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Vascular Disorders
Responsible for more morbidity & mortality than any other category of human disease
Clinically significant lesions: artery & venous diseases
2 Prinicipal Mechanisms of Vascular Pathology:
1.
Narrowing (stenosis) / Complete Obstruction, either:
Progressively (atherosclerosis)
Precipitously (thrombosis/embolism)
2.
Weakening of vessel walls
Leads to dilation or rupture
STRUCTURE & FUNCTION OF BLOOD VESSELS
General architecture and cellular composition are the same throughout the CVS.
HOWEVER, certain features vary w/ & reflect distinct functional requirements at different
locations:
ARTERIAL WALLS generally thicker than walls of veins, to withstand the pulsatile flow &
higher blood pressure in arteries
Thickness diminishes(gradually) as the vessels become smaller
Thickness:Lumen Diameter (ratio) increases as vessels become smaller
Basic constituents of BV walls:
Endothelial Cells
Smooth Muscle Cells
Extracellular Matrix (ECM) + elastin, collagen & glycosaminoglycans
3 Concentric Layers:
1.
INTIMA
has single layer of endothelial cells w/ minimal underlying substance
connective tissue
separated from media by INTERNAL ELASTIC LAMINA (dense elastic membrane)
2.
MEDIA
SMOOTH MUSCLE CELL LAYERS: receive oxygen & nutrients from vessel lumen
(direct diffusion), facilitated by holes in the internal elastic membrane.
INADEQUATE DIFFUSION: Outer portions of media in LARGE & MEDIUM-SIZED
vessels
THEREFORE, nourished by small arterioles outside the vessel (VASA VASORUM
vessels of the vessels) which courses into outer - 2/3 of the media
OUTER LIMIT (most arteries): External Elastic Lamina
3.
ADVENTITIA
Consists of: connective tissue with nerve fibers & vasa vasorum
Muscular Arteries & Arterioles: regional blood flow & blood pressure is regulated by
changes in lumen size (vasoconstriction & vasodilation), controlled in part by ANS,
local metabolic factors & cellular interactions
3.
Small arteries 20 to 100um in diameter; within the substance of tissues & organs
ARTERIOLES: principal points of physiologic resistance to blood flow
Relative amount & configuration of basic constituents differ along the arterial system
owing to local adapatations to mechanical or metabolic needs. (Structural Variations at
MEDIA and ECM, principally)
CAPILLARIES (7-8um)
Have an endothelial cell lining but NO MEDIA
Have a very large total cross-sectional area
Flow rate SLOWS dramatically + thin walls, situated ideally to the rapid
exchange of diffusible substances between blood and tissues
Metabolically highly active tissues (eg MYOCARDIUM) have highest density of
capillaries
Blood (capillary bed)
postcapillary venules
collecting venules (vascular
leakage & leukocyte exudation occurs here in times of INFLAMM)
small veins
medium veins
large veins
VEINS
Larger diameters compared to arteries
Larger lumen
Thinner and less well organized walls
Predisposed to irregular dilation, compression and easy penetration by tumors
& inflamm processes due to poor support
Has a large capacity (CAPACITANCE VESSELS); 2/3 of blood is here
Reverse flow: prevented by venous valves
LYMPHATICS
Thin-walled, endothelium-lined channels
Serve as a drainage system for returning interstitial tissue fluid & inflammatory
cells to the blood
Constitute a pathway for disease dissemination
Regional specializations of the vasculature. Although the basic organization of the vasculature is
constant, the thickness and composition of the various layers differ according to hemodynamic
forces and tissue requirements.
