case 10: ischemic stroke Flashcards
1
Q
What Is a CT Scanner?
A
- Computerized axial tomography scan (CT scan, CAT scan),
uses computer-processed combinations of many X-ray images
taken from different angles to produce cross-sectional images
2
Q
Provisional Diagnosis
A
- A provisional diagnosis – acute ischemic stroke secondary
to occlusion of the M1 segment of middle cerebral artery
(MCA) - Treatment – intravenous injection of tissue plasminogen
activator (tPA) at 2 h after symptom onset
3
Q
What is a Stroke?
A
- Stroke is a sudden impairment in brain function, sudden
paralysis or sensation - The term “brain attack” – is increasingly being used as an
indication of medical emergency - The term “stroke” does not imply the causes. There are
many causes
4
Q
What causes a stroke?
A
- A stroke occurs when a blood vessels that carries O2 and
nutrients to the brain is either blocked by a clot (ischemic
stroke) or bursts (hemorrhagic stroke)
5
Q
Adult Human Brain – Facts
A
- ~2% body weight
– ~1,350 g (male); ~1,200 g (female) - Receives 15-20% of cardiac output
- Consume 20% resting O2
- Preferred energy substrate – glucose
– When do neurons use ketone bodies? during starvation
6
Q
Cerebral Blood Flow (CBF) – Facts
A
- CBF – 750 ml/minute
- Normal CBF – ~50-65 ml/100 g/min
– ~1/3 in white matter; ~2/3 in gray matter - CBF at 20-30 ml/100g/min -> loss of electrical activity
(“ischemic penumbra”) - CBF at <10 ml/100g/min -> neuronal death
- 8” of interruption in blood flow -> unconsciousness
7
Q
Stroke Facts
A
- Stroke is the fourth leading cause of death in the U.S.
– 795,000 people in the U.S. suffer strokes each year
– 133,000 deaths in the U.S. each year
– One person suffers a stroke every 40 seconds in the U.S. - A leading cause of adult disability
– Women suffer greater disability after stroke then men - Up to 80% of all strokes are preventable through risk factor
management - Stroke kills more than twice as many American women every
year as breast cancer - African Americans is nearly double that of Caucasians for
incidence of stroke
8
Q
Stroke Symptoms
A
- sudden and severe headache
- trouble seeing in one or both eyes
- sudden dizziness
- trouble walking
- sudden confusion
- trouble speaking
- sudden numbness or weakness of face, arm or leg
9
Q
Stroke Strikes FAST
A
- F – Face, ask the person to smile
– If not symmetry -> weakness on one side - A – Arm, ask the person to raise both arms
- S – Speech, ask the person to speak a simple sentence
- T – Time (with a stroke, time lost is brain loss)
– If you observe any of these signs, call emergency immediately
10
Q
Risk Factors of Stroke
A
- Risk factors of stroke – SHAME
– Smoking; Hypertension; Atrial fibrillation; Male; Elderly - Risk factors in young age – 5C
– Cancer; Cardiogenic emboli; CNS infection (HIV conditions);
Congenital arterial lesion; Cocaine - Other risk factors
– Things you cannot change - Race (African Am, native Am, and Alaskan natives)
- Family history, history of stroke or TIA
– Things you can change - Hypertension; DM; high cholesterol; diet (salt, antioxidants)
- Physical inactivity and being overweight
- Birth control pills and hormone replacement therapy; alcohol
11
Q
Transport of Lipoproteins in Blood
A
- What are lipoproteins?
