Robbins pg. 332-342 Flashcards Preview

Cardio Week 1 > Robbins pg. 332-342 > Flashcards

Flashcards in Robbins pg. 332-342 Deck (57)
Loading flashcards...
31

Other factors that contribute to CV disease risk?

- Inflammation
- CRP levels
- Hyperhomocysteinemia
- Metabolic syndrome
- Lipoprotein(a) levels
- Elevated levels of procoagulants

32

Why would high levels of CRP increase plaque formation?

CRP is an acute-phase reactant synthesized in response to a variety of inflammatory cytokines. Locally, CRP secreted by cells within atherosclerotic plaques can activate endothelial cells, increasing adhesiveness and inducing a prothrombotic state.

CRP levels strongly and independently predict the risk of MI, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy persons.

While there is no direct evidence that lowering CRP diminishes cardiovascular risk, it is of interest that CRP is reduced by smoking cessation, weight loss, and exercise. Moreover, statins reduce CRP levels independent of their LDL cholesterol-lowering effects, suggesting a possible anti-inflammatory action of these agents.

33

What are the two dominant theories regarding atherogenesis?

one emphasizing intimal cellular proliferation in response to endothelial injury, and the other focusing on repeated formation and organization of thrombi

34

What is the response-to-injury
hypothesis?

the model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression involves interaction of modified lipoproteins, monocyte derived macrophages, T lymphocytes, and the cellular constituents of the arterial wall

35

Describe atherogenesis via the response-to-injury hypothesis.

• Endothelial injury—and resultant endothelial
dysfunction—leading to increased permeability, leukocyte adhesion, and thrombosis

• Accumulation of lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall

• Platelet adhesion

• Monocyte adhesion to the endothelium, migration
into the intima, and differentiation into macrophages and foam cells

• Lipid accumulation within macrophages, which release
inflammatory cytokines

• Smooth muscle cell recruitment due to factors
released from activated platelets, macrophages, and vascular wall cells

• Smooth muscle cell proliferation and ECM
production

36

T or F. Early human atherosclerotic lesions begin at sites of intact, but dysfunctional endothelium

T. These dysfunctional endothelial cells exhibit increased permeability, enhanced leukocyte adhesion, and altered gene expression, all of which may contribute to
the development of atherosclerosis

37

How are lipids usually transported in blood?

Lipids typically are transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes).

38

What do dyslipidemias arise from?

Dyslipoproteinemias can result from mutations in genes that encode apoproteins or lipoprotein receptors, or from disorders that derange lipid metabolism, e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes
mellitus

39

The dominant lipids in atheromatous plaques are what?

cholesterol and cholesterol esters.

40

How does dyslipidemia contribute to atherogenesis?

Chronic hyperlipidemia, particularly hypercholesterolemia,
can directly impair endothelial cell function by increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.

• With chronic hyperlipidemia, lipoproteins accumulate
within the intima, where they are hypothesized to generate
two pathogenic derivatives, oxidized LDL and cholesterol
crystals.

41

How is LDL oxidized?

LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or endothelial cells and ingested by macrophages through the scavenger receptor, resulting in foam cell formation.

42

What does oxidized LDL result in?

Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to endothelial cells and smooth muscle cells. More recently, it has been shown
that minute extracellular cholesterol crystals found in early atherosclerotic lesions serve as “danger” signals that activate innate immune cells such as monocytes and
macrophages (aka initiating inflammation)

43

What does inflammation promote?

Normal vessels do not bind inflammatory cells. Early in atherogenesis, however, dysfunctional endothelial cells express VCAM-1, in particular, binds monocytes and T cells.

After these cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines.

44

What do monocytes do once in the intima?

Monocytes differentiate into macrophages and avidly
engulf lipoproteins, including oxidized LDL and small
cholesterol crystals

Activated macrophages also produce toxic oxygen species that further drive LDL oxidation and elaborate growth factors that stimulate smooth muscle cell proliferation.

45

What do T cells do once in the intima?

Activated T cells in the growing intimal lesions elaborate inflammatory cytokines (e.g., IFN-γ), which stimulate macrophages, endothelial cells, and smooth muscle cells.

46

As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote smooth muscle cell proliferation and matrix synthesis.

As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote smooth muscle cell proliferation and matrix synthesis.

47

How does infection lead to atherosclerosis? Which viruses?

Herpesvirus, CMV, and Chlamydia pneumoniae all have been found in atherosclerotic plaque, and sero-epidemiologic studies show increased antibody titers to Chlamydia pneumoniae in patients with more severe atherosclerosis.

Infections with these organisms, however, are exceedingly common (as is atherosclerosis), making it difficult to draw conclusions about causality.

48

What is a fatty streak?

Intimal smooth muscle cell proliferation and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into a mature atheroma, thus contributing to the progressive growth of atherosclerotic lesions

49

What is the role of smooth muscle cells in plaque formation again?

The recruited smooth muscle cells synthesize ECM (most
notably collagen), which stabilizes atherosclerotic plaques

50

What are fatty streaks composed of?

They are composed of lipid-filled foamy macrophages but are only minimally raised and do not cause any significant flow disturbance.

51

When are fatty streaks common?

Fatty streaks can appear in the aortas of infants younger than 1 year of age and are present in virtually all children older than 10 years, regardless of genetic, clinical, or dietary risk factors.

52

Do all fatty streaks progress to plaque?

The relationship of fatty streaks to atherosclerotic plaques is uncertain; although fatty streaks may evolve into plaques, not all are destined to progress.

Nevertheless, it is notable that coronary fatty streaks form during adolescence at the same anatomic sites that are prone to plaques later in life.

53

What vessels are most commonly affected by plaque formation?

-infrarenal abdominal aorta,
-the coronary arteries,
-the popliteal arteries,
-the internal carotid arteries,
-the vessels of the circle of Willis

54

Atherosclerotic plaques have three principal components:

(1) cells, including smooth muscle cells, macrophages, and T cells;

(2) extracellular matrix, including collagen, elastic fibers, and proteoglycans; and

(3) intracellular and extracellular lipid

55

Describe the composition of most plaques.

Most commonly plaques have a superficial fibrous cap composed of smooth muscle cells and relatively dense collagen.

Where the cap meets the vessel wall (the “shoulder”) is a more cellular area containing macrophages, T cells, and smooth muscle cells.

56

What is deep to the fibrous cap?

Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), necrotic debris, lipid-laden macrophages and smooth muscle cells (foam cells), fibrin, variably organized thrombus, and other plasma proteins.

The extracellular cholesterol frequently takes the forms of crystalline aggregates that are washed out during routine
tissue processing, leaving behind empty “cholesterol clefts.”

57

Lesion description

The periphery of the lesions shows neovascularization
(proliferating small blood vessels).

The media deep to the plaque may be attenuated and exhibit fibrosis secondary to smooth muscle atrophy and loss. Typical atheromas contain relatively abundant lipid, but some so-called fibrous plaques are composed almost exclusively of smooth muscle cells and fibrous tissue.