1
ARTERIOVENOUS FISTULAS
Abnormal, typically small, direct connections between arteries & veins,
bypasses the intervening capillaries
Occur mostly as developmental defects
Can also result from:
*rupture of an arterial aneurysm to an adjacent vein;
*penetrating injuries that pierce arteries & veins;
*inflammatory necrosis of adjacent vesses
Intentionally created AV-Fistulas (used to provide vascular access for chronic
hemodialysis)
Rupture can also be an impt cause of intracerebral haemorrhage
Large/Extensive AV-fistulas shunts blood from arterial to venous circulations &
forces heart to pump additional volume
high output cardiac failure
FIBROMUSCULAR DYSPLASIA
Focal, irregular thickening of walls of medium & large muscular arteries (renal,
carotid, splanchnic, vertebral vessels)
Cause unknown but probably DEVELOPMENTAL (1st degree relatives
increased incidence)
Segments of vessel wall are focally thickened by combinations of irregular
medial & intimal hyperplasia & fibrosis
luminal stenosis (if in renal arteries
renovascular hypertension)
Vascular outpouchings (aneurysms) may develop
Manifests at any age; seen most frequently in young women
No association w/ use or oral contraceptives or abn of sex hormone expression
Prostacyclin
Thrombomodulin
Heparin-like molecules
Plasminogen activator
VWF
Tissue factor
Plasminogen activator inhibitor
Collagen
Proteoglycans
Vasoconstrictors: endothelin, ACE
Vasodilators: NO, prostacyclin
IL-1, IL-6, chemokines
Adhesion molecules: VCAM-1, ICAM-1, Eselectin, P-selectin
Growth stimulators: PDGF, CSF, FGF
Growth inhibitors: heparin, TGF-
Oxidizes LDL
Endothelial cells have phenotypic variability depending on anatomic site
Endothelial cells in liver sinusoids/renal glomeruli: fenestrated to facilitate filtration
CNS: impermeable BBB
Responds to pathophysiologic stimuli by adjusting their usual functions & expressing newly acquired
properties
ENDOTHELIAL ACTIVATION
INDUCERS of endothelial activation:
Cytokines & Bacterial products
Hemodyn stress & lipids
(atherosclerosis)
Glycosylation end products (DM)
Viruses, complement, hypoxia
ACTIVATED endothelial cells express
ADHESION MOLECULES
produce
cytokines, chemokines, GF, vasoactive
molecs, MHC, etc.
Left figure: normal endothelial function is
charac by a balance of these responses
Vascular injury (cell loss or just dysfunction) stimulates smooth muscle cell growth &
matrix synthesis that thickens intima
Neointima : healing of injured vessels results to this
During healing: medial sm muscle cells migrate into the intima, proliferate and
synthesize ECM
Neointima covered by endothelial cells
Neointimal smooth muscle cells
Do not contract
Can divide
blood pressure - a continuously distributed variable; the higher the pressure, the
greater the detrimental effects; no rigidly defined threshold level of blood pressure
distinguishes risk from safety
Low pressures (hypotension) - inadequate
organ perfusion and can lead to dysfunction or
tissue death
Accdg. to the National Heart, Lung, and Blood Institute of the U.S.A.:
sustained DP > 89 mm Hg / sustained SP > 139 mm Hg - associated with a measurably increased risk of atherosclerosis;
represent clinically significant hypertension
Both the SP and DP are important in determining cardiovascular risk
25% of individuals in the general population are hypertensive
Patients with other risk factors for vascular disease such as diabetes, have lower thresholds.
Mechanisms that result in hypertension remain largely unknown in most individuals in spite of an improved
understanding of the molecular pathways that regulate normal blood pressure.
essentialhypertension - multifactorial, resulting from the combined effects of multiple genetic polymorphisms
and interacting environmental factors
Prevalence and vulnerability to complications of HPN increase with age; higher in African Americans
Hypertension - one of the major risk factors for atherosclerosis and underlies numerous other diseases:
can cause cardiac hypertrophy and heart failure (hypertensive heart dse.), multi-infarct dementia, aortic
dissection, and renal failure
typically remains asymptomatic until late in its course and even severely elevated pressures can be
clinically silent for years.
Roughly half of hypertensive patients die of ischemic heart disease (IHD) or congestive heart failure (CHF), one
third die of stroke if left untreated
Prophylactic blood pressure reduction dramatically reduces the incidence and death rates from all forms of
hypertension-related pathology
secondary hypertension
5% have underlying renal or
adrenal disease
primary aldosteronism
Cushing syndrome
Pheochromocytoma
narrowing of renal artery, by
an atheromatous plaque
(renovascular hypertension)
other identifiable cause
Pheochromocytoma
Hypothyroidism (myxedema)
Pregnancy-induced
5%, of hypertensives - show a rapidly rising blood pressure, leading to death within a year or two if untreated
accelerated or malignant hypertension syndrome; characterized by severe
hypertension:
SP> 200 mm Hg, DP > 120 mm Hg
renal failure
retinal hemorrhages and exudates
with or without papilledema
may develop in previously normotensive persons, often superimposed
on pre-existing benign hypertension, either essential or secondary
Regulation of Normal Blood Pressure
Blood pressure - a function of cardiac output and peripheral vascular resistance [hence, the formula: BP = CO x
PVR, with CO affected by SV and HR] (Fig. 11-4A )
Two hemodynamic variables that are influenced by multiple genetic, environmental, and demographic factors.
