Chapter 11/Lecture 1: Vascular Anomalies, HTN, Atherosclerosis, Aneurysms/Dissections Flashcards
In which layer of vessels will you find nerve fibers and the vasa vasorum (“vessels of the vessels”)?
Adventitia
Which type of vessel has an endothelial cell lining, no media, and variable number of pericytes?
Capillaries
In most inflammatory rxns, vascular leakage and leukocyte exudation occur via what vessels?
Post-capillary venules (veins)
All vessels except _______ share a 3-layered architecture consisting of an endothelium lined intima, a surrounding smooth m. media, and supportive adventititia.
Capillaries
Large or multiple AV fistulas may shunt blood from arterial or venous circulation, forcing the heart to pump additional volume and lead to what clinically significant event?
High-output cardiac failure
Fibromuscular dysplasia is a focal thickening in which arteries (size and type)?
Medium and large muscular arteries (i.e, renal, carotid, splanchnic, and vertebral)
Is there a genetic association with fibromuscular dysplasia and who is most often affected?
- First-degree relatives have ↑ incidence
- Most frequently in young women (NO assoc. w/ OC’s or ↑ estrogen)
Which layers of the vessel wall undergo hyperplasia and fibrosis in fibromuscular dysplasia?
Media and intima
Fibromuscular dysplasia of renal arteries can be a cause of?
Renovascular HTN
Endothelial dysfunction refers to an alteration in endothelial what?
Often has what 2 characteristics?
- Phenotype
- Often both proinflammatory and prothrombogenic
Alteration of endothelial phenotype seen in endothelial dysfunction is responsible for the initiation of what changes seen in pathological processes?
Initiation of thrombus formation, atherosclerosis, and vascular lesions of HTN
Vascular smooth m. cells have the capacity to proliferate when appropriately stimulated and can also synthesize what?
- Collagen
- Elastin
- Proteoglycans
- Elaborate cytokines and GF’s
What is the stereotypical response of the vessel wall to any insult?
Intimal thickening
Turbulent flow, HTN, cytokines, complement, bacterial/lipid prods., advanced glycation end-products, hypoxia, acidosis, viruses and cigarette smoke may cause endothelial activation which leads to increased/altered expression of what?
- Procoagulants, adhesion molecules, and pro-inflammatory cytokines
- Altered expression of chemokines, cytokines, and GF’s
Describe the 3 events in the stereotypical response to vascular injury.
- Recruitment of smooth m. cells or smooth m. precursor cells to intima
- Smooth m. cell mitosis
- Elaboration of extracellular matrix = intimal thickening
Secondary HTN is a result of an underlying disease in which organs?
- Renal –> renal a. stenosis
- Adrenal = 1’ aldosteronism, Cushing syndrome or pheochromocytoma, pregnancy induced
- CV = coarctation of aorta, polyarteritis nodosa
- Neuro = sleep apnea, acute stress, psychogenic
Which systolic and diastolic BP characterize malignant HTN?
>200/>120
Malignant HTN is often superimposed on what?
Pre-existing “benign” HTN
What are 5 cardiovascular causes of secondary HTN?
- Coarctation of aorta
- Polyarteritis nodosa
- Increased intravascular volume
- Increased cardiac output
- Rigidity of aorta
What are 4 neurologic causes of secondary HTN?
- Sleep apnea
- ↑ ICP
- Sleep apnea
- Acute stress, including surgery
Blood pressure is a product of _______ x________
Cardiac output x Peripheral Resistance
The most important determinant of stroke volume is what?
Regulated by?
- Filling pressure
- Regulated thru Na+ homeostasis (mineralocorticoids and ANP) and its effect on blood volume
How is cardiac output calculated?
CO = SV x HR
List the 5 humoral factors which are constrictors and have an effect on peripheral resistance?
- Angiotensin II
- Catecholamines
- Thromboxane
- Leukotrienes
- Endothelin
Peripheral resistance is regulated predominantly at the level of which vessels?
By which inputs?
- Arterioles
- Neural and hormonal inputs
What 2 relaxing substances are produced by the kidney to counterbalance the vasopressor effects of angiotensin?
- NO
- Prostaglandins
Explain the effects of renal artery stenosis and how they contribute to renovascular HTN?