– Transport of absorbed lipids in the blood –
lipids (hydrophobic) must bind to amphipathic
proteins (apo-lipoproteins) → lipoproteins →
water-soluble
– Lipoproteins – hydrophobic lipids (triglycerides,
TG) in core; hydrophilic lipids (phospholipids,
PL) on surface, interacting with blood plasma - Six lipoprotein forms based on densities:
– Chylomicrons (CM) – lowest in density (largest size)
– Very low density lipoproteins (VLDL)
– Intermediate density lipoproteins (IDL) – as
intermediates
– Low density lipoproteins (LDL)
– High density lipoproteins (HDL)
– Albumin-free fatty acids (FFA) – highest in
density
12
Q
Chylomicrons – Formation
A
- Pancreatic lipase digests triacylglycerols (triglycerides, neutral fat) ->
fatty acids & monoacylglycerol -> absorbed by enterocytes (intestinal mucosal cells) (enter freely because cell membrane has lipid bilayer) - Formation of chylomicron (CM) in enterocytes:
– In enterocytes (cytosol), fatty acids + monoacylglycerols -> triacylglycerols
– Absorbed triacylglycerols + apolipoprotein -> (nascent) CM
– CM – 98% lipids, mostly triacylglycerols (~85%)
the more FA the more glycerol enters into enterocyte
CM transported out via exocytosis into central lacteal (because of larger pores)
13
Q
Chylomicrons – Transport
A
- Transport of nascent chylomicron (CM)
– Exocytosis -> central lacteal -> lymphatic vessels -> thoracic duct -> vena
cava (into venous blood) -> entering blood circulation (not by portal circulation)
– Refract light, cloudy appearance in plasma
– CM deliver ~80% to adipose t., muscle & peripheral t.; ~20% to liver - Modifications of nascent CM particles:
– The nascent CM is rapidly modified into CM by combining apoE + apoC-II
from circulating HDL -> mature CM
– The apoC-II is important for the metabolism of lipids in the CM
14
Q
CM – Lipoprotein Lipase
A
- Lipoprotein lipase (LPL) – produced
mainly by adipocytes -> move to
endothelium
– Resides on the capillary walls
mainly on adipose tissue, cardiac &
skeletal muscles, lactating
mammary glands
– LPL is activated by apoC-II (from
HDL)
– LPL hydrolyzes the triacylglycerol to
yield monoacylglycerol, fatty acids
-> transport to adipocytes ->
promotes lipogenesis
– LPL (insulin-sensitive) – insulin -> increase LPL activities
pancreatic lipase is for digestion of lipid in lumen of small intestine. hormone sensitive lipase is to convert fat in adipose tissue into monoacylglycerol and FFA to circulate in blood, insulin decrease hormone sensitive lipase so less lipolysis occurring
LPL purpose is to synthesize neutral fat present in CM in blood
LPL anabolic
15
Q
CM – Metabolism
A
- After being degraded by
LPL:
– CM decrease in size and increase in density
-> apoC-II returned to the
HDL -> the remaining particle
is called a “CM remnant” - CM remnants in the blood -> the liver
– CM remnants deliver leftover lipids to liver
– Hepatocyte membranes
contain CM lipoprotein
receptors bind to
apoB-48/apoE complex
16
Q
VLDL – Production
A
- VLDL – produced by the liver
(hepatocytes) - 90% lipid, triacylglycerols (55-65%)
- The dietary intake of both fat and
carbohydrate, in excess of the needs of
the body, leads to the conversion into
triacylglycerols in liver - Function of VLDL – transport
endogenously synthesized triacylglycerols
from liver to peripheral tissues (mainly
muscle and adipose tissue)
– Cloudy appearance – somewhat visible in
plasma
17
Q
VLDL – Metabolism
A
- Modification of circulating VLDL – similar to
CM:
– VLDLs are released from the liver as nascent
VLDL
– Nascent VLDL acquires apoC (I, II, & III) and
apoE from circulating HDL.
– Degradation of triacylglycerol by lipoprotein
lipase (LPL) →VLDL decrease in size and
become more dense
– The apoC-II are transferred back to HDL.