The major factors that determine blood pressure variation within and between populations: age, gender, BMI, and
diet (particularly sodium intake)
Coarctation of aorta
Psychogenic
Polyarteritis nodosa
Increased intravascular
volume
Increased cardiac output
Increased ICP
Sleep apnea
Endocrine
Adrenocortical hyperfunction (Cushing
Exogenous hormones (glucocorticoids,
syndrome, primary aldosteronism,
estrogen [including pregnancy-induced
Cardiac output - highly dependent on blood volume, greatly influenced by the sodium homeostasis
Peripheral vascular resistance - determined mainly at the level of the arterioles, affected by neural and hormonal
factors
4
kinins
prostaglandins, inc. prostacyclin (PGI2)
NO
ANP
Neuralfactors(2-adrenergic)
Resistance vessels exhibit autoregulation: increased blood flow induces vasoconstriction to protect against tissue
hyperperfusion
Other local factors:
pH and hypoxia & the- and -adrenergic systems - influence heart rate, cardiac contraction, and vascular tone,
are also important in regulating blood pressure
The (GOAL) integrated function of these systems: to ensure adequate perfusion of all tissues, despite regional
differences in demand.
1. Gene defects affecting enzymes in aldosterone metabolism
aldosterone synthase
11-hydroxylase
17-hydroxylase
lead to an aldosteronesecretionsaltandwater
resorptionplasmavolumeexpansionhypertension
Nephrosclerosis due to chronic hypertension: arteriolar narrowing of hyaline arteriosclerosis causes diffuse
impairment of renal blood supply and causes glomerular scarring
DrBongatsadditionalinfo:
- Usually occur in benign hypertension
- Complication: Chronic Renal Failure
2) Hyperplastic Arteriolosclerosis
occurs in severe (malignant) hypertension
vessels exhibit onion-skinlesions, characterized by concentric, laminated thickening of the walls and luminal
narrowing
laminations consist of smooth muscle cells with thickened, reduplicated basement membranes
malignant hypertension (SP> 200 mm Hg, DP > 120 mm Hg) - accompanied by fibrinoid deposits and vessel wall
necrosis (necrotizing arteriolitis), particularly in the kidney
DrBongatsadditionalinfo:
Malignant HPN that hasfibrinoidnecrosiscancausethrombosisaneurysm
This aneurysm can have 3 consequences:
Rupture
Ulceration
Haemorrhage
Three complications:
Hypertensive Heart Disease (HHD) cardiac hypertrophy and heart failure
Stroke (hemorrhagic type)
Acute Renal Failure and Uremia
Atherosclerosis
-
Epidemiology
Present among most developed nations
less prevalent in Central and South America, Africa, and parts of Asia.
US highest mortality rate for ischemic heart disease (IHD) about 5x than japan
Japan - IHD is the 2nd leading cause of death.
FIGURE 11-5 Vascular pathology in hypertension. A, Hyaline arteriolosclerosis. The
arteriolar wall is thickened with increased protein deposition (hyalinized), and the
lumen is markedly narrowed. B, Hyperplastic arteriolosclerosis (onion-skinning; arrow)
causing lumenal obliteration
Arteriosclerosis (msperea)
literally means hardening of the arteries
it is a generic term reflecting arterial wall thickening and loss of elasticity.
There are three general patterns:
1.Arteriolosclerosis
Affects small arteries and arterioles, and may cause downstream ischemic injury.
2.Mnckeberg medial sclerosis
characterized by calcific deposits in muscular arteries in persons typically older than age
50.
The deposits may undergo metaplastic change into bone.
lesions do not encroach on the vessel lumen
not clinically significant
3.Atherosclerosis
Greek root words for gruel and hardening,
most frequent and clinically important
Genetics
Family history is the most significant risk factor for atherosclerosis
Multifactorial, relating to inheritance of:
o
various genetic polymorphisms
o
hypertension
o
diabetes
Modifiable risk factors in IHD.
acquired or related to behaviors that are potentially amenable to intervention
Hyperlipidemia / hypercholesterolemia
major risk factor for atherosclerosis (can be independent and cause dse.)
Increase LDL(bad cholesterol) increase risk
LDL is delivered to peripheral tissues.
Increased (HDL, good cholesterol) reduced risk
In contrast HDL mobilizes cholesterol from tissue and transports it to the liver for excretion
in the bile
High dietary intake of cholesterol and saturated fats raises plasma cholesterol levels.
Diets low in cholesterol and/or with higher ratios of PUFA lower plasma cholesterol levels
Omega-3 fatty acids (abundant in fish oils) are beneficial,
trans-unsaturated fats adversely affect cholesterol profiles.
Exercise and moderate consumption of ethanol raise HDL levels,
Obesity and smoking lowers HDL
Statins
o
drugs that lower circulating cholesterol levels by inhibiting (HMG-CoA)
reductase
Hypertension
increases the risk of IHD by approx 60%
Hypertension is the most important cause of left ventricular hypertrophy
Cigarette smoking
well-established risk factor in men
Accounts for the increasing incidence and severity of atherosclerosis in women.
