Atherosclerosis

______ are the carriers for lipids in the bloodstream.

Lipoproteins

Monocyte recruitment leads to:

Macrophage inflammation Macrophages evolve into foam cells.

What cells are found in the fatty streak?

Macrophages with some T-cells

Which regions of the artery is the most vulnerable region to rupture?

at the junction between the healthy tissue and plaque - the shoulder region.

Where are accumulations of lipids typically found?

at the point of vessel bifurcation

What cells are found in the atheroma?

blood-borne inflammatory + immune cells + endothelial cells + smooth muscle cells In the center of an atheroma, foam cells and extracellular lipid droplets form a core region which is surrounded by a cap of smooth muscle cells and a collagen rich matrix.

Plaques can become increasingly complex, with ______, ________, and ______.

calcification ulceration at the lumenal surface; hemorrhage from the small vessels that grow into the lesion from the media of the blood vessel wall.

What do lipoproteins carry?

cholesterol and triglycerides

The probability of a major thrombotic event depends upon the balance between the ...?

competing processes of coagulation and fibrinolysis

Activated immune cells in the plaque produce inflammatory cytokines (interferon-γ, interleukin-1, and tumor necrosis factor [TNF]), which induce the production of substantial amounts of ________.

interleukin-6

Lipolysis of VLDL leads to the formation of ______ and ______.

intermediate density lipoprotein (IDL); low density lipoprotein (LDL)

What are foam cells?

lipid-filled macrophages

Glycerol and FA in chylomicrons are taken to the liver for breakdown by ________.

lipoprotein lipase

What is the gold standard for detecting and defining the severity of atherosclerotic progression?

quantitative coronary angiography

What is VLDL?

transports triglycerides from liver to body tissues TG is removed and leaves LDL

Which layer of the artery contributes most to its mechanical strength?

tunica media

High levels of ___________ could indicate atherosclerotic development.

C-reactive protein (CRP)

____________ reduces NO and SOD production.

Turbulent flow *Laminar flow promotes NO production.

Where does the fibrous cap form?

in the lumen

What are the characteristics of endothelial cells after being activated by inflammation?

-Increase permeability -Increase inflammatory cytokines -Increase leukocyte adhesion molecules -Decrease vasodilatory molecules -Decrease antithrombotic molecules

Interleukin-6, in turn, stimulates the production of large amounts of acute-phase reactants, including ...?

C-reactive protein (CRP), serum amyloid A, and fibrinogen, especially in the liver.

What is atheroma?

-Atherosclerotic lesion -a fibroinflammatory lipid plaque -caused by abnormal lipid metabolism

What are the characteristics of smooth muscle cells after being activated by inflammation?

-Increase inflammatory cytokines -Increase extracellular matrix synthesis -Increase migration and proliferation into subintima

Three stages of plaque development:

1 - Fatty streak (accumulation of foam cells) 2 - Plaque progression-vessel occlusion 3 - Plaque disruption

The two most important risk factors worldwide for acute MI were...?

1. Abnormal apolipoprotein B/apolipoprotein A-1 (ApoB/ApoA-1) ratio 2. Cigarette smoking

Some complications of atherosclerosis:

1. Calcification -rigidity to vessel wall which increases fragility 2. Rupture/Ulceration -Leads to thrombus formation or further material incorporation into the plaque 3. Embolism -Embolization of fragments disrupted can transport to distal sites 4. Hemorrhage 5. Stenosis

What are modifiable risk factors for atherosclerosis?

1. Dyslipidemia -Elevated LDLs can result from either a high fat diet or a genetic defect of the LDL receptor. 2. Tobacco smoking -Increases LDL and induces endothelial dysfunction allowing for migration into the intimal layer. 3. Hypertension -Also leads to increase in LDL retention and higher LDL binding to SMC. 4. Diabetes -Diabetes causes glycation of LDL which will further induce endothelial dysfunction. 5. Sedentary lifestyle

Evolution of atherosclerotic plaque

1. LDL infiltration 2. Monocyte recruitment 3. T-cell activation 4. Cytokine cascade

Foam cell production

After monocytes adhere to and penetrate the intima, they differentiate into phagocytic macrophages and imbibe lipoproteins to form foam cells. Macrophages do not possess classic cell surface LDL receptors, rather possess scavenger receptors that preferentially bind and internalize mLDLs. Initially, there is benefit to the accumulation of mLDLs but ultimately the impaired efflux of these cells in plaque serves as a source of proinflammatory cytokines. Macrophages secrete various factors involved in propagating the atherosclerotic plaque, including factors involved in lipid metabolism, inflammation and proteolysis. VLA4, very late activation protein 4 (also known as 41-integrin).

Non-modifiable risk factors for atherosclerosis:

Age, male, heredity

Most of the activated T cells produce _______, which activate macrophages and vascular cells, leading to inflammation.

Th1 cytokines (e.g., interferon-γ)

What is atherosclerosis?

