PATH - Arteriosclerosis

arteriosclerosis where there is necrotising arteriolitis/ fibrinoid necrosis (describes the combination of fibrin and necrosis of endothelial cells)->Smooth muscle cells proliferate RAPIDLY.

hyperplastic arteriosclerosis

Pathogenesis is by smooth muscle hyperplasia due to acute moderate to severe hypertension->may lead to necrotizing arteriolitis/fibrinoid necrosis of vessels

hyperplastic arterosclerosis

Dystrophic calcification of Tunica media of small to medium-sized muscular arteries->largely sparing the intima and adventitia. Causes Vessels to become stiff and pulse pressure may increase.

monkeberg's aterosclerosis

The femoral, tibial, radial, and ulnar arteries and arteries of the genitalia are most commonly involved, typically after 50 years of age->Vessel becomes stiff and pulse pressure may increase.

monkeberg's aterosclerosis (dystrophic calcification)->Affects tunica media.

Pathogenesis of in Hyaline arteriosclerosis in KIDNEY: Benign ( )->endothelial ( ) ->( ) arteriosclerosis in kidney ->Decreased ( ) supply -> loss of functioning ( ) units. Finely ( ) appearance to the kidney surface

-Benign HTN (>140/90 mmHg)->benign nephrosclerosis -endothelial dysfunction -Hyaline arteriosclerosis -blood -nephrons -granular

Response to Injury Hypothesis: Chronic ( ) response of the arterial wall initiated by some form of injury to the ( ) usually due to longstanding benign or malignant ( ).

-Chronic inflammatory -endothelium -hypertension

Pathogenesis of atherosclerosis: ( ) cell ->dysfunction -> ( ) and ( ) accumulation -> foam cell formation -> fatty streak -> further endothelial damage and ( ) infiltration -> ( ) migration to intima and proliferation -> ( ) elaboration -> fibrous plaque -> complex atheroma (necrotic area of aorta with [ ] deposition and contraction of the [ ] cap) -> rough wrinkled appearance.

-Endothelial -macrophage -LDL -monocyte -SMC -ECM -calcium -fibrous

Pathogenesis hyperplastic arteriosclerosis: ( ) damage (necrosis) usually from longstanding ( ) hypertension->Increased ( ) of vessel wall->MASSIVE leakage of ( ) components (lots of [ ]) across the ( ) and deposition within the ( )->CONSEQUENCES: ( ) arteriolitis/ fibrinoid ( ) (Describes the combination of ( ) on endothelial cells)-> ( ) cells proliferate RAPIDLY : Responsible for onion skin ( ). Acute lumen narrowing means no time for ( ).

-Endothelial -Increased permeability of endothelium -plasma -fibrin -endothelium -vessel wall -Necrotising arteliotis -fibrinoid necrosis -fibrin and necrosis on EC -Smooth muscle -thickening -atrophy

Arteriosclerosis associated with benign hypertension caused by renal retention of ( ) -> increased ( ) volume -> increased ( ) output->increased blood pressure->endothelial ( )->increased permeability of vessel wall->leakage of ( ) ->deposition of ( ) occludes the lumen->proliferation of ( ) in vessel wall->hyaline thickening

-Hyaline arteriosclerosis -sodium -intravascular blood fluid volume -cardiac -endothelial dysfunction -increased enothelial permeability -deposition of fibrin occludes the lumen -proliferation of SMC -hyaline thickening

95% of cases of hyaline or hyperplastic arteriosclerosis are caused by Primary/ Essential ( ) which may be from increased peripheral ( ), or can be hormonal, neural, genetic, life style (Multifactorial/ Idiopathic). About 5-10% are due to Secondary ( ) which may be of Renal, Endocrine, Vascular, or Neurogenic origin. In some cases there is a known abnormality causing the secondary ( ) such as: Increased blood volume (d/t Sodium retention from oversecretion of [ ] or [ ]) -Increased sympathetic tone d/t ( ) tumors -Increased vasoactive hormones from ( ) disease or ( ) (adrenal cortex tumor).