Prolonged (years) smoking doubles the death rate from IHD.
Smoking cessation reduces the risk substantially.
Diabetes mellituss
induces hypercholesterolemia markedly increases the risk of atherosclerosis.
Risk is 2x in diabetics vs. non diabetics
increased risk of strokes
100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities.
Additional risk factors.
Inflammation
present during all stages of atherogenesis
linked with atherosclerotic plaque formation and rupture
C-reactive protein (CRP)
one of the simplest and most sensitive markers of inflam. correlate with IHD risk
CRP is an acute-phase reactant synthesized primarily by the liver.
plays a role in the innate immune response by opsonizing bacteria and activating
complement.
When CRP is secreted from cells within the atherosclerotic intima activate local
endothelial cells induce a prothrombotic state increase the adhesiveness of
endothelium for leukocytes.
predicts the risk of :
o
myocardial infarction
o
stroke
o
peripheral arterial disease
o
sudden cardiac death, even among apparently healthy individuals
No direct evidence that lowering CRP directly reduces cardiovascular risk.
Hyperhomocystinemia.
Clinical and epidemiologic studies show a strong relationship between total serum
homocysteine levels and coronary artery disease, peripheral vascular disease, stroke, and
venous thrombosis.
Elevated homocysteine levels can be caused by low folate and vitamin B 12 intake,
Homocystinuria
o
due to rare inborn errors of metabolism
o
results in elevated circulating homocysteine (>100 mol/L) and premature
vascular disease
Metabolic syndrome.
abnormalities that are associated with insulin resistance.
abnormal adipose tissue signaling has been proposed to drive the syndrome.
Dyslipidemia leads to endothelial cell dysfunction secondary to increased oxidative
stress
Lipoprotein (a)
altered form of LDL
contains the apo B-100 portion of LDL linked to apo-A.
Lipoprotein (a) levels are associated with coronary and cerebrovascular disease risk,
independent of total cholesterol or LDL levels.
Factors affecting hemostasis.
both are increasingly recognized as major contributors to local vascular pathology
o
Thrombin
o
Platelet-derived factors
Other factors.
Factors associated with a less pronounced and/or difficult-to-quantitate risk include
o
lack of exercise
o
competitive, stressful life style (type A personality)
o
obesity (which is often associated with hypertension, diabetes,
hypertriglyceridemia, and decreased HDL).
Pathogenesis of Atherosclerosis (jmvecida)
2 Hypotheses:
-
Events in Atherosclerosis
-
Platelet adhesion
Factor release from activated platelets, macrophages, and vascular cell walls
o
Leads to SMOOTH MUSCLE RECRUITMENT from TUNICA MEDIA or circulating
precursors
Smooth muscle cell proliferation and ECM production
Lipid accumulation both extracellularly and within cells
Endothelial Injury
-
Hemodynamic Disturbances
-
Lipids
-
Hypercholesterolemia in Atherosclerosis
-
Inflammation
-
Infection
-
Herpesvirus
Cytomegalovirus
Chlamydia pneumonia also associated with smoking related broinchitis Risk factor for
Ischemic Heart Dse
Smooth muscle proliferation + ECM deposition converts fatty streak to mature atheroma
Growth factors involved in smooth muscle cell proliferation and ECM synthesis:
o
PDGF from platelets, macrophages, endothelial cells, smooth muscle cells
o
FGF
o
TGF-alpha
Smooth muscle cells synthesize ECM, mainly collagen, that STABILIZES atherosclerotic
plaques
Overview
-
Morphology
Fatty Streaks
-
Atherosclerotic Plaque
-
Foam cells
Fibrin
Thrombus
Cholesterol crystalline aggregates washed out during preparation
clefts
o
Periphery neovascularization
Plaques change due to cell death and degeneration, synthesis of ECM, organization of
thrombus
Atheroma may calcify
MI (heart attack)
Cerebral infarction (stroke)
Aortic aneurysms
Peripheral vascular disease (gangrene of the legs)
The principal outcomes depend on the size of involved vessels, the relative stability of the plaque
itself & the degree of degeneration underlying arterial wall:
Smaller vessels can be occluded, compromising distal tissue perfusion
Ruptured plaque can embolize atherosclerotic debris & can cause distal vessel
obstruction or can lead to acute vascular thrombosis
Destruction of the underlying vessel wall can lead to aneurysm formation w/ secondary
rupture &/or thrombosis
9
Atherosclerotic Plaque
thin fibrous cap (undergoes remodeling), few smooth muscle cells or cluster of
inflammatory cells
Small Arteries
atherosclerotic plaques can gradually occlude vessel lumens compromising blood
flow & causing ischemic injury
Early Stages: outward remodeling of the vessel media tends to preserve luminal diameter as the total
circumference expands
vulnerable plaques
Collagen
Major structural component of the fibrous cap
Accounts for its mechanical strength & stability balance btwn its synthesis &
degradation affects stability
In atherosclerotic plaque
produced primarily by smooth muscle cells
loss of these
results to weakening of the cap
Collagen turnover:
a.
controlled by MMPs & enzymes elaborated largely by macrophages w/in the
atheromatous plaque
b.