- ↓ pressure in afferent arteriole = ↓ GFR
- ↑ Renin secretion = RAAS system activation = ↑ vascular tone and blood volume
Liddle syndrome is due to gain-of-function mutations in which protein and leads to what?
- ENaC protein
- Causes ↑ Na+ reabsorption in response to aldosterone
Gene defects in which enzymes involved in aldosterone metabolism lead to primary hyperaldosteronism and in turn secondary HTN?
- Aldosterone synthase
- 11β-hydroxylase
- 17α-hydroxylase
HTN is associated with what 2 forms of small blood vessel disease?
1) Hyaline arteriolosclerosis
2) Hyperplastic arteriosclerosis
Homogenous pink hyaline thickening with associated luminal narrowing is characteristic of?
Hyaline arteriosclerosis
What type of arteriosclerosis is associated with severe HTN and is often a component of malignant HTN?
Hyperplastic arteriosclerosis
Vessels exhibiting concentric, laminated (“onion-skin”) thickening of the walls with luminal narrowing is characteristic of?
Hyperplastic arteriosclerosis
Nephrosclerosis due to chronic HTN is a form of what type of arteriosclerosis?
Hyaline arteriosclerosis
What type of arteriosclerosis is a common feature of diabetic microangiography?
Hyaline arteriosclerosis
The laminations of hyperplastic arteriosclerosis are accompanied by what other morphological changes in malignant HTN?
- Fibrinoid deposits
- Vessel wall necrosis (necrotizing arteriolitis)
What do the laminations of hyperplastic arteriosclerosis consist of?
Smooth muscle cells w/ reduplicated BM
Monckeberg medial sclerosis most often occurs in which age group and is characterized by what?
Clinically significant?
- >50 yo
- Calcification of walls of muscular arteries, typically internal elastic membrane
- No narrowing of lumen and no clinical significance
What is the most frequent and clinically important pattern of arteriosclerosis?
Atherosclerosis
The likelihood of atherosclerosis is determined by the combination of which acquired and inherited risk factors?
- Acquired = cholesterol levels, smoking and HTN
- Inherited = LDL receptor gene mutations
What are in the intimal lesions seen in atherosclerosis and describe their morphology?
- Atheroma = atheromatous = atherosclerotic plaque
- Raised lesion w/ a soft grumous core of lipid covered by fibrous cap
Besides obstructing blood flow, atherosclerotic plaques can rupture leading to what?
Catastrophic obstructive vascular thrombosis
Which country is known to have the highest ischemic heart disease-associated mortality?
Soviet Union
What are the 5 major modifiable risk factors for atherosclerosis?
- Hyperlipidemia
- HTN
- Cigarette smoking
- Diabetes
- Inflammation
How do multiple risk factors present act in concert to increase risk of atherosclerosis?
Have a multiplicative effect = Synergism
Woman of which age are somewhat protected from atherosclerosis?
May due to effect of?
- Pre-menopausal woman
- Effect of estrogen
Atheroprotective effects of estrogen therpay seem to be related to what factor?
Age at which therapy is initiated –> younger postmenopausal woman are more protected
What is a major risk factor for atherosclerosis even in the absence of other factors and is sufficient to initiate lesion development?
Hypercholesterolemia
What are 2 activities which raise HDL levels?
- Exercise
- Moderate consumption of ethanol
Which disease causes a 100x ↑ risk for atherosclerosis-induced gangrene of LE’s?
Diabetes mellitus
Which circulating marker of inflammation associated wth ischemic heart disease is one of the easiest to measure and one of the most sensitive?
CRP
Expression of CRP is increased by a number of inflammatory mediators, especially what?
IL-6
What is a useful serum marker to gauge the effects of risk reduction measures, such as smoking cessation, weight loss, exercise, and statins?
CRP
Serum homocysteine levels correlate with risk for what 4 vascular pathologies?
- Coronary atherosclerosis
- Peripheral vascular disease
- Stroke
- Venous thrombosis
Metabolic syndrome associated with central obesity is characterized by what dysfunctions?
- Insulin resistance
- HTN
- Dyslipidemia
- Hypercoagulability
- Pro-inflammatory state
The systemic hypercoagulable and proinflammatory state associated with metabolic syndrome contribute to what 2 pathological processes?
