Lecture 7 - Ischemic Heart Disease

What governs blood pressure and blood flow dynamics?

interactions between cellular components of the arterial wall

What does the adventitia help with?

structure and anchor

What does the media help with?

mechanical stimuli

What does the intima help with?

blood flow exposure

What is the function of the endothelium?

• forms a selectively-permeable barrier (blood-tissue exchange)

• produces antithrombotic molecules (prevents clotting)

• secretes substances modulating vascular tone

• inhibits smooth muscle cell migration/proliferation in the intima

• helps in the inflammatory response

What is atherosclerosis?

injury to the endothelium

What are the types of theories of endothelial injury?

• physical forces

• toxic chemical environment

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What are the physical forces of endothelial injury?

arterial branch points disturb laminar flow

What are the toxic chemical environments of endothelial injury?

• smoking

• hyperlipidemia

• hypertension

What does laminar flow create?

low shear stress environment

What is a low shear stress environment?

force exerted by blood against the endothelium

What are lipoproteins?

molecules that transport lipids in circulation

What are the 3 types of lipoproteins?

• high density

• low density

• very low density

What is the atherogenic property of high density lipoprotein?

anti-atherogenic

What is the atherogenic property of low density lipoprotein?

pro-atherogenic

What is the atherogenic property of very low density lipoprotein?

pro-atherogenic

What type of cholesterol is high density lipoprotein?

good

What type of cholesterol is low density lipoprotein?

bad

What type of cholesterol is very low density lipoprotein?

bad

What are the 3 stages of lipoprotein stages?

• entry and modification

• recruitment

• foam cell formation

What are the steps to lipoprotein entry and modification?

• activated endothelium has increased permeability

• LDL accumulates in subendothelial space, binding to proteoglycans of the extracellular matrix

• trapped LDL stays for a long time, promoting chemical modification

• LDL is oxidized

• modified LDL promotes leukocyte recruitment and foam cell formation

What is LDL oxidized by?

• ROS

• pro-oxidant enzymes

What are the steps of leukocyte recruitment?

• modified LDL induces endothelial expression of leukocyte adhesion molecules/chemoattractant signals

• chemoattractant signals direct monocytes/T cells to the endothelial surface

• leukocyte-adhesion molecules bind leukocytes

• leukocytes enter the subendothelial space along the chemoattractant gradient

• monocytes differentiate into macrophages within the subendothelial space

What are the stages of leukocyte recruitment?

• margination

• adhesion

• transmigration

What is the margination stage?

chemoattractant signals direct monocytes/T cells to the endothelial surface

What is the adhesion stage?

leukocyte-adhesion molecules bind leukocytes

What is the transmigration stage?

leukocytes enter the subendothelial space along the chemoattractant gradient

What are the steps of foam cell formation?

• ingestion by ‘scavenger receptors’ evading feedback inhibition (don’t stop eating)

• macrophages become engaged with modified LDL

• lipid-laden macrophages are called foam cells

• accumulation of foam cells is called a fatty streak

What is a fatty streak?

an accumulation of foam cells

How do atherosclerotic plaques progress?

remains stable or regresses

Does a fatty streak disturb laminar flow?

no

Does a fatty streak cause symptoms of ischemia?

no

What colour are fatty streaks?

yellow and white

Where do fatty streaks exist?

• aorta

• coronary arteries

What promotes plaque progression?

vascular smooth muscle cells

Where do the fatty streaks mainly occur?

intima

What are the 3 steps of fatty streaks becoming fibrous plaques?

• migration

• proliferation

• secretion

What is the migration stage of fatty streak to fibrous plaque?

vascular smooth muscle cells go from the media to the injured intima within the subendothelial space

What is the proliferation stage of fatty streak to fibrous plaque?

vascular smooth muscle cells grow within the intima

What is the secretion stage of fatty streak to fibrous plaque?

fibrous connective tissue is released by the vascular smooth muscle cells

What drives VSMC migration and proliferation?

• chemokines/cytokines

• activated platelets

• endothelial cells

What are fibrous plaques made of?

• VSCM mass

• accumulated leukocytes

• foam cells

• fibrous cap of extracellular matrix

What is the fibrous cap made of?

collagen secreted by the VSMC

What happens during early plaque formation?

compensatory outward remodeling of arterial wall

What does the arterial wall preserve?

• vessel diameter

• blood flow

What happens when plaque growth continues?

• outstrips compensatory remodeling

• restricts vessel diameter

What are atherosclerotic plaques?

fibrous cap structures that help keep the plaque stable and intact

What are the types of atherosclerotic plaques?

• stable

• unstable/vulnerable

What are stable plaques?

thick fibrous caps with a small lipid core

What are unstable plaques?

thin fibrous caps with a rich lipid core

Are stable plaques more likely to rupture?

no

Are unstable plaques more likely to rupture?

yes

What are stable plaques associated with?

vessel narrowing

What are unstable plaques associated with?

thrombosis

What is thrombosis?

forming of a blood clot

What are common causes of plaque ruptures?

• hemodynamic shear forces

• vasoconstriction

• circulating substances

What happens when a blood clot forms at a rupture?

• mixes in with plaques

• partially protrudes into vessel lumen

What are the outcomes of blood clots forming?

• ruptures heals

• myocardial infarction

What do rupture heals look like?

• narrowed vessel lumen

• fibrous intima

What do myocardial infarctions look like?

• blood flow occluded locally by clots (ischemia forms)

• embolism

What is an embolism?

clots dislodging and blocking flow at a different location

What is myocardial ischemia?

an imbalance between myocardial oxygen supply and demand

When do myocardial ischemias normally occur?

exercise

What do myocardial ischemias come from?

• fixed vessel narrowing

• endothelial dysfunction

What is an example of fixed vessel narrowing?

presence of a plaque

What is an example of endothelial dysfunction?

reduced dilation capacity

What are the factors of myocardial oxygen supply?

• oxygen content

• coronary blood flow

What are the factors of myocardial oxygen demand?

• wall stress

• heart rate

• contractility

What are the factors of coronary blood flow?

• perfusion pressure

• vascular resistance

What are the factors of vascular resistance?

• external compression

• intrinsic regulation

Where can fixed vessel narrowing occur?

• heart

• distal/proximal coronary arteries

Where do large and proximal coronary arteries lie?

heart’s surface

Where do smaller and distal resistance vessels lay?

myocardium

Which vessels are subject to develop plaque?

large coronary arteries

Whcih vessels dilate easily to meet metabolic demands?

small resistance vessels

How much does the lesion diameter have to be before plaque develops?

90%

How much does the lesion diameter have to be before it feels ischemic?

70%

How does abnormal endothelial dysfunction contribute to pathophysiology of ischemia?

• inappropriate constriction of coronary vessels

• loss of normal antithrombotic properties

What is not produced during vasoconstriction?

nitric oxide

What is sympatholysis?

increase in sympathetic activity

What happens during inappropriate vasoconstriction of coronary vessels?

vasodilators are not released so there is less constriction

What marks coronary artery vasodilation in healthy vessels?

physical activity

What happens during the loss of normal antithrombotic properties?

endothelial-derived factors are not released as much so the effect is reduced

What marks the loss of antithrombotic properties in healthy vessels?

factors released from the endothelium, interfering with platelet aggregation

What happens during impaired releases of nitric oxide/prostacyclin?

platelets aggregate and secrete substances

What substances do platelets secrete?

• procoagulants

• vasoconstrictors

What does the myocardium rely on in relation to ischemia?

severity and duration of imbalance

What are the different fates of myocardium?

• ischemic

• stunned

• hibernating

• myocardial infarction