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Flashcards in Robbins pg. 332-342 Deck (57)
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What is hypertension defined as systolically and diastolically?

diastolic pressures greater than 90 mm Hg, or sustained systolic pressures in excess of 140 mm Hg-- associated with an increased risk of atherosclerosis


What is malignant hypertension?

A small percentage of hypertensive patients (approximately 5%) present with a rapidly rising blood pressure that, if untreated, leads to death in within 1 to 2 years.

Such malignant hypertension usually is severe (i.e., systolic pressures over 200 mm Hg or diastolic pressures over 120 mm Hg) and associated with renal failure and retinal hemorrhages, with or without papilledema. It can arise de novo but most commonly is superimposed on preexisting benign hypertension.


What are the major causes of hypertension?

- idiopathic (95%)- aka essential hypertension
- 'secondary hypertension'


What are the major causes of secondary hypertension?

- Primary renal disease
- Endocrine dysfunction
- CV
- Neurologic


Some relatively rare single-gene disorders cause hypertension (and hypotension) by affecting renal sodium resorption. Name some.

• Gene defects in enzymes involved in aldosterone
metabolism, leading to increased aldosterone secretion, increased salt and water resorption, and plasma volume expansion

• Mutations in proteins that affect sodium resorption
(as in Liddle syndrome, which is caused by mutations in ENaC, leading to increased distal tubular resorption of sodium induced by aldosterone)


Although the specific triggers are unknown, what are some of the main processes involved in essential hypertension?

• Reduced renal sodium excretion in the presence of normal arterial pressure. At the new higher blood pressure, the kidneys excrete additional sodium.

• Increased vascular resistance may stem from
vasoconstriction or structural changes in vessel
walls. These are not necessarily independent factors, as chronic vasoconstriction may result in permanent thickening of the walls of affected vessels.

• Genetic factors
Hypertension has been linked to specific angiotensinogen
polymorphisms and angiotensin II receptor variants; polymorphisms of the renin-angiotensin system also may contribute to the known racial differences in blood pressure regulation.

• Environmental factors, such as stress, obesity, smoking, physical inactivity, and high levels of salt consumption, modify the impact of genetic determinants.


How does reduced sodium excretion increase blood pressure?

Decreased sodium excretion causes an obligatory increase in fluid volume, increasing filling pressure, and thus increased cardiac output, thereby elevating AP.


Does hypertension cause atherogenesis?

Yes, it accelerates atherogenesis but also causes degenerative changes in the walls of large and medium sized arteries that can lead to aortic dissection and cerebrovascular hemorrhage.


What are two forms of small blood vessel disease that are hypertension-related?

-hyaline arteriolosclerosis
-hyperplastic arteriolosclerosis


What is hyaline arteriolosclerosis?

A condition associated with benign hypertension that is marked by homogeneous, pink hyaline thickening of arteriolar walls and lumenal narrowing


What causes hyaline arteriolosclerosis?

Leakage of plasma components across injured endothelial cells into vessel walls results in increased ECM production by smooth muscle cells in response to chronic hemodynamic stress.


How is the kidney affected by hyaline arteriolosclerosis?

The arteriolar narrowing caused by hyaline arteriosclerosis leads to diffuse vascular compromise and nephrosclerosis (glomerular scarring).


What is hyperplastic arteriosclerosis?

a condition associated with severe hypertensions in which vessels exhibit "onionskin" concentric laminated thickening of arteriolar walls and luminal narrowing

In malignant hypertension these changes are accompanied by fibrinoid deposits and vessel wall necrosis (necrotizing
arteriolitis), which are particularly prominent in the kidney


Vascular injury leading to endothelial cell loss or dysfunction stimulates what?

smooth muscle cell growth and associated matrix synthesis.


T or F. Intimal thickening is a stereotypical response of the vessel wall to any insult

T. With persistent or recurrent insults, further thickening can occur that leads to the stenosis of small and medium-sized blood vessels


What is different about neointimal smooth muscle cells from medial smooth muscle cells in the media?

neointimal smooth muscle cells lack the capacity to contract like medial smooth muscle cells, but do have the capacity to divide and have a considerably greater synthetic capacity than their medial colleagues


How are neointimal smooth muscle cells formed?

- previously thought to arise from dedifferentiated medial smooth muscle cells
- increasing evidence suggests that at least a subset is derived from circulating precursor cells


Intimal thickening is an invariable consequence of endothelial insult. When else does it occur?

Intimal thickening appears to be a part of normal aging.

Such age-related intimal change typically is of no consequence, in part because compensatory outward remodeling of the vessel results in little net change in the luminal diameter.


What is arteriosclerosis?

“hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity.


What are the three types of arteriosclerosis?

• "Arteriolosclerosis" affects small arteries and arterioles and may cause downstream ischemic injury. The two variants are hyaline and hyper plastic arteriolosclerosis.

• "Mönckeberg medial sclerosis" is characterized by the presence of calcific deposits in muscular arteries, typically in persons older than 50. The lesions do not encroach on the vessel lumen and usually are not clinically significant

• "Atherosclerosis" is the most frequent and clinically important pattern


What is Atherosclerosis?

a condition characterized by the presence of intimal
lesions called atheromas (or atheromatous or atherosclerotic plaques). Atheromatous plaques are raised lesions composed of soft grumous lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps.


What are some possible complications of atherosclerotic plaque?

- can mechanically obstruct vascular lumina and are prone to rupture, resulting in catastrophic vessel thrombosis.

- Plaques also weaken the underlying media, sometimes leading to aneurysm formation.


Where in the world is atherosclerosis common?

-US and Europe
-less common in Central and South America, Africa, and parts of Asia


T or F. The risks (constitutional or environmental/acquired) of MI have a multiplicative effect

T, Thus, two factors increase the risk of myocardial infarction approximately four-fold, and three (i.e., hyperlipidemia, hypertension, and smoking), increase the rate by a factor of 7


What are some constitutional risk factors for atherosclerosis?

-gender (premenopausal women are slightly protected)

After menopause, however, the incidence of atherosclerosis-related diseases increases and, in old age, even exceeds that in men


T or F. Postmenopausal estrogen replacement appears
to decrease cardiovascular risk.

F. it increases it


What are some acquired risk factors for atherosclerosis?

- hyperlipidemia (hypercholesterolemia)
- hypertension
- cigs
- diabetes mellitus


What does LDL do? HDL?

LDL distributes cholesterol to peripheral tissues. When LDL is too high, some cholesterol is deposited into vessel walls.

By contrast, high-density lipoprotein (HDL) mobilizes cholesterol from developing and existing vascular
plaques and transports it to the liver for biliary excretion. Consequently, higher levels of HDL correlate with reduced risk.


Is hypertension really associated with heart disease?

Yes, it can increase the risk of IHD by 60%. Hypertension also is the major cause of left ventricular hypertrophy (LVH),
which also can contribute to myocardial ischemia


Why would diabetes mellitus increase IHD risk?

Diabetes mellitus is associated with raised circulating
cholesterol levels and markedly increases the risk of atherosclerosis. Other factors being equal, the incidence of MI is twice as high in diabetics as in non-diabetics.

In addition, this disorder is associated with an increased risk of stroke and a 100-fold increase in atherosclerosis-induced gangrene of the lower extremities.


Other factors that contribute to CV disease risk?

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


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.


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


What is the response-to-injury

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


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


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


How are lipids usually transported in blood?

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


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


The dominant lipids in atheromatous plaques are what?

cholesterol and cholesterol esters.


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


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.


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)


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.


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.


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.


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.


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.


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


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


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.


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.


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.


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


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


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.


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.”


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.