- Endothelial dysfunction
- Thrombosis
What is lipoprotein A [Lp(a)]?
Increases risk for what?
- Altered form of LDL –> contains ApoB-100 portion of LDL linked to ApoA
- Associated w/ coronary and cerebrovascular disease risk, independent of total cholesterol or LDL levels
Elevated plasminogen activator inhibitor 1 is a potent predictor of?
Risk for major atherosclerotic events, including MI and stroke
What are the 2 most important causes of endothelial dysfunction leading to atherosclerosis?
- Hemodynamic disturbances = turbulence
- Hypercholesterolemia
Where do plaques seen in atherogenesis most commonly occur?
- Openings of exiting vessles
- Branch points
- Posterior wall of the aorta
Which genetic disorder is associated with defective LDL receptors and inadequate hepatic LDL uptake which can precipitate MI before the age of 20?
Familial hypercholesterolemia
Chronic hypercholesterolemia can directly impair endothelial cell function by increasing the production of what?
ROS = membrane/mitochondrial damage + accelerated NO decay
With chronic hyperlipidemia, lipoproteins accumulate where in the vessel and undergo what?
- Intima
- Aggregate and are oxidized by free radicals –> modified LDL
What occurs to the modified LDL that aggregates in the intima of vessels?
- Phagocytosed and accumulates in macrophages = FOAM CELLS
- Smooth m. cells can also transform into lipid-laden foam cells
What is the lesion caused by the accumulation of foam cells in the intima of vessels called?
Stimulates what?
- Fatty streak
- Lead to ↑ cytokine, ↑ GFs and ↑monocyte recruitment + activation
Chronic inflammation which contributes to the initiation and progression of atherosclerotic lesions is triggered by what?
Leads to activation of the inflammasome and secretion of what?
- Accumulation of cholesterol crystals and FFA’s in macrophages
- Secretion of IL-1
Secretion of IL-1 assoc. w/ chronic inflammation in atherosclerotic lesions leads to the recruitment and activation of what?
More macrophages + T lymphocytes = ↑ cytokines/chemokines which recruit and activate more inflammatory cells
Intimal smooth m. cell proliferation + extracellular matrix deposition convert fatty streaks into what?
Mature atheroma
Which GF’s are implicated in smooth muscle proliferation associated w/ atherogenesis?
- PDGF
- FGF
- TGF-α
Smooth m. cells stimulated by GF’s in atherogenesis synthesize what that stabilizes atherosclerotic plaques?
Extracellular matrix (notably collagen)
Atheromas are dynamic lesions consisting of what 4 cell types?
- Dysfunctional endothelial cells
- Proliferating smooth m. cells
- T lymphocytes
- Macrophages
Fatty streaks are a normal finding in which subset of pts?
- Aorta of infants
- Virtually all adolescents
How do atherosclerotic plaques appear grossly inside of a vessel?
- White, yellow and patchy, only portion of wall involved
- Eccentric appearance
In descending order of frequency/severity of involvement list the 5 vessels most extensively affected by atherosclerotic plaques.
- Lower abdominal aorta
- Coronary arteries
- Popliteal arteries
- Internal carotid arteries
- Vessels of circle of Willis
The extracellular matrix of atherosclerotic plaques consist of what 3 components?
- Collagen
- Elastic fibers
- Proteoglycans
What is found deep to the fibrous cap of atherosclerotic plaques?
- Necrotic core containing lipids (primarily cholesterol and cholesterol esters)
- Debris from dead cells + Foam cells + Fibrin
What is seen morphologically at the periphery of atherosclerotic plaques?
- Neovascularization
- May also see calcification over time
Rupture, ulceration or erosion of the surface of atherosclerotic plaques exposes what and leads to?
- Exposes highly thrombogenic substances
- Leads to thrombosis
Rupture of the overlying fibrous cap, or of the thin-walled vessels in the area of neovascularization of atherosclerotic plaques can lead to what?
- Hemorrhage into the plaque (intraplaque hemorrhage)
- Contained hematoma may expand the plaque or induce plaque rupture
Atherosclerotic plaque rupture can discharge atherosclerotic debris where and lead to what?
