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1

What are the differences between normal and active endothelial cells and SM cells?

Normal EC: Impermeable to large molecules, anti-inflammatory, resist leukocyte adhesion, promote vasodilation, resist thrombosis

Active EC: Increased permeability, inflammatory molecules, and leukocyte adhesion molecules, as well as decreased vasodilators and anti-thrombotic agents

Normal SMCs: Normal contractile function, maintain EC matrix, contained in medial layer

Active SMCs: Increased inflammatory cytokines, EC matrix synth, and migration and proliferation into subintimal layer.

2

Describe specific steps in the formation of an atheroma.

LDL is retained in the intimal layer, then modified. Once modified, it activates endothelial cells and is taken up by macrophages. Activated endothelial cells have leukoctye adhesion molecules that bind monocytes which then migrate and enter intimal layer where they differentiate into macrophages with TLRs which can bind oxidized LDL. When the macrophages take up LDL, they release inflammatory cytokines, chemokines, proteases, and radicals, leading to more inflammation and tissue damage. This also leads to activation of other immune cells (T cells) which leads to more inflammation and the activation of SMCs. SMCs migrate and proliferate into the intima and release EC matrix to form a fibrous layer. Macrophages release MMPs which break up the fibrous layer.

3

What does a stable plaque consist of? Vulnerable?

Stable: Small lipid pool, thick fibrous cap, preserved lumen.

Unstable: Thin Fibrous Cap, large lipid pool, many inflammatory cells.

4

What can happen in the systemic system due to the localized inflammation in the atheroma. Explalin how it happens.

Inflammatory process in atheroma can activate systemic
inflammation.

Atheroma releases IFN-gamma, IL-1, and TNF.
Adipose tissue releases IL-1 and TNF.

These cytokines lead to the formation of IL-6 which causes the liver to release systemic inflammatory acute phase reactants CRP and Serum amyloid A.

5

Explain specifically how atheromas can lead to plaque rupture.

Microbes, autoantigens, and inflammatory molecules lead to the activation of T cells, macrophages, and mast cells which release prothrombotic factors and proteases.

For example, T cells release IFN-gamma causing SMCs to form less collagen. T cells also activate macrophages causes MMPs to be released.

6

What are some atherosclerosis risk factors?

Dyslipidemia ( LDL HDL)

Tobacco Smoke

Hypertension

Diabetes Mellitus

Lack of Physical Activity

Age

Male gender

Heredity ( mutations leading to gene

defects in LDL receptors)

7

Explain dyslipidemia as a CV risk factor.

Many observational studies have shown

that elevated LDL leads to increased CV

risk

Risk of CVD is 2x higher in person with

LDL 240 mg/dL vs. person with LDL 200

mg/dL

Excess LDL can accumulate in

subendothelial space undergoing

transformation to plaque

8

What are lipoproteins? List them. How do they differ?

Water-soluble proteins that transport water-insoluble
fats through the bloodstream and direct them to specific receptors

All contain varying amounts of phospholipids, esterified and unesterified cholesterol and TG

Chylomicrons, VLDL, IDL, LDL, HDL

From chylomicrons to HDL, they get more dense, they get less TGs, and more phospholipids and cholesterol.

9

Describe the exogenous pathway, including the lipoproteins, their receptors, etc.

Exogenous pathway[edit]
Bile emulsifies fats contained in the chyme, then pancreatic lipase cleaves triacylglyceride molecules into two fatty acids and one 2-monoacylglycerol. Enterocytes readily absorb these molecules from the chymus. Inside of the enterocytes, fatty acids and monoacylglycerides are transformed again into triacylglycerides. Then these lipids (i.e. triacylglycerols, phospholipids, cholesterol, and cholesteryl esters) are assembled with apolipoprotein B-48 into nascent chylomicrons. These particles are then secreted into the lacteals in a process that depends heavily on apolipoprotein B-48. As they circulate through the lymphatic vessels, nascent chylomicrons bypass the liver circulation and are drained via the thoracic duct into the bloodstream.

In the blood stream, nascent chylomicron particles interact with HDL particles resulting in HDL donatation of apolipoprotein C-II and apolipoprotein E to the nascent chylomicron. The chylomicron at this stage is then considered mature. Via apolipoprotein C-II, mature chylomicrons activate lipoprotein lipase (LPL), an enzyme on endothelial cells lining the blood vessels. LPL catalyzes the hydrolysis of triacylglycerol (glycerol covalently joined to three fatty acids) that ultimately releases glycerol and fatty acids from the chylomicrons. Glycerol and fatty acids can then be absorbed in peripheral tissues, especially adipose and muscle, for energy and storage.