– VLDL → IDL → LDL (no apoC-II) - ↑ Liver lipogenesis (from high lipid or carb
intake) → exceed liver production of VLDL →
non-alcoholic fatty liver
VLDL formed into liver and converted to neutral fat to adipose tissue then lipogenesis
18
Q
Metabolism of IDL
A
- Production of LDL from VLDL in plasma:
– After degradation of triacylglycerol by lipoprotein lipase, VLDL has
been converted in the plasma to an intermediate-sized particle
(IDL) then to LDL.
– IDL contain more proteins, thus less cholesterol than LDL. - The fate of IDL (a.k.a. VLDL remnants):
– 1. Direct uptake by liver – through receptors (apoB-100/apoE
complex) → endocytosis - In most animal species, the majority of IDL is removed from blood by
liver. - In primates, 60-70% IDL are converted to LDL
– 2. Conversion to LDL – contain only apoB-100 - Characteristics of IDL
– IDL are essentially absent from serum under normal
circumstances
19
Q
Metabolism of LDL
A
- ~80% Lipids – cholesterol > phospholipids > triacylglycerols > FFA
- The primary function of LDL is to provide cholesterol to peripheral
tissues (liver 75%, adrenals, gonads, blood vessels & adipose t.) - Hormones and LDL uptake
– Insulin and tri-iodothyronine (T3) increase the binding of LDL to liver
cells. Cholesterol then is eliminated via bile (bile salt, bile acid, bilirubin, cholesterol).
– Diabetes or hypothyroidism → hypercholesterolemia → ↑ risk of
atherosclerosis in primates
20
Q
Metabolism of HDL
A
- HDLs are synthesized de novo in the liver and small intestine, as
protein-rich particles
– These newly formed HDLs are nearly devoid of any cholesterol and
cholesteryl esters.
– The primary apoproteins of HDLs are apo-A-I, apo-C-I, apo-C-II and
apo-E. - 50% lipoproteins, another 50% lipid (phospholipids > cholesterol ~
triacylglycerols) - HDLs are converted into spherical lipoprotein particles through the
accumulation of cholesteryl esters - Functions of HDL
– As a reservoir of apolipoproteins (apoC-II, apo-E) for CM & VLDL
– Reverse cholesterol transport – carry cholesterol back to liver
– Cholesterol can be eliminated to feces through bile
21
Q
Summary – Lipoprotein Functions
A
- Chylomicrons deliver dietary triacylglycerols
from the intestine to adipose and muscle
– Chylomicron remnants deliver leftover lipids to
liver - VLDL from liver deliver endogenous
triacylglycerols to adipose tissue and muscle - LDL deliver cholesterol to many tissues
- HDL deliver excess cholesterol from other
tissues to liver, reservoir of apolipoproteins (apoC-II) - Liver is the main organ that can eliminate
cholesterol out of the body
22
Q
Structure of a Normal Artery
A
- 3 layers (tunica) – intima, media & adventitia
- Intima – endothelial cells, the underlying extracellular
matrix, and a smattering of smooth muscle cells - Media – smooth muscle cells (SMC)
23
Q
Atherosclerosis – Definition
A
- Sclerosis – abnormal hardening of body tissue
- Arteriosclerosis – the thickening, hardening and loss of elasticity of arterial wall (eg. calcification, atherosclerosis)
- Atheroma – the lipid deposits in intima of arteries, producing a yellow swelling on the endothelial surface
- Plaque (atheromatous plaque) is made up of fat,
macrophages, calcium, and other substances found in the blood - Atherosclerosis – a disease in which plaque builds up
inside your arteries
24
Q
Atherosclerosis Begins in Childhood
A
due to endothelial dysfunction
25
Q
Risk Factors and Endothelial Dysfunction
A
- Initiation of atherosclerotic lesions – endothelial dysfunction, mostly caused by risk factors
- Characteristics of endothelial dysfunction
– ↑ Vascular permeability
– ↓ Synthesis and/or release of NO
– ↑ Secretion of adhesion molecules
* eg. Vascular cell adhesion molecule 1 (VCAM-1) – (in tunica intima) mediates the adhesion of monocytes (macrophages), lymphocytes, eosinophils, and basophils to vascular endothelium
– ↑ Secretion of chemo-attractants – recruit inflammatory cells to areas of lipid accumulation - The intact and yet dysfunctional endothelium becomes sticky → infiltration of plasma LDL and monocytes
26
Q
Atherosclerosis – Complications
A
- Complications of atherosclerosis
– Stenosis (narrowing) of muscular arteries – angina pain while walking (increase blood pressure which increase the friction of blood in the athroma area)
– Provides sites for development of thrombosis
– Aneurysm (localized enlargement of an artery caused by a weakening of the artery wall) formation
27
Q
Atherosclerosis – 1. Risk Factors
A
- Risk factors
– Smoking
– ↑ LDL
– Diabetes
– Hypertension
– Chronic infection
– Others - Which result in:
– ↓ NO production
– ↑ free radicals - To reduce risks –
antioxidants
pic
28
Q
High Plasma Levels of LDL-Cholesterol
A
refer to pic
increase risk
29
Q
Sites for Atherosclerosis
A
- What do those sites for atherosclerosis have in common?
