension (BP > 140/95 mmHg)
3. Cigarette smoking
4. Diabetes mellitus
5. Genetics (influence HDL: LDL levels)

SOFT risk factors:

6. Hormonal factors e.g. increased incidence after menopause in women
7. Obesity
8. Sedentary lifestyle
9. Stress

Question 5

Are hard risk factors for IHD additive or multiplicative?

Answer 5

• Hard risk factors for IHD are multiplicative
  e. g. A hypertensive, diabetic smoker has a 20x increased risk of atherosclerosis compared to someone without these risk factors (5 x 2 x 2 = 20)

Question 6

What are the clinical effects of atherosclerosis?

Answer 6

1. Intermittent ischaemic effects
2. Angina pectoris (chest pain)
3. Intermittent claudation (reduced blood flow to legs)
4. Neurological impairment
5. Secondary hypertension

Question 7

What does an atherosclerotic lesion consist of?

Answer 7

• In atheroscleroris the tunica intima (connective tissue layer) becomes thickened and enlarged by an atheroma/atherosclerotic lesion
• Atherosclerotic lesions consist of a fibrous cap (made up of collagen) and a lipid core (synthesised by foam cells)

Question 8

What are some risk factors for atherosclerotic plaque rupture?

Answer 8

1. Thin fibrous cap (decreased collagen synthesis and increased collagen degradation by MMP)
2. Large lipid pool
3. Decrease in amount of smooth muscle in plaque

• Rupture of an atheroma frees the contents of the atheroma which can cause disease such as MI and stroke by causing emboli

Question 9

What is a partial occlusion and its symptoms?

Answer 9

• The more mild presentation of IHD, due to a luminal size reduction due to atherosclerosis
• Manifests as transient pectoral angina (particularly due to exertion)

Question 10

What is the general chronology of atherosclerotic plaque formation?

Answer 10

1. Normal artery
2. Fatty streak appears due to LDL deposition in lamina intima
3. Macrophages are recruited to the area where they form foam cells that deposit more lipids into the lipid core and cause the plaque to progress
4. Fibrosis occurs which forms the fibrous cap- making a fibrotic plaque
5. The fibrotic plaque continues to accumulate lipids within the lipid core causing more occlusion of the artery (this is typically when clinical events begin to occur)
6. Due to MMP degradation of the fibrous cap or excessive lipid core content- the plaque may rupture causing platelet aggregation leading to MI, stoke or peripheral ischemia

Question 11

What is a complete occlusion and its symptoms?

Answer 11

• Occurs when a previously atherosclerotic vessel becomes completely occluded usually due to the effect of a superposed thrombosis

Symptoms:

• Causes persistent chest pain un-related to cardiac workload
• Also called myocardial infarction when it occurs in the coronary arteries

Question 12

What are the sequelae of myocardial infarction?

Answer 12

1. Sudden death (due to extensive necrosis of cardiac muscle)
2. Death within two days (due to shock or heart failure)
3. Congestive heart failure resulting in pulmonary oedema (as the heart does not have sufficient capacity to pump blood out of lungs)
4. Fibrosis and healing after 6 weeks (normal cardiac muscle is replaced with fibrotic tissue)
5. Pericarditis after 6 weeks (acute inflammation within the pericardium causes the pericardium to rub on the heart resulting in a friction rub)

Question 13

What localisation of myocardial infarctions is most likely to cause a secondary stroke?

Answer 13

• Subendocardial and transmural infarcts can both stimulate thrombosis in the left ventricle which can lead to a thromboembolism that can cause stroke

Question 14

What are the types of typical arterial occlusions?

Answer 14

1. Left anterior descending coronary artery occlusion:
   - Causes extensive necrosis in anterior wall of LV and apex of heart
   - Most common (50% of MIs)
2. Right coronary artery occlusion:
   - Causes necrosis in posterior wall of LV
   - 30% of MIs
3. Left Circumflex Coronary Artery Occlusion:
   - Causes necrosis on lateral wall of LV
   - 20% of MIs

Question 15

What Investigations are done to diagnose MI?