-Hypertension -resistance -Hypertension -hypertension -ADH, Aldosterone -adrenal tumors -Cushing's, disease -Pheochromocytoma

Atherosclerosis is Chronic inflammatory disorder of the TUNICA ( ) of large arteries ->Characterized by the formation of fibro fatty ( ) called ( ) forming a raised lesion with a soft, yellow core of ( ) (mainly cholesterol and cholesterol esters) which can ultimately protrude into the lumen of the vessel. ( ) are characterized by progression of fatty streak to formation of fibromuscular cap between the vessels lumen and the constituents of the mature plaque. The Fibromuscular cap forms from ( ) and often undergoes ( ). Increased severity of atheroma is often correlated to high levels of ( ).

-INTIMA -plaques -atheromas -lipid core -modified smooth muscle cells -calcification (dystrophic) -LDLs and cholesterol

familial hypercholesterolemia creates predispostion to atheroma fomation d/t defective ( ) receptor which decreases hepatic uptake of ( ) which causes increased circulating levels. The exact defect involves an abnormal ( ) protein which cannot bind to ( )->decrease hepatic uptake of cholesterol

-LDL (lipoprotein receptor on hepatocytes) -LDL -Apo E -LDL

( ) is etiologic for atherosclerosis because it is an altered form of LDL which can cause ( ) accumulation, ( ) cell modification, ( ) proliferation and also controls ( ) (formation of functional microvascular networks with RBC perfusion from scratch unlike angiogenesis which is from pre‐existng blood vessels)

-Lipoprotein A -lipid -endothelial -SCM -neo‐vascularization

Structural homology of ( ) to ( ) features similar areas are called kringles because they resemble a type of Danish pastry-> allows for competition of ( ) with ( ) for clots thus preventing the ability of the latter to form ( ) and clear clots->predisposes development of ( ).

-Lipoprotein A to plasminogen -Lipoprotein A -plasminogen->prevented from converting into plasmin by competirion from Lipoprotein A -atherosclerotic plaques (atheromas)

( ) is a complication of ( )arteriosclerosis that is characterized by deposits of fibrinoid and acute necrosis of the vessel wall->Causes reduced vessel ( )-> end organ ( ).

-Necrotizing Arteriolitis/fibrinoid necrosis -hyperplastic arteriolosclerosis -reduced vessel calibure -end organ ischemia

( ) stimulates recruitment and proliferation of smooth muscle cells in atherosclerosis. ( ) from ( ) transform the normally anticoagulant endothelial surface into a procoagulant surface by stimulating endothelial cells to produce ( ) factor, ( ) factor, and ( ) inhibitor.

-PDGF from macrophages -TNF and IL-1 from macrophages -platelet activating factor (PAF) -tissue factor (TF) -plasminogen activator inhibitor (PAI)

A ( ) usually forms on ruptured plaque lesions and may partly or completely occlude the lumen. These form because of exposure of the ( ) core of the atheroma which activates the ( ) cascade. Plaque rupture is more likely with ( ) atherosclerotic plaques. Major consequences include ( ).

-Superimposed thrombosis -necrotic core of plaque -coagulation cascade -unstable -infarction, ischemia, aneurysms, peripheral vascular disease (gangrene of legs), emboli

STABLE ATHERSCLEROTIC PLAQUE: ( ) fibrous cap that obstructs the whole lumen (>75%) owing to marked ( ) proliferation. Decreased blood flow -> decreased ( ) stresses. Entire ( ) of vessle involved - concentric and thus no shoulders. Deficient in ( ) cells w/ ( ) necrotic core. UNSTABLE ATHERSCLEROTIC PLAQUE: ( ) fibrous cap that obstructs 50-75% of the lumen- less evidence of ( ) proliferation. Increased blood flow -> increased ( )stresses -> likely to rupture. Eccentric - not uniform around the vessel ( ) and has shoulders. Rich in ( ) cells: (foam cells) and ( ) cells. Also rich in ( ), Can see needle shaped cholesterol crystals - ( ) necrotic core.