Tissue inhibitor of MMP produced by endothelial cells, smooth muscle cells &
macrophages
modulate MMP activity
w/ limits on outward remodeling & eventually the expanding atheroma impinges on blood flow
Critical Stenosis- Rubicon at w/c chronic occlusion significantly limits flow & demand begins
exceedingly supply
In Coronary Circulations- it occurs at approx. 70% fixed occlusion; at this degree patients classically
develop chest pain/angina on exertion
Stable Angina
Chronically diminished arterial perfusion:
Mesenteric occlusion & bowel ischemia, chronic IHD, ischemic encephalopathy &
intermittent claudication
All are consequence of limiting stenosis
Plaque Inflammation
net increase in collagen degradation & reduces collagen synthesis
destabilizing the mechanical integrity of the fibrous cap
Statins: beneficial therapeutic effect not only by reducing circulating cholesterol levels but also by
stabilizing plaques through reduction in plaque inflammation
The effect of vascular occlusion ultimately depends on arterial supply & metabolic demand of the
affected tissues.
Acute Plaque Change
Plaque erosion/rupture is typically promptly followed by partial or complete vascular thrombosis
acute tissue infarction
Plaque changes fall into 3 categories:
Rupture/fissuring, exposing highly thrombogenic plaque constituents
Erosion/ulceration, exposing thrombogenic subendothelial bm to blood
Hemorrhage in atheroma, expanding its volume
It is now recognized that the precipitating lesion in px who develop MI & other acute coronary
syndromes is not necessarily a severely stenotic & hemodynamically significant lesion before its acute
change.
Pathological & Clinical Studies
majority of plaques undergo abrupt disruption & coronary
occlusion previously showed only mild to moderate luminal stenosis
Extrinsic Influences:
1.
Adrenergic Stimulation
-increase systemic bp or induce local vasoconstriction
increase physical stress on the
plaque
-associated w/ walking & rising
bp spikes
linked to pronounced circadian periodicity
for the peak time of onset of acute MI
6am to 12 nn
2.
Conclusion: rather large number of now asymptomatic adults may well have a real but
unpredictable risk of catastrophic coronary events
Events Triggering Abrupt Changes in Plaque Configuration & Superimposed Thrombosis:
Complex
Include both intrinsic & extrinsic factors
Rupture of plaque
unable to withstand the mechanical stress of vascular shear forces
Composition of Plaques
Dynamic
Contribute to risk of rupture
w/ large foam cells & extracellular lipids
total
In others: incomplete & can even wax & wane with time
Mural Thrombus in coronary artery can also embolize
-potent activator of multiple growth-related signals in smooth muscle cells
atherosclerotic lesions
growth of
10
Vasoconstriction
-compromises lumen size & by increasing the local mechanical forces can potentiate plaque
disruption
Vasoconstriction at site of atheroma is stimulated by:
1.
Circulating adrenergic agonist
2.
Locally released platelet contents
3.
Impaired secretion of endothelial cell relaxing factors (NO) relative to contracting factors
(endothelin) as a result of endothelial cell dysfunction
4.
