Atherogenesis & Coronary Artery Disease (incl O2 demand+supply) Flashcards
How do most of Acute Coronary Syndromes (ACSs) occur?
Over 90% of ACLs happen due to disruption of an atherosclerotic plaque -> platelet aggregation + formation of thrombus -> narrowing or complete occlusion of coronary arteries -> impaired blood flow -> lack of O2 to satisfy myocardial demand
What is the name of a partially occluded thrombus in the myocardium?
Unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI).
NSTEMI = non-Q-wave MI.
NSTEMI = unstable angina + myocardial necrosis
What is NSTEMI?
Non-ST-elevation myocardial infarction (NSTEMI)
NSTEMI = non-Q-wave MI.
NSTEMI = unstable angina + myocardial necrosis
NSTEMI = partial occlusion of coronary vessel
What do you call a partial occlusion of coronary vessel with accompanying myocardial necrosis?
NSTEMI - non-ST-elevated myocardial infarction
What is STEMI?
STEMI = ST-elevation myocardial infarction
STEMI is present when the thrombus completely obstructs the coronary artery - severe ischemia and more necrosis then in NSTEMI = Q wave MI
Name the condition in which a thrombus completely obstructs coronary artery, leading to severe ischemia and significant amount of myocardial necrosis?
STEMI is present when the thrombus completely obstructs the coronary artery - severe ischemia and more necrosis then in NSTEMI = Q wave MI
Describe renin-angiotensin-aldosterone system?
angiotensinogen (LIVER)
l <- renin (KIDNEY)
angiotensin I
l<- ACE converting enzyme (LUNGS)
angiotensin II
angiotensin II in turn:
increases sympathetic activity
increases tubular reabsorption of Na+, Cl-, increases K+ exretion => water retention
encourages adrenal cortex to produce aldosterone (which again leads to increased tubular reabsorption of Na+ and water retention)
increases arteriolar vasoconstriction and so increases blood pressure
influences pituitary to increase ADH secretion -> increases H2O reabsorption in collecting duct
ACE (angiotensin converting enzymes) also convert bradykinin into inactive form. Bradykinin is a vasodilator (but produces cough). Therefore, ACE inhibitors stop vasodilation by preventing bradykinin inactivation. ACE inhibitors also block conversion of angiotensin I into angiotensin II. Angiotensin II is a direct vasoconstrictor, so ACE inhibition drugs block vasoconstriction.

What are the three layers of arterial wall?
intima - closest to arterial lumen
media - elastic, thick, contains smooth muscle cells that can stretch and recoil
adventitia - external, has nerves, blood vessels and lymphatics

what is vasa vasorum?
vasa vasorum is a network of tiny blood vessels that supply large blood vessels
What is intima?
intima = one of the three layers of the artery, closest to lumen.
single layer of endothelial cells, metabolically active (produces antithrombotic elements,etc can produce thrombotic elements in stress, produces substances to change contraction of smooth muscle cells in media)
barrier btwn blood and the vessel wall
What is media?
media = one of the layers of arterial wall
media is the thickest layer of the artery
elastin - smooth muscle + extracellular matrix- elastin
elastic component more prominent in big arteries (ex. aorta) to help stretch during high pressure systole and recoil during diastole, moving blood
more smooth muscle in smaller arteries to change vessel resistance (and flow)
extracellular network is produced by smooth muscle cells
collagen = strengths, proteoglycans + elastin = flexibility
what is adventitia?
adventitia = external layer of artery, contains blood vessels (vasa vasorum), nerves, lymphatics
What is the formula for flow?
flow = pressure/resistance
In healthy arteries, which cells regulate nonthrombogenic, vasodilatory and anti-inflammatory properties?
endothelial cells from intima layer can produce
- antithrombotic molecules that sit on surface of intima (heparan sulfate, thrombomodulin, plasminogen activators)
- antithrombotics that enter circulation =prostacyclin and NO
- can produce thrombotic molecules during stress
- substances that can modulate contraction - NO, prostacyclin (in circulation, vasodilatory) and endothelin (vasoconstrictory)
- vasodilatory substances predominate in healthy endothelium -> net smooth muscle relaxation
- some of the vasodilators above prevent smooth muscle from traveling and multiplying in intima
- healthy endothelium resists leukocyte adhesion = opposes local inflammation
- in inflammation, postcapillary venules release chemokines - WBC attracted to the area -> endothelial cells produce cell surface adhesion molecules that anchor leukocytes to endothelium to migrate to site of injury. endo cells use KLF2 - Kruppel-like factor 2 = gene regulator in endothelial cells to help this adhesion

What properties do smooth muscle cells in arterial wall have?
- contractile function (regulated by things like angiotensin II, endothelin and NO from endothelial cells, acetylcholine from nerve terminals)
- produce collagen, elastin and things that form extracellular matrix
- CAN synthesize IL-6 and tumor necrosis factor alpha, which promote leukocyte formation and expression of leukocyte adhesion molecules
What are the three general stages of atherosclerotic inflammatory process?
fatty streak (normal)
plaque progression
plaque disruption

What is fatty streak?
fatty streak = earlieast visible atherosclerosis
areas of yellow discoloration on arterial inner surface
exist in aorta and coronary arteries of most people by age 20, do not cause symptoms, but in some locations become worse over time
thought to be due to endothelial dysfunction that allows entry and modification of lipids into subendothelial space, where they start inflammation process, inviting leukocytes to the party and becoming foam cells