-Thick -smooth muscle -hemodynamic -circumference -inflammatory -smaller necrotic core -Thin -smooth muscle -haemodynamic -circumference -inflammatory -macrophages -T cells -metalloproteinase -larger

Deep to the fibrous cap of a ( ) is a ( ) core, containing lipid (primarily ( ) and ( ) esters), debris from dead cells, foam cells (lipid‐laden ( )), fibrin, variably organized ( ) cells which migrated from media, and other plasma proteins.

-complex atheroma -necrotc -cholesterol and cholesterol -macrophages -SMCs -thrombus

Genetc or acquired diseases that can lead to premature and severe artherosclerosis.

-diabetes mellitus -hypothyroidism -Familial hypercholesterolemia

Normal muscular arteries have little elastic tissue limited only to the internal and external ( ). The tunica ( ) contains smooth muscle cells. In ELASTIC arteries, Tunica ( ) is composed mainly of elastic fibres->( ) propels the blood downstream. Examples include: aorta and its branches.

-elastic lamina -Tunica media -media -Elastic recoil

IFN-alpha and Transforming growth factor (TGF) form macrophages inhibit ( ) proliferation causing failure of ( ) to repair ( ) defects, which in turn provides entry areas for ( ) and ( ) and serves as an area where thrombi are formed.

-endothelial cell -endothelial cells -endothelial -lipoproteins and plasma-derived factor

Minor risk factors for atherosclerosis include: -postmenopausal ( ) deficiency, -( ) fat intake -Inhibitors of fibrinolysis (e.g. Low [ ] ) -High ( ) diet and -( ) pneumonia are all risk factors for

-estrogen -Trans‐unsaturated -low PA‐1 inhibitor -carbohydrate diet -Chlamydia

Precursor lesion seen in atherosclerosis is the fatty ( ) formed when fatty dots coalesce. Composed of lipid laden ( ), ( ) lymphocytes and some extracellular lipid that are found within the sub-( ) of vessel wall.->located around ostia because of increased ( ) flow hence endothelial cells are under greater stress at these points. Not all ( ) are destined to become athermoas. In fact, fatty streaks are seen in all children older than 10 years

-fatty streak -macrophages -T lymphocytes -subendothelium -turbulent -fatty streaks

( ) are precursor lesion to plaque, however, they DO NOT constitute ATHEROSCLEROSIS!! They form from coalescence of ( ) (multiple Yellow Fat less than 1 mm in diameter)->form a streak greater than 1 cm->Composed of ( ) cells and some extraceullar ( ).Seen somewhere in all children older than 10 years.

-fatty streaks -fatty dots -foam cells and some extracellular lipid

The intimal surface of atherosclerotic aorta is roughened, nodular, and wrinkled. This is due to contraction of the ( ) cap over the ( ) areas, together with the deposition of ( ) (the nodules). These changes would render the aorta almost totally ( ).

-fibrous -necrotic -calcium (dystrophic calcifications?)->inelastic

( ) promotes premature vascular disease caused by vitamin B intake and folate deficiency ([ ] anemia); involves Plasma ( ) (amino acid): leads to formation of ( ) which cause lipid ( ), ( ) oxidation, Proliferation of ( ) of tunica media, and endothelial dysfuncton → Atherosclerosis

-hyperhomocystinuria -megaloblastic -Homocysteine -ROC -peroxidation -LDL oxidation -SMCs

Risk factors of atherosclerosis: 1) Increased cholesterol defined as( ) levels 2) ( ) will create a 5-fold increase in Ischemic Heart Disease from ( ) (usually after age 45) 3) Disease which, when combined with increased cholesterol, creates 100-fold increased risk of AS-> induced gangrene of lower extremity; also increases risk of MI and Stroke (Altered Metabolism). 4) Higher incidence in post-menopausal women, possible response to ( )

-hyperlipidemia: defined as high LDL or low HDL -Hypertension -diabetes mellitus -Hormone Replacement Therapy (HRT)

Causes of endothelial cell dysfunction (predisposing thrombosis)

-hypertension, turbulent blood flow, bacterial endotoxins (e.g. LPS or LOS)

In which vessels does ATHEROsclerosis occur? Where do the fibrous plaques form?

