B P4 C24 The Vascular Biology of Atherosclerosis Flashcards
This molecule serve as a cofactor for antithrombin III, causing a conformational change that allows this inhibitor to bind to and inactivate thrombin
Heparan Sulfate
Molecule that binds thrombin molecules and can exert antithrombotic properties by activating proteins S and C
Thrombomodulin
The _____ cell of the arterial intima constitutes the crucial contact surface with blood
Endothelial cell (EC)
Should a thrombus begin to form, the normal EC possesses potent fibrinolytic mechanisms associated with its surface. The EC can produce both:
Tissue-plasminogen activator (t-PA)
and
Urokinase-type plasminogen activator (u-PA)
Catalyze the activation of plasminogen into plasmin, a fibrinolytic enzyme
t-PA and u-PA
The second major cell type of the normal artery wall, the _____, has many important functions in normal vascular homeostasis, as a target of therapies in cardiovascular medicine and in the pathogenesis of arterial diseases
Smooth muscle cell (SMC)
However, in larger arteries involved in atherosclerosis, abnormal smooth muscle contraction may cause _____, a complication of atherosclerosis that may impede blood flow.
Vasospasm
Death of SMCs may promote:
Destabilization of atheromatous plaques
Ectatic remodeling
Aneurysm formation
In the descending aorta and arteries of the lower body, the regional ___ serves as the source of smooth muscle precursors.
Mesoderm
However, in arteries of the upper body, SMCs can derive from a completely different germ layer—the _____,rather than mesoderm
Neuroectoderm
The heterogeneity of SMCs may have direct clinical implications to help understand several common observations, such as the propensity of certain arteries or regions of arteries to develop atherosclerosis or heightened responses to injury (e.g., _____), and medial degeneration (e.g., ____)
Propensity to develop atherosclerosis/heightened response to injury (pLAD)
Medial degeneration (proximal aorta in Marfan Syndrome)
The vasa vasorum and nerve endings localize in this layer of the arterial wall
Adventitia
This structure appears well adapted to the storage of the kinetic energy of left ventricular systole by the walls of great arteries.
Tunica Media
The first steps in human atherogenesis remain largely conjectural, but the integration of observations of tissues obtained from young humans with the results of experimental studies of atherogenesis in animals provides hints in this regard.
On initiation of an atherogenic diet, typically rich in cholesterol and saturated fat, _____.
Small lipoprotein particles accumulate in the intima (steps 1 and 2)
Lipoprotein particles bound to _____ have increased susceptibility to oxidative or other chemical modifications, considered by many to contribute to the pathogenesis of early atherosclerosis (step 2)
Proteoglycan
Another hallmark of atherogenesis is ____
Leukocyte recruitment and accumulation
Members of the immunoglobulin (Ig) superfamily include:
VCAM-1
CD106
This integrin is characteristically expressed by only those classes of leukocytes that accumulate in nascent atheroma—monocytes and T cells.
Very late antigen-4 (VLA-4)
The location of the lesion predilection at _____ portions of arteries after branch points or bifurcations at flow dividers, suggests a hydrodynamic basis for early lesion development.
Proximal
Arteries without many branches (e.g., the internal mammary and radial arteries) tend not to develop atherosclerosis.
_____ can reduce oxidative stress by catabolizing the reactive and injurious superoxide anion.
SOD
Endothelial NOS produces the well-known endogenous vasodilator _____.
Nitric oxide
Beyond its vasodilating actions, NO can resist inflammatory activation of endothelial functions, including the expression of VCAM-1.
NO appears to exert this anti-inflammatory action at the level of gene expression by interfering with the transcriptional regulator nuclear factor kappa B (NF-kB).
IkBa, an intracellular inhibitor of this important transcription factor. NFkB regulates numerous genes involved in inflammatory responses in general and in atherogenesis in particular.
Pulsatile (unidirectional) laminar flow induced the pivotal transcription factors (__), which coordinately elicit a palette of atheroprotective function.
Krüppel-like factor [KLF]-2
KLF4
Nuclear factor erythroid 2–related factor [Nrf]-2
The monocyte, once recruited to the arterial intima, can imbibe lipid and become a _____.
Foam cell or lipid-laden macrophage (Step 5)
Instead of the classic LDL receptor, various _____ receptors appear to mediate the excessive lipid uptake characteristic of foam cell formation
Scavenger receptors
The factors that trigger macrophage cell division in the atherosclerotic plaque probably include hematopoietic growth factors such as:
Macrophage colony-stimulating factor (M-CSF)
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
Interleukin-3 (IL-3)
Precursor lesion of a complex atheroma
Fatty Streak
____ can exert anti-inflammatory effects.
TGF-β and IL-10
Angiogenesis factors include:
VEGF
FGF
Placental growth factor (PlGF)
Oncostatin M
____ can antagonize plaque mineralization by inhibiting RANKL signaling.
Osteoprotegerin
_____, a genome- wide association study (GWAS) “hit” on atherosclerosis, regulates the loading of alkaline phosphatase into extracellular vesicles, thereby promoting calcification.
Sortilin (Sort-1)
Luminal stenosis tends to occur only after the plaque burden exceeds approximately __% of the cross-sectional area of the artery.
40% of CSA
Lesions that produce stenoses of greater than ___% can cause flow limitations under conditions of increased demand.
> 60%
Several major modes of plaque disruption provoke most coronary thrombi.
The first mechanism, accounting for about two thirds of acute MIs, involves a _____.
Another mode involves a _____, accounting for a quarter to a third of acute MIs.
Fracture of the plaque’s fibrous cap (2/3)
Superficial erosion of the intima (1/3)
The process of in-stent stenosis, in contrast with restenosis after balloon angioplasty, depends primarily on _____ as opposed to negative remodeling.