- Why would atherosclerosis occur at these sites?
refer to pic
30
Q
Vessels Involved by Atherosclerosis
A
- Large elastic arteries – particularly coronary, internal carotid, cerebral, and lower extremity
– Bifurcations, bends, and branch points (in common) (areas for turbulent flow)
31
Q
Atherosclerosis – 2. Turbulence Flow
A
- Turbulence (disturbed) flow → creates endothelial shear stress (friction with blood, esp. in hypertension) → ↓ NO production → vasoconstriction → ↑ infiltration of lipids (LDL)
& inflammatory cells
laminar vs disturbed flow in pic
32
Q
Atherosclerosis – 3. Inflammation
A
- Endothelial dysfunction → vascular inflammation →
accumulation of lipids & cellular debris in intima - Inflammation plays a key role in atherosclerosis
- Atherosclerotic deposits arise in, not on, vessel walls
33
Q
Atherosclerosis – Oxidized LDL
A
- LDL → vascular intima → LDL oxidized by ROS into oxi-LDL (proinflammatory) → oxi-LDL activates endothelial cells through the
induction of the cell surface adhesion molecules - → monocytes are adhered then entered across endothelium to the
sub-endothelial matrix
34
Q
Atherosclerosis – Foam Cells
A
- LDL (> 160 mg/dl) → dysfunctional endothelium → oxidized LDL (oxi- LDL) as antioxidative activity is depleted
- Blood (plasma) monocytes infiltration into subendothelial area of the vascular wall → differentiate into macrophage and take oxi-LDL → foam cells
- Foam cells (monocytes that contain a lot of LDL) contain scavenger LDL receptors (no feedback) → more and more cholesterol in foam cells → secrete more cytokines → inflammation → cell death
35
Q
Inflammatory Markers and CVD
A
- C-reactive protein (CRP) – produced by liver, released to blood
- Chronic inflammation → ↑ macrophage IL-6 → ↑ CRP
- CRP – a biomarker and a mediator in pathogenesis of
atherosclerosis
pic
36
Q
C-Reactive Protein (CRP)
A
- Chemical properties
– CRP is synthesized by the liver in response to factors released by macrophages and adipocytes
– The levels of CRP increases during acute inflammation - CRP binds to cell surface of damaged cells or some bacteria
– → Activate complement system
– → ↑ Phagocytosis by macrophages
– → ↑ Destruction of bacteria
37
Q
Atherosclerosis – 4. Atheroma Formation
A
- Vascular inflammation → macrophages infiltration → becomes foam cells → secrete pro-inflammatory cytokines:
– ↑ Smooth muscle cells (SMC) proliferation
– ↑ SMC migration to intima, SMC secrete cytokines
– ↑ formation of extracellular matrix in intima
– ↑ fatty deposit in intima - → Formation of atheroma → grow outward to lumen
originally t. intima contains few SMC but now they recruit more
38
Q
Stable and Vulnerable Atheroma
A
- Stable atheroma – thick fibrous cap, small lipid core, more
SMC, well-preserved endothelium - Vulnerable atheroma – thin fibrous cap (bioactive), large and necrotic lipid core → more inflammatory cells and cytokines→ eroded endothelium
pic
39
Q
Atherosclerosis – 5. Atheroma Rupture
A
- 95% of ruptured fibrous caps were below 65 μm in thickness
- Thinning of the fibrous cap:
– Heavily infiltrating foam cells secrete proteolytic enzymes, degrade the collagen-rich cap matrix and cause the gradual loss of SMCs and collagen from the fibrous cap.