-large vessel -Fibrous plaques and atheromas in intima -intima

Endothelial Injury leads to Activation of endothelial cells-> increased ( ), increased adhesion of ( ), increased expression of ( ) molecules and activation of ( ) factors. Lipids are ( ) to endothelium and when ( ) have atherogenic properties, including being chemotactic for more ( ). Lipids also inhibits the motility of ( ) already in lesion ->stimulates release of ( ).

-permeability -leukocytes -adhesion -growth factors -Cytotoxic -oxidized -monocytes -macrophages -growth factors and cytokines

Rarely will you have atherosclerosis in the ( ) circulation because this is a low pressure system and ( ) is rarely tolerated for the length of time required to form atheromas. However, the case of prolonged ( )(Eisenmenger's complex etc) there may be concurrent atherosclerosis.

-pulmonary -hypertension -hypertension

Arteriolosclerosis is characterized: -narrowing of ( ) -Divided into two types: ( ) (protein deposition) and ( ) ("onion skinning") arteriosclerosis -may or may not involve full thickness of vessel ( ) -Occludes the ( )

-small arterioles -hyaline and hyperplastic arteriolosclerosis -concentric or eccentric -lumen of vessel

What are the histological difference between stable and unstable atherosclerotic plaques with regard to fibrous caps and necrotic areas?

-stable: thick fibrous cap and, small necrotic area, and thin cholersterol crystals -unstable: thin fibrous cap, large necrotic area, and thin cholesterol caps

Two causes of damage to endothelium predisposing thrombis formation

1) Physical endothelial damage/injury 2) endothelial cell dysfunction

1) chemotactic for circulating monocytes, inhibits motility of macrophages already in the lesion, stimulates release of growth factors and cytokines 2) Play pivotal role in conversion of fatty streak into fibrofatty atheroma

1) Role of Lipids in pathogenesis of atherosclerosis (plaque formation) 2) SMC proliferation

1) lesion which implies that there is a portion of the vessel wall that is devoid of any atheroma formation 2) Portion of atheroma (plaque) composed of SMCs and relatively dense collagen.

1) eccentric lesion 2) fibrous cap (or fibromuscular cap)

Complication of atherosclerotic plaques that 1) can lead to thrombus formation, cholesterol emboli or atheroemboli = needle shaped clefts 2) can increase size of block 3) caused by atrophy of underlying media often secondary to impaired oxygen diffusion across the layers of the vessel wall 4) characterized by claudication - hardening of arteries in legs/feet 5) caused by mesenteric occlusion-> gangrene

1) focal rupture or gross ulceration or both 2) hemorrhage 3) aneursymal dilations 4) peripheral vascular disease (PAD) 5) ischemic bowel disease

1) Cells contained in atherosclerotic plaques 2) Portion of vascular wall composed of collagen, elastic fibers, and proteoglycans

1) macrophages (converted from migrated monocytes), SMC, leukocytes, foam cells 2) ECM

1) When is monkeberg's aterosclerosis associated with any actual symptoms? 2) What type of change (injury) does this represent? 3) Which layers of vessel are affected and in which vessels? 4) When can it lead to arterial stiffness or poorer prognosis or disease? 5) Which medical conditions increase the frequency of monkeberg's in their patients?

1) not associated with symptoms unless complicated by arterioloscerosis (particularly atheroscelrosis) calciphylaxis, or accompanied by some other disease 2)Tunica media of small to medium-sized muscular arteries->largely sparing the intima and adventitia. 3) dystrophic calcification without associated inflammation,->Affects tunica media. 4) if arteriosclerosis is also present 5) Diabetes mellitus, chronic renal disease, SLE, chronic inflammation, hypervitaminosis D

Composed of smooth muscle cells, macrophages and other leukocytes -> ECM (collagen, elastic fibers and proteoglycans) -> intracellular and extracellular lipid deposits)

Atherosclerotic plaque

What role can diabetes play in the pathogenesis of hyaline arteriosclerosis?