Mediators released from perivascular inflammatory cells
False Aneurysm
- pseudo-aneurysm
- Defect in the vascular wall leading to an
extravascular hematoma that
communicates with intravascular space
pulsating hematoma
- the wall is ruptured
collection of blood
(hematoma) that is bounded externally by
adherent extravascular tissue
- Examples:
Ventricular rupture after MI
Classification by shape and size (not specific for any disease or manifestations)
Saccular
- Spherical outpouchings (involves only a
portion of the vessel wall)
- Often contain thrombus
Fusiform aneurysms
- Diffuse, circumferential dilation of a long
vascular segment
- Can involve aortic arch, abdominal aorta
or iliac arteries
Dissection
Arises when blood enters the arterial wall itself, as a hematoma dissecting between its layers
Often but not always aneurysmal
Blood enters the dissected wall of the vessel & separate the layers
Note:
Both true, false and dissections CAN RUPTURE, often with catastrophic consequences
Pathogenesis of aneurysms:
Arteries maintain their integrity by constantly synthesizing, degrading & repairing damage to
their ECM constituents
Aneurysms occur when the structure or function of the connective tissue within vascular wall is
compromised
Weakening of vessel walls is important in common, sporadic forms of aneurysms
Intrinsic quality of the
Marfan Syndrome
vascular wall connective
Defective synthesis of fibrillin leads to aberrant TGF- activity
tissue is poor
progressive weakening of elastic tissue
Aorta : progressive dilation due to remodeling of inelastic
media
Loeys-Dietz syndrome
Mutations in TGF- receptors lead to abnormalities in elastin &
collagen I & II
Aneurysms rupture easily (even at small size)
Ehlers-Danlos syndrome
weak vessels due to defective type III collagen synthesis
(hallmark)
causes aneurysm
11
Balance of collagen
degradation & synthesis is
altered by local
inflammatory infiltrates &
the destructive
proteolytic enzymes they
produce
Vascular wall is
weakened through loss of
smooth muscle cells /
inappropriate synthesis of
noncollagenous/nonelastic ECM
Debakey classifications of
Aortic dissection (next
page)
12
ANEURYSMS
Disease
Abdominal Aortic
Aneurysm (AAA)
Definition / Epidemiology
Associated with atherosclerosis
Major cause of AAA
At risk of IHD & stroke
MMP from inflamm cell infiltrates
Major influence that leads to aneurysm
Frequent in men & in smokers, rarely
before age 50
Two variants:
1.
Inflammatory AAAs (+) dense
periaortic fibrosis with lymphoplastic
inflamm with many macrophages & giant
cells
Cause uncertain
2.
Mycotic AAAs lesions that are infected
by microorgs that lodge in the wall
(primary Salmonella gastroenteritis)
suppuration futher destroys media
rapid dilation & rupture
Thoracic Aortic
Aneurysm
Pathogenesis
Athero plaque in the intima
compresses media
Morphology / Characteristics
Positioned below renal arteries &
above bifurcation of aorta
Can be saccular or fusiform
15 cm in diameter & 25 cm in length
Intima of the aneurysm (+) severe
atherosclerosis with destruction &
thinning of underlying media
Aneurysm contains: bland,
laminated, poorly organized mural
thrombus that may fill some or all of
dilated segment
Can affect renal & superior / inferior
mesenteric arteries by direct
pressure / by narrowing or
occluding vessel ostia with mural
thrombi
Accompanied by smaller aneurysms
of iliac arteries
1.
2.
3.
4.
5.
6.
7.
Aortic
Dissection
dissecting
aneurysm older
term, avoided
Manifestations:
Sudden excruciating pain (ant chest
back between the scapulae
downward)
Pain can be confused with that of MI
Cardiac tamponade
Aortic insufficiency
MI
Vascular obstruction
Transverse myelitis
Rupture of the dissection outward into
pericardial, pleural or peritoneal cavities
Most common cause of death
2 types of aortic dissections:
1.
Type A dissections (1 & 2 of Debakey)
more common & dangerous
Involves both ascending & descending
aorta / just the ascending aorta
2.
Type B dissections (2 of Debakey)
Distal lesions NOT involving ascending
part
Begins distal to subclavian artery
13
Arterioles, venules,
capillaries, occasionally
small arteries
MPO-ANCAs
- antineutrophilic cytoplasmic
Antibodies
- against myeloperoxidase (pANCA)
PR3-ANCAs
antineutrophilic cytoplasmic
antibodies
- against proteinase3 (c-ANCA)
Examples
Giant-cell
(temporal) arteritis
Takayasu arteritis
Polyarteritis nodosa
Kawasaki disease
Wegener
granulomatosis
Churg strauss
syndrome
Microscopic
poluangitis
Description
Granulomatous inflammation
Frequent: temporal artery
Patients > 50
Associated with polymyalgia
rheumatica
Granulomatous inflammation
Patients > 50
Necrotizing inflammation
Involves renal arteries
Spares pulmonary vessels
Arteritis with mucocutaneous
lymph node syndrome
In children
Involves coronary arteries with
aneurysm formation/thrombosis
Granulomatous inflammation
Involves respi tract
Necrotizing vasculitis
Small vessels(glomerular
vessels)
Associated with PR3-ANCAs
Eosinophil rich granulomatous
inflammation
Respi tract
Necrotizing vasculitis
Small vessels(glomerular
vessels)
Associated with
Asthma
Blood eosinophilia
MPO-ANCAs
Necrotizing small vessel vascultis
with few or no immune deposits
NOTE!
SMALL & LARGE VESSEL VASCULITIS: may involve medium-sized arteries
LARGE & MEDIUM SIZED VESSEL VASCULITIS: DO NOT involve vessels smaller than arteries
14
Disease
Non-infectious
vasculitis
1.