Answer 15

1. ECG: a change in ECG recording patterns e.g. a pathological Q wave, can be indicative of injury to the heart
2. Troponin blood test: increase in concentration in blood after infarcts due to cell death
3. Cardiac Enzymes: Creatinine phosphokinase (CDK), Lactic dehydrogenase (LDH), HDH and SGOT are all elevated after MI
4. Blood Lipids: High blood cholesterol and LDL/HDL ratio is indicative of cardiac disease
5. Full Blood Examination: Raised neutrophil count (response to necrotic tissue) and also increase in RBC mass (to aid in carrying oxygen to compensate for less effective heart)
6. Chest X-Ray

Question 16

How is ischaemic heart disease managed?

Answer 16

ACUTE:

1. Defibrillation
2. Fluid replacement (IV saline)
3. Pulmonary oedema management (morphine)
4. Furosemide (to increase urine output)
5. O2 therapy
6. Inotropic agents (increase ventricular output)
7. Acute coronary thrombolysis (e.g. streptokinase given within 3 hours to treat atherosclerosis of coronary artery)
8. Analgesia
9. Antiarrthymics: to restore rhythm to heart

LONG TERM:

1. Antithrombotic medication e.g. aspirin or warfarin
2. Lifestyle changes
3. Rehabilitation

Question 17

What is the likelihood of the most common consequences of stroke?

Answer 17

• 30% of patients survive with no disability
• 30% that survive 1 year will have severe disability (dependent at 6 months)
• 30% die within 1 year
• 5% of survivors per year have a stroke recurrence
• 3% of survivors per year have a MI

Question 18

What is the respective contribution of ischaemic heart disease and stroke to mortality in Australia?

Answer 18

• IHD is the highest cause of mortality

- Stroke is the second highest cause of mortality (but highest cause of morbidity)

Question 19

What are the two types of stroke?

Answer 19

1. Ischaemic Stroke:
   - 80% of strokes
   - Occurs when a thrombosis or embolism becomes lodged in a cerebral vessel and occludes the vessel
   - All tissues supplied by that vessel or downstream vessels become ischaemic
2. Haemorrhagic Stroke:
   - 20% of strokes
   - Due to rupture of cerebral blood vessel resulting in bleeding into the brain
   - Has a more severe outcome

Question 20

What are the causes of ischamic stroke?

Answer 20

1. Embolism:
   - A clot formed elsewhere e.g. heart or cartotid artery, that travels to the cerebral blood vessels and becomes lodged and occludes the vessel
   - Most common cause
2. Thrombosis:
   - A blood clot forms on an atherosclerotic narrowing of a large cerebral artery

Question 21

What are the causes of hemorrhagic stroke?

Answer 21

1. Hypertension (intracranial BP becomes too high)
2. Thrombocytopenia (causes excessive bleeding)
3. Weakening of the blood vessels:
   - Aneurysm
   - Arteriovenous malformation
   - Cerebral amyloid angiopathy

Question 22

What are the fundamental aims of stroke management?

Answer 22

1. Acute treatment: remove the clot or stop the bleeding

2. Long term: reduce the probability of another stroke occurring

Question 23

What are the different pathological features that occur due to an ischaemic stroke?

Answer 23

1. Ischaemic core:

• The area where blood flow is reduced to <15% of normal, it is the area affecting the territory proximal to the site of the occlusion
• If the occlusion is in place for long enough, there will be irreversible tissue damage and death of cells in this area

2. Ischaemic penumbra:

• The area where the blood flow is reduced to between 15%-40% of normal (limited blood flow is still occurring)
• In this area, the tissue is stressed and is on the verge of tissue damage and death
• It is imperative to attempt to rescue the ischaemic penumbra, as the damage to these cells is not irreversible. If blood flow is restored, the penumbra can be prevented from becoming a larger ischaemic core or damaged and dead tissue

Question 24

How does ischemia cause neuronal injury and cell death?