Causes non-enzymatic glycosylation of basement membrane of endothelium->increased permeability, etc.....

Formed by progression of fatty streak to formation of fibromuscular cap between the vessels lumen and the constituents of the mature plaque.

Complex atheroma (advanced/complicated atheroma)

Physical damage to endothelium

Endothelial damage/injury (DIFFERENT from endothelial cell dysfunction)

Located around ostia because of increased turbulent flow hence endothelial cells are under greater stress at these points

Fatty streaks->seen in all children 10 years and older

cause ROS -> endothelial dysfunction, proliferation of vascular smooth muscle cells, lipid peroxidation, oxidation of LDL -> atherothrombosis

Homocysteine (hyper-homocystinuria)

Microscopic morphology: arterioles are narrowed by homogenous pink (hyaline) deposits in the walls

Hyaline arteriosclerosis

Minor risk factor for artheroscelorosis of the aorta which causes premature vascular disease often because of low folate and vitamin B.

Hyperhomocystinaemia

Microscophy: Onion-skin ,concentric, laminated thickening of the walls of arterioles causing progressive narrowing and obliteration of lumens

Hyperplastic arteriosclerosis (same microscopic changes seen in malignant nephrosclerosis form hyperplastic arteriolosclerosis)

Atherosclerosis in order of location

In order of frequency 1) Abdominal aorta 2) coronary artery 3) popliteal artery, femoral artery, thoracic aorta 4) Internal carotid artery 5) Circle of Willis

Structural homology allows for competition with plasminogen for clots thus preventing the ability of the latter to form plasmin and clear clots

Lipoprotein A->atherosclerosis

Etiology and Pathogenesis Flea bitten kidney (malignant nephrosclerosis)

Malignant HTN->hyperplastic arterioloscerosis->laminated thickening of the walls of arterioles causing progressive narrowing and obliteration of kidney lumens->glomerulosclerosis and nephrosclerosis ->Microscopy: Onion-skin ,concentric, hyperplastic arteriosclerosis

Arteriosclerosis that: -Occurs in muscular arteries esp. renal and ulnar -Dystrophic calcification of tunica media -Does not occlude the lumen

Medial calcific sclerosis a.k.a. Mockenberg sclerosis

Growth Factors released by macrophages which promote SMC proliferation and ECM elaboration.

PDGF, FGF, TGF‐a

Also rich in metalloproteinase, Can see needle shaped cholesterol crystals - larger necrotic core

Unstable atheroma plaque

Characterized as Eccentric -> not uniform around the vessel circumference and has shoulders Rich in inflammatory cells -> macrophages (foam cells) and T cells.

Unstable atheroma plaque

Features thin fibrous cap that obstructs 50-75% of the lumen-> less evidence of smooth muscle proliferation-> Increased blood flow -> increased haemodynamic stresses -> likely to rupture

Unstable atheroma plaque

What is the difference in pathogenesis of hyaline and hyperplastic arteriosclerosis in kidney?

hyaline: benign nephrosclerosis->Decreased blood supply -> loss of nephrons->Finely granular appearance to the kidney surface hyperplastic: malignant nephroscelrosis->Flea bitten kidney->Microscopy: Onion-skin ,concentric, laminated thickening of the walls of arterioles causing progressive narrowing and obliteration of kidey lumens