- Into the bloodstream
- Producing micoemboli
Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness and potential rupture due to formation of a?
Aneurysm
What are the 4 major consequences of atherosclerosis?
- MI (heart attack)
- Cerebral infarction (stroke)
- Aortic aneurysms
- Peripheral vascular disease (gangrene of the legs)
The stage at which occlusion of a vessel is sufficiently severe to produce ischemia is known as?
Critical stenosis
What % decrease in luminal cross-section area is considered critical stenosis?
70%
Critical stenosis of the arterial lumen may lead to chronic ischemia where?
- Myocardium
- Bowel (mesenteric ischemia)
- Brain (ischemic encephalopathy)
- Extremities (intermittent claudication)
Critical stenosis of the coronary artery can lead to chest pain w/ exertion, known as?
Stable angina
Acute plaque change falls into what 3 general categories?
- Rupture/fissuring
- Erosion/ulceration
- Hemorrhage into the atheroma
What are the characteristics of “vulnerable plaques” in terms of the fibrous cap, foams cells, and smooth m. cells?
- Contain large areas of foam cells/extracellular lipids
- THIN fibrous caps
- Few smooth m. cells + dense clusters of inflammatory cells
What is the major structural component of the fibrous caps of atherosclerotic plaques and what produces this structural component?
- Collagen
- Produced by smooth m. cells
What are 2 influences extrinsic to plaques which contribute to acute plaque change?
- Adrenergic stimulation: ↑ BP + ↑ vasoconstriction= ↑ stress on plaque —> seen with wakening and rising in the AM
- Intense emotional stress: ↑ BP = ↑ stress on plaque
Spherical outpouchings involving only a portion of the vessel wall describes what type of aneurysm?
Saccular
Diffuse, circumferential dilation of long vascular segments defines what type of aneurysm?
Fusiform aneurysms
Defect in the vascular wall leading to an extravascular hematoma that freely communicates with the intravascular space (“pulsating hematoma”) defines what?
False aneurysm (aka pseudo-aneurysm)
Defective synthesis of the scaffolding protein fibrillin leading to aberrant TGF-β activity and weakening of elastic tissue leading to aneurysms underlies what disease?
Marfan syndrome
Mutations in TGF-β receptors causing defective synthesis of elastin and collagens I and III and potential aneurysms is associated with what disorder?
Loeys-Dietz Syndrome
Weak vascular walls due to defective type III collagen synthesis is a hallmark of the vascular forms of which syndrome?
Ehlers-Danlos Syndrome
There is a nutritional basis for aneurysm formation in people with which vitamin deficiency?
Vitamin C (scurvy)
Increased expression of what by macrophages in atherosclerotic plaques or in vasculitis may contribute to aneurysm formation?
MMP
The release of elastolytic MMP from macrophages is stimulated by what cytokines and is often seen in AAA’s?
IL-4 and IL-10
Systemic HTN can cause significant narrowing of arterioles of the vasa vasorum, which causes ischemia of which part of the vessel?
Outer medial ischemia
Loss of vascular wall elastic tissue/ineffective elastic synthesis, with disrupted and disorganized elastin filaments and increased ground substance (glycosaminoglycan) gives what hallmark histological finding?
Cystic medial degeneration
What is a final common result of different conditions, including ischemic medial damage and Marfan syndrome?
Cystic medial degeneration
Which finding characteristic of late stage tertiary syphillis is a cause of aortic aneurysms?
Predilection for which vessels?
- Obliterative endarteritis
- Predilection for small vessels, including those of vasa vasorum of the thoracic aorta
The obliterative endarteritis of late-stage tertiary syphillis leads to what vascular/heart complications?
- Ischemic injury of the aortic media and aneursymal dilation
- Sometimes involving the aortic valve annulus (aortic valve regurgitation)
The 2 most important causes of aortic aneurysms are what?
Which is a greater factor in AAA’s and which for ascending aortic aneurysms?
- Atherosclerosis = AAA’s
- HTN = ascending aortic aneurysms
Mycotic aneurysms can originate via what 3 ways?
- Embolization of a septic embolus (usually as complication of infective endocarditis)
- Extension of an adjacent suppurative process
- Circulating organisms directly infecting arterial walls
AAA’s occur in the abdominal area most typically where?