Type
Immune complex
associated vascultis
Pathogenesis
Antibody & complement
Ag-Ab complexes
Morphology
Clinical Features
2.
-
ANCA
Autoantibodies
c-ANCA or p-ANCA
antigenic targets are
intracellular
but PR3: (+) at low levels
on plasma membrane or
translocated to cell
surface in activated &
apoptotic neutrophils
3.
Giant-cell (Temporal
arteritis)
Most common
form in elderly
Anti-endothelial cell
antibodies
Chronic granulomatous
inflammation of large to smallsized arteries
HLA class 2 haplotypes
Response to steroids
Kawasaki disease
T cell mediated immune
response against an
unknown vessel wall antigen
Pro-inflamm cytokines
Anti-endothelial cell
humoral response
Takayasu Arteritis
pulseless disease
Most frequent in
Granulomatous vasculitis of
medium and larger arteries
Unknown;
Ocular disturbances
Immune reactions
speculated
corticosteroids
anti- TNF tx
Initial: non-specific
- fatigue
- weight loss
- fever
15
global, but
traditionally in
Japan
Polyarteritis Nodosa
(PAN)
Disease of young
adults (but can
occur at any age)
Dx: biopsy
Tx:
cyclophosphamide
(90% remission or
cure)
Fatal if untreated
- during acute
fulminant or
- protracted course
Unknown
Immune complex mediated
(HbsAg-HbsAb)
Different classes:
- classic idiopathic PAN
- cutaneous PAN
- PAN associated w/
chronic hepatitis
No association w/ ANCA
Lesions only involve part of vessel
circumference w/ predilection for
branch points
30% of patients:
- (+) hep B antigenemia
- (+) HbsAg-HbsAb
complexes in lesions
Kawasaki Disease
Mucocutaneous LN
syndrome
Acute, febrile, selflimited illness of
infancy and
Uncertain
Possibly genetic
Viral
Can be d/t delayed type
hypersensivity response of T
cells to unknown Ag
PAN-like
- pronounced inflammation on
vessel wall
- less prominent fibrinoid
necrosis
Acute vasculitis:
- subsides spontaneously or in
MI
childhood (80%
younger than 4)
Leading cause of
acquired heart
disease in children
Microscopic
Polyangiitis
Hypersensitivity
vasculitis
Leukocytoclastic
vasculitis
Tx:
cyclophosphamide
- induces remission
- improves long
term survival
- EXCEPT if have
widespread renal
or brain
involvement
Churg-Strauss
Syndrome
B cell activation
Formation of auto-Ab in
endothelial cells and
smooth muscles
Necrotizing vasculitis
Segmental fibrinoid necrosis of
media w/ focal transmural
necrotizing lesions
generally affects:
- capillaries, arterioles,
and venules smaller
than those affected in
PAN
MPO-ANCA: casually
implicated
Obscure
Can result from hyperresponsiveness to allergic
stimulus
Angiitis
Asthmatics:
- trigerred by leukotriene
receptor antagonists
Rare (1:1M)
Limited form:
Restricted to
respiratory tract
Widespread form:
Affects eyes, skin,
other organs (esp.
heart)
Resembles PAN, but
w/ respiratory
involvement
Pathogenic immune
complex deposition or
trigger secondary immune
complex (devt of p-ANCA)
Allergic
granulomatosis
Wegeners
Granulomatosis
Acute vasculitis
Ab response to Ag in:
- drugs (penicillin)
- microorganisms
(streptococci)
- heterologous proteins
- tumor proteins
Necrotizing vasculitis
T-cell mediated
hypersensitivity rxn
(+) granuloma and response
to immunosuppressive
therapy = possibly from
inhalation of infectious or
environmental agent
PR3-ANCA:
- (+) in 95% of cases
- marker for disease
- participates in
pathogenesis
Relapse:
- rise in PR3-ANCA after
immunosuppressive
therapy
response to Tx
Desquamative rash
Cervical LN enlargement
No granulomatous inflammation
Lesions are similar to PAN, but spare
medium-sized and larger arteries
Macroscopic infarcts uncommon
Only infiltrating, fragmenting
neutrophils are seen in post-capillary
venules
leukocytoclastic vasculitis
aneurysm
rupture,
thrombose
MI
sudden death
Pauci-immune injury:
little or no immunoglobulins
seen
pulmonary capillaritis
Associated with:
- asthma
- allergic rhinitis
- lung infiltrates
- peripheral hypereosinophilia
- extravascular necrotizing
granuloma
Triad:
1. Acute Necrotizing Granuloma
URT: ear, nose, throat, sinus
LRT
or both
2. Necrotizing or
Granulomatous Vasculitis
affects small to medium
vessels
(capillaries, venules,
arterioles, arteries)
most prominent in lungs
and upper airways
3. Renal disease:
- focal necrotizing
- crescenteric
glomerulonephritis
UR tract lesions:
- inflammatory sinusitis w/
muscosal granulomas
- ulcerative lesions of nose,
palate, or pharynx
rimmed by granulomas w/
geopgraphic patterns of
central necrosis and
vasculitis
Necrotizing Granuloma:
- surrounded by zone of
fibroblastic proliferation w/
giant cells and leukocyte
infiltrate
Multiple granulomas
coalesce
radiographically visible nodules that
can cavitate
Major Associations:
- cutaneous involvement
(palpable
purpura)
- GIT bleeding
- renal disease (primarily focal
and
segmental glomerulosclerosis)
Cardiomyopathy:
- d/t myocardial infiltrates and
eosinophils
involvement of heart in 60%
usual cause of death
M>F
Ave age: 40 y.o.