Complications: Cerebral and brainstem hemorrhages, hypertension and increased BUN and creatine (secondary to reduced GFR)

hyperplastic arteriosclerosis

Etiology: Acute or severe elevation of blood pressure - malignant hypertension (greater than 220 systolic and 120 diastolic

hyperplastic arteriosclerosis

Pathogenesis of atherosclerosis: (a) injury facilitates -> increased vascular (b), adhesion of (c), expression of (q) molecules and the release of (d) factors that turn the (d) into a procoagulant surface. Oxidised (f) are chemotactic to circulating (g)->readily ingested by (h) which are then inhibited from moving and triggered to release growth factors and cytokines. (i) proliferation, recruited and stimulated by (j) from macrophages, facilitate the conversion of fatty streak into fibrofatty atheroma. (k) and (l), also form macrophages, transform the normally anticoagulant endothelial surface into a procoagulant surface by stimulating endothelial cells to produce (s). (m) and (n), also released by macrophages, inhibit cell proliferation causing failure of endothelial cells to repair endothelial defects, which in turn provides entry areas for (o) and (p)-derived factor and serves as an area where thrombi are formed.

a-Endothelial b-permeability c-leukocytes d-growth factors e-endothelium f-oxidized lipids g-monocytes h-macrophages i-smooth muscle j-PDGF K-TNF and L-IL-1 M-Interferon alpha (IFN-alpha) and N-Transforming growth factor (TGF) O-lipoproteins P-plasma-derived q-adhesion s- platelet activating factor (PAF), tissue factor (TF) and plasminogen activator inhibitor (PAI)

Lipoprotein a is an altered form of LDL that contains the ( ) linked to ( )->creates hyperlipidemia predisposing atherscelorosis

apoprotein B 100 linked to apoprotein (a)

severe atherosclerosis in this location will show atherosclerotic vessels with severe rigidity and tortuosity of the vessel. Increased damage leads to fibrosis of the vessel leads to crunching of the vessels hence the vessels appear tortuous.

cerebral vessels

necrotic area of aorta with calcium deposition and contraction of the fibrous cap

complex atheroma (artherosclerotic plaque)

Composed of lipid laden macrophages, T lymphocytes and some extracellular lipid that are found within the subendothelium but does not constitute atherosclerosis

fatty streaks

arteriosclerosis where there is acute lumen narrowing->no time for atrophy

hyperplastic arteriosclerosis

release cytokines like IL-1 and TNF which stimulate the expression of pro‐atherogenic genes in EC

macrophages

May lead necrotizing arteriolitis and resulting in rapid progression to end organ damage->causes acute lumen narrowing->no time for atrophy

malignant hypertension (BP>220/120) associated with hyperplastic arteriosclerosis

"Flea bitten kidney"

malignant nephrosclerosis caused by reduced vessel caliber and renal ischemia from underlying hyperplastic arteriolosclerosis

Characterized by focal calcification in the media of small to medium-sized muscular arteries, without associated inflammation, largely sparing the intima and adventitia. This is an example of dystrophic calcification->Vessel becomes stiff and pulse pressure may increase.

monkeberg's aterosclerosis

Frequency increased by diabetes mellitus, chronic renal disease, SLE, hypervitaminosis D, and chronic inflammation. What type of cell injury is this and which layers of vessel are affected?

monkeberg's aterosclerosis: dystrophic calcification, mostly of tunica media (largely spares intima and adventitia)

Major consequences include infarction, ischaemia, aneurysms, peripheral vascular disease (gangrene of legs), emboli. More likely with unstable atherosclerotic plaques.

plaque rupture (thromboembolism)

Causes concurrent atherosclerosis in pulmonary circulation, where atherosclerosis is unusual d/t to inability of pulmonary vessels to tolerate HTN for very long.

prolonged hypertension (Eisenmenger's complex etc)

Facilitate the conversion of fatty streak into fibrofatty atheroma in formation of atherosclerosis.

smooth muscle proliferation

Features thick fibrous cap that obstructs the whole lumen (>75%) owing to marked smooth muscle proliferation Decreased blood flow -> decreased haemodynamic stresses.

stable atheroma plaques

Vascular development where entire circumference involved ->concentric and laminated,no shoulders-> Deficient in inflammatory cells - smaller necrotic core

stable atheroma plaques

Plaque rupture occurs->( ) usually forms on these disrupted lesions and may partly or completely occlude the lumen.

superimposed thrombosis

Also rich in metalloproteinase, Can see needle shaped cholesterol crystals - larger necrotic core

unstable atherosclerotic plaques