40
Q
Atherosclerosis – 6. Thrombosis
A
- Endothelial disruption due to rupture:
- → Exposure of platelet adhesion factors
– Collagen & Von Willebrand factor (vWF) - → vWF + glycoprotein Ib/IX/V complex
- → Platelet activation → granule release
– ADP (mediator of platelet aggregation)
– GPIIb/IIIa binding of vWF and fibrinogen - → Platelet aggregation
- → Activation of coagulation cascade
- → Conversion of fibrinogen to fibrin → blood clot formation → pathological thrombosis
41
Q
Atherosclerosis & Thrombosis
A
refer to pic
- Thrombosis in brain
– stroke - Thrombosis in lower
extremities → vascular
perfusion problems - Thrombosis in heart –
coronary artery disease
(CAD) - Thrombosis in kidneys →
renal hypertension
42
Q
Transient Ischemic Attack (TIA)
A
- TIA – equivalent to “angina” of the brain, a.k.a. mini-stroke
- TIA – reversible focal brain dysfunction due to ischemia
- Transient stroke symptoms that last from seconds to hrs
- TIA is a key opportunity to prevent stroke (permanent
damage) – only 3% patients sought medical care
43
Q
TIA – Mechanisms
A
- Causes of TIA – essentially the same as those for stroke
and heart diseases
– High blood pressure
– Heart diseases (heart rhythm disturbances → turbulent flow →
clot formation)
– Narrowing of arteries (esp. carotid artery) → thromboembolic - Blood blot forms → body recognizes the presence of clot →
triggers clot dissolution mechanism → vessel reopen →
symptoms go away - After TIA, 10X the risk of ischemic stroke
– Risk is the highest in the first 48 hrs
– Risk remains high over first 3 months
– 35% stroke risk within 3-5 yr after TIA
44
Q
Types of Stroke
A
- Ischemic stroke – inadequate
blood flow (85% of stroke)
– Thrombotic ischemia
– Embolic ischemia - Hemorrhagic stroke
– Intracerebral hemorrhagic
stroke
– Subarachnoid hemorrhagic
stroke – ↑ intracranial P
45
Q
Ischemic Stroke – Thrombotic Stroke
A
- Thrombosis occurs in relation to injury to a blood vessel wall
→ blood clot
– 2/3 are associated with hypertension (HTN) & DM
– Often preceded by a TIA
*atherosclerosis is most common cause
*thrombosis- clot forms at rough or narrow artery
*complete blockage
*accounts for half of all strokes
refer to pic
46
Q
Ischemic Stroke – Embolic Stroke
A
- Embolus lodges in and occludes a cerebral artery, results in infarction and edema of the area
supplied by the vessel - Majority of emboli originate in heart, with plaque breaking off
from the endocardium and
entering circulation
– Recurrence is common unless the underlying cause is aggressively treated
47
Q
Hemorrhagic Stroke
A
- Account for approximately 15% of all stroke
- Intracerebral hemorrhage – hypertension is the most
important cause, commonly occurs during activity - Subarachnoid hemorrhage – bleeding into cerebrospinal space between the arachnoid and pia mater
48
Q
Pathogenesis of a Stroke
A
*Stenosis/occlusion/rupture of arteries
* → Interrupted blood supply to brain
* → Interrupted O2 supply
* → Neurologic deficit
– Hemiplegia; paraplegia;
monoplegia; quadriplegia
– Paresis; paralysis
– Speech impairment (dysarthria)
– Sensory impairment
– Coma
refer to pic
49
Q
Pathophysiology – Stroke and Glutamate Excitotoxicity
A