Below the renal arteries and above bifurcation of the aorta
AAA’s are characterized by severe atherosclerosis of the aorta, and are frequently covered by what?
Bland, laminated, poorly organized mural thrombus
AAA is often accompanied by smaller aneurysms in which arteries?
Iliac arteries
Which type of AAA is more common in younger patients and presentation includes back pain and elevated inflammatory markers?
Inflammatory AAA
Inflammatory AAA’s are characterized by what type of inflammation and inflammatory infiltrate?
Abundant lymphoplasmacytic inflammation w/ many macrophages (and even giant cells)
Which variant of AAA is associated with aortitis and periaortitits that weakens the wall and may also have sx’s associated with affected pancreas, bilirary system, and salivary glands?
IgG4-related disease
Why is recognition of IgG4-related disease as a variant cause of AAA important?
Responds well to steroid therapy
Which variant of AAA is due to lodging of circulating microorganisms in the wall w/ suppuration further destroying the media, potentiating rapid dilation and rupture?
Mycotic AAA
AAA’s of which size are usually managed aggressively via surgery?
5cm or >
What are 4 potential complications of an AAA?
- Rupture into peritoneal cavity or retroperitoneal tissues w/ hemorrhage
- Obstruction of vessel branching off of aorta (iliac, renal, mesenteric, or vertebral as.)
- Embolism from atheroma or mural thrombus
- Impingement on adjacent structure (i.e., compressed ureter or erosion of vertebra)
Thoracic aortic aneurysms are most commonly due to what?
May also be caused by what congenital defects?
- Most common = HTN
- Also seen in Marfan syndrome and Loeys-Dietz syndrome
What are some of the major signs/sx’s of thoracic aortic aneurysms due to their location?
- Impingement –> Resp. difficulties or Dysphagia or Persistent cough (recurrent laryngeal n.)
- Pain due to erosion of bone (ie ribs and vertebral bodies)
- Aortic valve dilation w/ valve insufficiency or narrowing
- RUPTURE!
Most patients with syphilitic aneurysms die of?
Heart failure 2’ to aortic valvular incompetence
Aortic dissection occurs principally in what 2 groups of patients?
- Men aged 40-60 yo w/ HTN
- Younger adults w/ disorders of CT affecting the aorta (i.e., Marfan)
Sudden onset of severe chest pain (usually beginning in anterior chest), radiating back between the scapulae and moving downward is the classic presentation of what?
Aortic Dissection
Aortic dissections can be catastrophic if what occurs?
Rupture through the adventitia –> massive hemorrhage into adjacent spaces (i.e., thoracic or abdominal cavities) or cardiac tamponade (hemorrage into pericardial sac)
What is the major risk factor for aortic dissection?
HTN
Aortas of patients with HTN have what type of hypertrophy and degenerative changes associated with loss of what?
- Medial hypertrophy of the vasa vasorum
- Degenerative changes w/ loss of medial smooth m. cells + disorganized ECM
What is the most frequent pre-existing histologically detectable lesion in aortic dissections?
Inflammation?
Cystic medial degeneration and inflammation is absent
Most aortic dissections arise where?
Initiates via what type of tear?
- Ascending aorta within 10cm of the aortic valve
- Via an intimal tear
If a dissecting hematoma from an aortic dissection re-enters the lumen of the aorta through a 2nd distal intimal tear, creates a new false vascular channel known as?
Over time these false channels can be endotheliazed to become recognizable as?
- “Double-barreled aorta”
- Chronic dissections
The more common (and dangerous) aortic dissections, type A dissections involve what?
- Boththeascendinganddescending aorta
- Or just the ascending aorta
Aortic dissections which extend into and involve the spinal arteries can cause what?
Transverse myelitis
Most common cause of death from aortic dissections is due to what?
Rupture into the pericardial, pleural, or peritoneal cavities
Retrograde dissection into the aortic root can lead to what?
Dilation of aortic valve –> aortic valve insufficiency
How are type A dissections dealt with at clinical presentation?
- INTENSIVE anti-hypertensive therapy
- Surgical repair of intimal tear
How are type B dissections managed clinically?
Conservatively; with surgery or anti-hypertensive therapy