Atherosclerosis is a pathologic process that causes disease of coronary, cerebral, peripheral arteries and aorta. Atherosclerosis begins in childhood and atherosclerotic lesions develop with age. A progressive disease characterized by accumulation of lipids and fibrous elements in the large arteries. Atherosclerosis is a general term describing any hardening (and loss of elasticity) or medium or large arteries.

What is the #1 cause of death in the US?

Cardiovascular disease (about 25% of Americans have some form)

What is the major form of circulating triglycerides?

Chylomicrons

A factor causal in the development of atherosclerosis characterized by abnormal lipid levels:

Dyslipidemia

Normal structure of the artery wall

Endothelial cells -Structural, functional and signaling roles -Resist attachment of WBC -Normally exhibits anticoagulant, profibrinolytic properties (prevent clot) Vascular smooth muscle cells -Contractile and synthetic capabilities -Can migrate and proliferate Extracellular Matrix -Collagen - biomechanical strength -Elastin - flexibility -Involved in regulation of cell growth and apoptosis

T/F: Fatty cells are most prevalent in older individuals.

False. Young people.

In which decade of life does atherosclerosis begin?

Fatty lesions which result as lipids accumulate in the subendothelial space can be found as early as the first decade, but are clinically silent. Further accumulation of lipids continue with expansion of the lesion. Fatty lesions = intracellular lipid accumulations

First decade = Second decade = Third decade = Fourth decade =

First decade = Fatty streaks in aorta Second decade = Fatty streaks in coronary Third decade = Fatty streaks in cerebral vessels Fourth decade = Fatty streaks in cerebral vessels

What is the underlying pathology of atherosclerosis?

Imbalanced lipid metabolism and maladaptive immune response

Plaques develop in which arterial layer?

Intima

In normal endothelium, what molecule prevents platelet aggregation and is anti-inflammatory?

Nitric oxide NO is a vasodilator.

Can cardiac cells regenerate?

No

Are atherosclerotic lesions symmetrical?

No - assymetrical

Do you find atherosclerosis in veins?

No - medium/large arteries

Leukocyte recruitment

Recruitment of leukocytes (monocytes, neutrophils, dendritic cells, mast cells and T-lymphocytes) is key in atherogenesis. The process depends on leukocyte adhesion molecules (LAM) and chemoattractant signals that direct the cellular passage. Two major subsets of LAMs persist in the plaque: 1 - immunoglobulins molecules vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1) 2 - selectin molecules, particularly P and E selectin. Macrophages also release factors that leads to the accumulation of smooth muscle cells.

Which regions of the artery is the least vulnerable region to rupture?

Regions with thick fibrous caps are less likely to rupture and are known as stable plaques whereas those with thin caps are known as vulnerable plaques.

Some factors that lead to endothelial dysfunction through ROS production:

Smoking, high lipid environment, and diabetes

In normal endothelium, what normally protects against reactive oxygen species (ROS)?

Superoxide dysmutase (SOD)

LDL infiltration activates:

The endothelium

Plaque rupture can lead to:

Thrombus formation and vessel occlusion --> main cause of infarction

Endogenous triglyceride metabolism starts with the formation and secretion of _______ by the liver.

VLDL

What is atherosclerosis characterized by?

accumulation of inflammatory cells, smooth muscle cells, lipid, and connective tissues in the intima

The atheroma is proceeded by a ______, an accurate,ulation of lipid-laden cells beneath the endothelium.

fatty streak

What is HDL?

high density lipoprotein (good cholesterol) -Carry cholesterol from periphery back to liver -Protective

Lipoproteins have a ______ lipid core and _____ outer layer of ______ and _____.

hydrophobic; hydrophilic; phospholipid; apolipoprotein

What is LDL?

low density lipoprotein (bad cholesterol) -Rich in cholesterol -Carry cholesterol to non-liver cells -Most significant

Degradation is mediated in part by a class of proteolytic enzymes known as ________ which are released from the foam cells.

matrix metalloproteinases (MMP)

The activation of macrophages and mast cells also causes the release of _______ and _________, which directly attack collagen and other components of the tissue matrix, further weakening the vessel wall. These cells may also produce _______ and _______ factors that directly precipitate the formation of thrombus at the site of plaque rupture.

metalloproteinases; cysteine proteases; prothrombotic; procoagulant

Fatty streaks have a fibrous cap made of ______ and _____ that enclose a _____ rich necrotic core.

smooth muscle cells; extracellular matrix; lipid

Chylomicrons

the class of lipoproteins that transport lipids from the intestinal cells to the liver reaches the systemic circulation via the thoracic duct they are cleared rapidly by lipoprotein lipase (LPL) present on the endothelium of capillaries in skeletal muscle and adipose tissue.

The transition from foam cell to fibrous atheromatous plaque involves ....?

the migration of smooth muscle cells from the arterial media to the intima, proliferation of SMCs occurs within the intima and secretion of extracelluar matrix macromolecules by the SMCs.