- Stroke → ↑ ↑ ↑ glutamate release → overstimulation of glutamate R (esp. NMDA R) → …→ neurodegeneration &
neuronal damage
50
Q
Glutamate Excitotoxicity – Glutamate
A
- Structure – functional group = CH2CH2COOH
- Glutamate
– The most prominent NT in the body
– The brain’s main excitatory NT, present
in over 50% of nervous tissue
– Is the precursor for γ-aminobutyric acid (GABA), the brain’s main inhibitory NT - Functions
– Neurons’ postsynaptic excitation
– Memory formation, learning, and regulation
51
Q
Glutamate Excitotoxicity – Receptors
A
- Glutamate receptors (R)
are synaptic R - Glutamate released into synaptic cleft
– → Binds to glutamate R on
postsynaptic membrane - Glutamate-R binding:
– → Activation of glutamate R
– → Opens ion channels coupled to R
– → Allows extracellular Ca2+ pass into the intracellular cytosol
– → Triggers a series of
biochemical events
too much glutamate released causes excitation of post synaptic neuron
52
Q
Stroke and Glutamate Excitotoxicity
A
- Stroke → ↑ ↑ ↑ glutamate release → overstimulation of glutamate R (esp. NMDA R) → high levels of Ca2+ influx the postsynaptic neurons → excitotoxicity → neurodegeneration &
neuronal damage - (Exp.) This cell death is blocked by antagonists of NMDA R
53
Q
Stroke, Excitotoxicity and Cytokines
A
- Initial ischemic event → excitotoxicity → microglia, astrocytes activated & ↑ neutrophil infiltration → secrete cytokines & matrix metalloproteases → neuronal death
54
Q
Stroke, Excitotoxicity and Free Radicals
A
- Initial ischemic event → excitotoxicity → ↑ reactive oxygen stress (free radicals):
– → endothelial cell injury → disruption of BBB → ↑ inflammation… → ↑ neuronal death → cerebral damage
55
Q
Acute Stroke Treatments
A
- Ischemic stroke (brain clot)
– Clot busting medication – t-PA
– Endovascular thrombectomy - Merci Retriever
- Solitaire FR device
- Question – what is the rationale of treating with tPA?
- Hemorrhagic stroke (brain bleed)
– Clipping
– Coiling
56
Q
Fibrinolysis – the Breakdown of a Clot
A
- Fibrinolysis (removal of clot) is a normal process after damaged vessel is repaired
- Plasminogen – produced in liver (inactive) → blood
- Plasminogen activators (PAs) convert plasminogen into plasmin (active):
- Plasmin → fibrin degradation
if not hemorrhagic stroke, use plasminogen activator to treat
57
Q
Plasminogen Activators
A
- Tissue plasminogen activator (tPA) – released into blood very slowly (days) by the damaged endothelium
- Urokinase – produced in kidney for degradation of fibrin clots within renal tubules
- Bacterial plasminogen activators – with concern of side effects
- tPA can be used as “clot buster drugs” for treating heart attack & stroke
- Plasmin → fibrin degradation
– Plasmin is a protease which degrades fibrin, fibrinogen, V,
VIII, complements, and some polypeptide hormones
58
Q
Coagulation and Fibrinolysis
A
refer to pic
59
Q
Endovascular Thrombectomy
A
- Merci Retriever
– Grab the clot with device,
pull it out and reopen the
blood vessel - Solitaire FR device
– Same mechanism just
work much better
60
Q
Hemorrhagic Stroke – Treatment
A
- Clipping
- Coiling – through a catheter the small soft coils are
introduced into the aneurysm to block it completely