Answer 24

• When cells are starved of oxygen and glucose they become stressed, when this occurs in neurons they enter a state known as excited toxicity
• This involves: excessive release of glutamate from cells (which can cause neuronal overstimulation and thus neural toxicity)
• Influx of calcium into neurons occurs, causing calcium overload- which causes perturbation of intracellular signalling pathways

Question 25

How Does Reperfusion of Blood to Ischaemic Areas Cause Cell Injury?

Answer 25

• Although the aim of acute stroke management is to restore blood flow to tissue, restoring blood flow can lead to even more cell damage and death by causing reperfusion injury
• Reperfusion injury occurs because during the time of ischemia, the cells attempt to adapt to the very low oxygen/glucose environment, when blood flow is suddenly restored- the cells can suffer from reperfusion injury as they are not able to adjust to the influx of oxygen and glucose
• Reperfusion injury involves reperfusion-induced oxidative stress, this is accompanied by the deterioration of brain mitochondria, additionally mediators of inflammation such as cytokines are upregulated in the injured cells e.g. TNF and IL-1B

Question 26

What is fibrinolysis?

Answer 26

• The endogenous proteolytic removal of fibrin (scaffold of blood clot) in the body
• This occurs when either t-PA or u-PA converts plasminogen into plasmin which can degrade proteins such as fibrin

Question 27

What is thrombolysis?

Answer 27

• The therapeutic breakdown of fibrin within a blood clot

Question 28

How is the Fibrinolytic System Activated?

Answer 28

1. When the blood clotting cascade is activated, fibrinogen is converted to fibrin which cross-links to form the structure of blood clots
2. When the fibrin becomes cross-linked in a blood clot lysine residues are exposed, both t-PA/u-PA and plasminogen have binding sites for lysine so they are localised to the blood clot surface
3. t-PA then coverts the plasminogen into plasmin which breaks down fibrin into fibrin degradation products

Question 29

How is the Fibrinolysis System Activated?

Answer 29

1. Inhibition of t-PA or u-PA by PAI-1 and PAI-2
2. Inhibition of plasmin by antiplasmin (why plasmin has such as short half-life)
3. Inhibition of plasminogen and t-PA binding to blood clot lysine residues by TAFI or Lysine analogues:
   - TAFI (thrombin activatable fibrinolysis inhibitor): is a carboxypeptidase that removes C-terminal lysine residues from the fibrin and thus stops t-PA or plasminogen from binding to it
   - Lysine analogues: e.g. tranexamic acid, competes with lysine to bind to plasminogen and t-PA (thus useful for use as a therapeutic to prevent bleeding in surgery)

Question 30

How is t-PA used to treat ischaemic stroke?

Answer 30

• First used in 1995
• Administered intravenously over an hour
• Must be given within 4.5 hours of stroke onset (later use is associated with reduced clinical benefit and an increase in risk of intracranial haemorrhage)

Question 31

What is the role of t-PA in the CNS outside of fibrinolysis?

Answer 31

• Has both neuroprotective and neurotoxic roles:

1. Neuroprotective benefits:
   - role in memory and learning
   - can be neuroprotective at low levels
2. Neurotoxic role:
   - promotes excited toxic injuries (which occur due to reperfusion injury) by acting on the NMDA receptor
   - can interact with endothelial cells to increase permeability which promotes extravasion of fluid into the brain

Question 32

What is the benefit of Tenecteplase?

Answer 32

• A t-PA derivative with a longer half-life and retained fibrin selectivity
• May have less neurotoxic effects
• Under clinical development

Question 33

How does mechanical thrombectomy work?

Answer 33

• t-PA is administered to thrombose the clot/emboli

- A stent retriever is placed into the artery that can be used to physically remove the clot