Classic features:
- persistent pneumonitis w/
bilateral nodular and cavitary
infiltrates (95%)
- chronic sinusitis (90%)
- muscosal ulcerationf of
nasopharynx (75%)
- renal disease (80%)
Other features:
- rashes
- muscle pains
- articular involvement
- mononeuritis or polyneuritis
- fever
17
Remission:
- negative test
- falling titers
Late stage:
- marked by extensive necrotizing
granulomatous involvement of
parenchyma
- alveolar hemorrhage
- lesions undergo progressive fibrosis
and organization
Renal Lesions:
- early: focal necrosis w/ thrombosis of
isolated glom capillary loops (focal
and segmental necrotizing
glomerulonephritis)
- minimal parietal cell proliferation in
Bowmans capsule
Thromboangiitis
Obliterans (Buerger
Disease)
Exclusive to
cigarette smokers
Usually before 35
y.o.
Common in:
- Israeli
- Indian
- Japanese
Tx:
- abstain from
smoking in early
stage
dramatic
relief
Tobacco
direct
endothelial cell toxicity OR
idiosyncratic immune
response
Patients have
hypersensitivity to injected
tobacco extracts
vessels
have IMPAIRED endothelium
dependent vasodilation
when challenged w/ Ach
Thrombus contents:
small microabscesses made of
neutrophils surrounded w/
granulomatous inflammation
thrombus
recanalize
vasculitis that resembles hypersensitivity angiitis or classic PAN can be associated with:
o
RA, SLE
o
Cancer
o
Systemic illness
Mixed cryoglobinemia
Antiphospholipid antibody syndrome
Henoch-Schonlein purpura
Rheumatoid Vaculitis:
o
Occurs after long-standing, severe RA
o
Usually affects small and medium arteries
o
Leads to:
visual infarction
clinically significant aortitis
Therapeutically impt. to identify underlying pathology
o
Ex. Lupus vasculitis and antiphosholipid antibody syndrome are morphologically
similar
Early:
- superficial nodular phlebitis
- cold sensitivity (Raynaud
type) in hands
- pain in instep of foot d/t
exercise
instep
claudication
Diff. from atherosclerosis:
- severe pain even at rest d/t
neuronal involvement
Chronic ulceration of toes, feet,
fingers
frank gangrene
Infectious Vasculitis:
localized arteritis
d/t direct invasion of infectious agents
o
bacteria or fungi
o
Aspergillus or Mucor species
Vascular Invasion:
o
Part of localized tissue infection (bacterial pneumonia or adjacent to abscess)
Can arise from hematogenous seeding of bacteria
Vascular Infections:
o
Weaken arterial walls
o
Culminates myotic aneurysm
o
Induce thrombosis and infarct
Inflammation induced thrombosis of meningeal vessels in bacterial meningitis cause
infarction of underlying brain
18
Esophageal varices
Liver cirrhosis (less frequently, portal vein obstruction or hepatic vein thrombosis)
hepatocellular carcinoma
renal cell carcinoma
IVC obstruction induces:
marked lower extremity edema
distention of the superficial
collateral veins of the lower
abdomen
massive proteinuria (because of
renal vein involvement)
LYMPHEDEMA
Primary lymphedema
due to an isolated congenital defect
(simple congenital lymphedema)
or as familial Milroy disease
(heredofamilial congenital lymphedema),
which causes lymphatic agenesis or
hypoplasia
Secondary or obstructive lymphedema
due to a blockage of a previously normal
lymphatic
obstruction can result from:
Malignant tumors obstructing
lymphatic channels or regional
lymph nodes
Surgical procedures that remove
regional groups of lymph nodes
Post-irradiation fibrosis
Filariasis
Post- inflammatory thrombosis and
scarring
increases hydrostatic pressure in the
lymphatics distal to the obstruction
20