Intimal Thickening
The stent provides a firm scaffold that prevents constriction from the ______
Adventitia
The risk of late thrombosis after radiation brachytherapy or with stents that contain anti-proliferative agents may relate to ______, with attendant loss of the anticoagulant and pro-fibrinolytic properties of the normal intimal lining
Impaired endothelial healing
Characteristics of thrombosis due to erosion
- Fibrous cap thick and intact
- “White” fibrin-rich thrombus
- Collagen trigger
- Smooth muscle cells prominent
- Often sessile, nonocclusive thrombus
- Usually less remodeled outward
- Neutrophil extracellular traps (NETs) involved
- More frequent in non-STEMI?
Characteristics of thrombosis due to rupture
- Thin fibrous cap with fissure
- “Red” fibrin-rich thrombus
- Tissue factor trigger
- Macrophages prominent
- Often occlusive thrombus
- Usually expansively remodeled
- Less NET involvement?
- More frequently causes STEMI?
Thin fibrous caps associate with plaque rupture, probably resulting from _____.
Reduced collagen synthesis and increased degradation
Plaques that have fatally ruptured exhibit another microanatomic feature:
Prominent accumulation of macrophages with a large lipid pool
Most plaque disruptions do not give rise to clinically apparent coronary events.
True/False
True
Careful pathoanatomic examination of hearts obtained from patients who have succumbed to noncardiac death has shown a surprisingly high incidence of focal plaque disruptions with limited mural thrombi.
The “burned-out” fibrous and calcific atheroma may represent a _____ stage of a plaque that previously was lipid rich with characteristics associated with rupture, but that has become fibrous and hypocellular because of a wound-healing response mediated by the products of thrombosis and calcification seeded by cell death
Late
The amount of _____ in the lipid core of a plaque (the solid state) can control the degree of clot formation that will ensue after disruption
Tissue Factor
The level of ______ in the fluid phase of blood can influence whether a plaque disruption will cause an occlusive thrombus that can precipitate an acute ST-segment elevation myocardial infarction (STEMI) or yield merely a small asymptomatic mural thrombus
Fibrinogen
Elevated levels of inhibitors of fibrinolysis, such as _____, will impede the ability of endogenous thrombolytic enzymes to limit thrombus growth or persistence
Plasminogen Activator Inhibitor-1 (PAI-1)
Work on the pathophysiology of restenosis after angioplasty initially focused on smooth muscle proliferation.
Much of the thinking regarding the pathobiology of restenosis or in-stent stenosis depended on the extension to the human situation of the results of withdrawal of an _____ in previously normal animal arteries.
Overinflated balloon or overexpanded stent
The use of _____ stents that release agents with anti-inflammatory and antiproliferative properties has greatly reduced in-stent stenosis, and newer-generation DES appear to have a limited potential for augmenting late stent thrombosis associated with earlier DES
Drug-eluting stents (DES)
The risk of late thrombosis after radiation brachytherapy or with stents that contain antiproliferative agents may relate to:
- Impaired endothelial healing
- Attendant loss of the anticoagulant and profibrinolytic properties of the normal intimal lining
The term _____(hardening of the arteries) rather than atherosclerosis (gruel-hardening) is preferable in describing this process because of the inconstant association with lipids (the “gruel” in atherosclerosis)
Arteriosclerosis
Graft coronary disease is _____, not only affecting the proximal epicardial coronary vessels but also penetrating smaller intramyocardial branches
Concentric and diffuse
Characteristics of graft arteriosclerosis
Concentric lesion
No lipid core
Diffuse distribution
Characteristics of typical atherosclerosis
Eccentric lesion
Lipid deposits
Focal distribution
Interruption of _____ signaling can prevent experimental graft coronary disease in mice.
IFN-γ
In particular, aneurysmal disease characteristically affects the _____ abdominal aorta. This region is highly prone to the development of atherosclerosis.
Infrarenal
Data from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study show that the _____ surface of the infrarenal abdominal aorta has a particular predilection for the development of fatty streaks and raised lesions in Americans younger than 35 years who died of noncardiac reasons
Dorsal surface
Because of the absence of _____, the relative lack of blood supply to the tunica media in this portion of the abdominal aorta might explain the regional susceptibility of this part of the arterial tree to aneurysm formation.
Vasa vasorum
In addition, the _____ lordosis of the biped human may alter the hydrodynamics of blood flow in the distal aorta, causing flow disturbances that may promote lesion formation.
Lumbar lordosis
In typical coronary artery atherosclerosis, expansion of the intimal lesion produces stenotic lesions. The tunica media underlying the expanded intima often is _____, but its general structure remains relatively well _____.
Expanded intima: thinned
General structure: preserved
_____ destruction of the arterial architecture occurs in aneurysmal disease. In particular, the usually well-defined laminar structure of the normal tunica media disappears with obliteration of the elastic laminae.The tunica media of advanced aortic aneurysms have _____ SMCs, which are often prominent in typical stenotic lesions.
Transmural
Few SMCs
Mechanisms of the pathology of aneurysmal disease
- MMP overexpression
- ATII
- TGF-β signaling mutation
- Adventitial inflammation
- Elastic laminae destruction
In atherosclerotic mice, _____ potentiates aneurysm formation.
Angiotensin II
A considerable body of seroepidemiologic evidence supported a role for certain bacteria, notably _____, and certain viruses, notably _____, in the etiology of atherosclerosis
Chlamydia pneumoniae
Cytomegalovirus (CMV)
These microvessels probably form in response to angiogenic peptides overexpressed in atheroma. These angiogenesis factors include:
Vascular endothelial growth factor (VEGF) forms of fibroblast growth factors
Placental growth factor (PlGF)
Oncostatin M