Provide a rough outline of how fatty streak forms? Focus on injury to arterial endothelium
- injury to arterial endothelium
can be due to chemical irritants (tobacco, abnormal lipid levels, high glucose (risk factors!!!). these irrinats also increase endothelial production of reactive oxygen species - promotes inflammation
physical forces (hemodynamic stress, turbulent flow - high blood pressure (risk factor!!!))
branch points are more predisposed - more turbulent flow, compared to laminar flow in straight sections (laminar flow activates NO and KLF-2, accentuates antioxidant production, etc)
=> common carotid and left coronary artery have lots of branches and are more likely to have atherosclerosis
So what?
endothelial function interrupted - can no longer function as good permeability barrier, releases inflammatory cytokines, increases production of cell survace adhesion molecules for leukocytes to bind, reduced release of vasodilators like NO -> less antithrombotic properties.
- lipoprotein entry into intima (especially LDL = bad lipid), once in intima LDL accumulates in subendo space by binding to proteoglycans and undergoes modification (oxidation via ROS or glycation in diabetis)
- inflammation = leukocyte recruitment
- monocytes -> macrophages -> eat lipids and become foam cells

OPTIONAL: What on earth is KLF-2?
KLF2 expression is induced by fluid laminar flow shear stress, as is caused by blood flow in normal endothelium.
KLF2 then has four key functions in endothelium:
By inhibiting activation of p65 by transcription coactivator p300, VCAM1 and SELE expression is downregulated, genes that encode endothelial cell adhesion molecules, causing decreased lymphocyte and leukocyte activation and hence decreasing inflammation
It upregulates THBD (thrombomodulin) and NOS3 (endothelial nitric oxide synthase) expression, having an anti-thrombotic effect
Through the upregulation of NOS3, as well as NPPC (natriuretic precursor peptide C), KLF2 has a vasodilatory effect
KLF2 also inhibits VEGFR2 (VEGF receptor 2) expression, having an anti-angiogenic effect
Thus KLF2 has an important role in regulating normal endothelium physiology. It is hypothesized that myeloid-specific KLF2 plays a protective role in atherosclerosis.
Provide a rough outline of how fatty streaks form. Focus on lipoprotein entry and modification?
- injury to arterial endothelium
- lipoprotein entry into intima (especially LDL = bad lipid), since endothelium injured. Once in intima LDL accumulates in subendothelial space by binding to proteoglycans (components of extracellular matrix) and undergoes modification (oxidation via ROS or glycation in diabetis). Hypertension promotes retension of LDLs in the intima by increasing production of LDL-binding proteoglycans by SMC (smooth muscle cells)
Modifications of LDL contribute to inflammation -> leukocyte recruitment, especially glycosylated LDL, which now has antigenic properties.
- inflammation = leukocyte recruitment
- monocytes -> macrophages -> eat lipids and become foam cells
Describe the steps in fatty streak formation, focus on inflammation and leukocyte recruitment ; foam cell formation
- injury to arterial endothelium
- lipoprotein entry into intima (especially LDL = bad lipid), since endothelium injured. Modification of LDL, such as glycosylation of LDL ->antigenic properties ->
- inflammation = leukocyte recruitment
process depends on expression of leukocyte adhesion molecules on endothelial surface (normal endo does not express) and proinflammatory cytokines, stimulated by mLDL (modified LDL)
- monocytes -> macrophages -> eat lipids and become foam cells -> accumulation of plaque, lipid rich center of plaqye forms necrotic foam cells -> foam cell apoptoss and release of more proinflammatory cytokines.
Describe plaque progression?
not all fatty streaks progress into plaque. early plaque shows a compensatory outward remodelling of the arterial wall that preserves the diameter of the lumen and permits plaque accumulation without limiting blood flow => no ischemic symptoms (may not be seen on angio). late plaque can no longer compensate and will show on angio.
fatty streak turns into athero plaque when smooth cells migrate from media to intima, proliferate within it and produce extracellular matrix.
smooth cells migrate b/c foam cells produce cytokines such as TNF alfa, ILs,e tc and platelet-derived growth factor (PDGF).
smooth muscle cells favour fiber growth and so contribute to formation of fibrous cap around atherosclerosis. unfortunately, inflammatory cytokines stimulate local foam cells to secrete colagen and elastin-degrading matrix metaloproteinases, which weaken fibrous cap and predispose it to rupture

Describe plaque disruption?
Disrupted plaque integrity
tug of war between matrix synthesis and degradation (smooth muscle cells produce, MMPs from foam cells degrade)
size of plaque has influences on stability. with increasing size into lumen, stress on plaque border increases. also as size increases, necrosis and degradation of extracellular matrix (via inflammatory proteins) increases, making region more vulnerable to rupture.
thick fibrous caps are thought of more stable plaques, those with thin fibrous caps are called vulnerable plaque.
Thrombus formation
small thrombi may reabsorb into the plaque, encouraging more smooth muscle growth and fibrous content. others can dislodge and clot arteries.

Describe the difference between “stable” plaque and “vulnerable” plaque?
- Stable plaque - small pool of lipid, thick fibrous cap, good size lumen
- Vulnerable plaque - large pool of lipid, thin fibrous cap, many inflammatory cells
- ruptured plaque can heal, causing narrowed lumen and more fibrous intima or can cause acute MI