The hydrolyzed chylomicrons are now called chylomicron remnants. The chylomicron remnants continue circulating the bloodstream until they interact via apolipoprotein E with chylomicron remnant receptors, found chiefly in the liver. This interaction causes the endocytosis of the chylomicron remnants, which are subsequently hydrolyzed within lysosomes. Lysosomal hydrolysis releases glycerol and fatty acids into the cell, which can be used for energy or stored for later use.

10

Describe the endogenous pathway including lipoproteins, receptors, etc.

The liver is the central platform for the handling of lipids: it is able to store glycerols and fats in its cells, the hepatocytes. Hepatocytes are also able to create triacylglycerols via de novo synthesis. And they also produce the bile from cholesterol.

In the hepatocytes, triacylglycerols, cholesterol cholesteryl esters are assembled with apolipoprotein B-100 to form nascent VLDL particles. Nascent VLDL particles are released into the bloodstream via a process that depends upon apolipoprotein B-100.

In the blood stream, nascent VLDL particles bump with HDL particles; as a result, HDL particles donate apolipoprotein C-II and apolipoprotein E to the nascent VLDL particle; Once loaded with apolipoproteins C-II and E, the nascent VLDL particle is considered mature.

Again like chylomicrons, VLDL particles circulate and encounter LPL expressed on endothelial cells. Apolipoprotein C-II activates LPL, causing hydrolysis of the VLDL particle and the release of glycerol and fatty acids. These products can be absorbed from the blood by peripheral tissues, principally adipose and muscle. The hydrolyzed VLDL particles are now called VLDL remnants or intermediate-density lipoproteins (IDLs). VLDL remnants can circulate and, via an interaction between apolipoprotein E and the remnant receptor, be absorbed by the liver, or they can be further hydrolyzed by hepatic lipase.

Hydrolysis by hepatic lipase releases glycerol and fatty acids, leaving behind IDL remnants, called low-density lipoproteins (LDL), which contain a relatively high cholesterol content[2] (see native LDL structure at 37°C on YouTube). LDL circulates and is absorbed by the liver and peripheral cells. Binding of LDL to its target tissue occurs through an interaction between the LDL receptor and apolipoprotein B-100 on the LDL particle. Absorption occurs through endocytosis, and the internalized LDL particles are hydrolyzed within lysosomes, releasing lipids, chiefly cholesterol.

11

Describe the pathway of HDL including receptors, enzymes, etc.

HDL is the smallest of the lipoprotein particles. It is the densest because it contains the highest proportion of protein to lipids. Its most abundant apolipoproteins are apo A-I and apo A-II.[5] The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles; the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1). A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually causing the newly synthesized HDL to assume a spherical shape. HDL particles increase in size as they circulate through the bloodstream and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, for example by the interaction with the ABCG1 transporter and the phospholipid transport protein (PLTP).

HDL transports cholesterol mostly to the liver or steroidogenic organs such as adrenals, ovary, and testes by both direct and indirect pathways. HDL is removed by HDL receptors such as scavenger receptor BI (SR-BI), which mediate the selective uptake of cholesterol from HDL. In humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (CETP). This protein exchanges triglycerides of VLDL against cholesteryl esters of HDL. As the result, VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor pathway. The triglycerides are not stable in HDL, but are degraded by hepatic lipase so that, finally, small HDL particles are left, which restart the uptake of cholesterol from cells.

The cholesterol delivered to the liver is excreted into the bile and, hence, intestine either directly or indirectly after conversion into bile acids. Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormones.

12

Describe the genetics of dyslipidemia? What is the most common disorder? Describe it.

There are many different defects. They involve enzymes and receptors in the various lipoprotein pathways. The most common disorder is familial hypercholesterolemia. It is AD. Involves the LDL receptor which takes up LDL. Therefore, there are high levels of LDL in the blood and thus high levels of cholesterol. 1/500.

13

Explain tobacco smoking as a risk factor for atherosclerosis.

Atherogenic mechanisms:

Causes endothelial dysfunction

Tissue hypoxia

Induces a pr0-coagulant state

Inappropriate stimulation of

sympathetic nervous system by

nicotine

These risks are reversed by

tobacco cessation so that three yrs

after quitting, a former smokers risk

is the same as a never smoker

14

Explain hypertension as a risk factor for atherosclerosis.

Leads to injury to vascular endothelium which

promotes entry of lipoproteins

Increased hemodynamic stress can increase number

of scavenger receptors on macrophages leading to

foam cell formation

Angiotensin which is a mediator of HTN also can

increase oxidative stress

Treat with diet, weight loss, pharmacologic therapies

15

Explain diabetes mellitus as a risk factor for atherosclerosis.

Cardiovascular disease is the cause of

death in 80% of diabetic patients

DM is thought to promote atherogenesis

through glycation of lipoproteins which

leads to increased uptake by scavenger

receptors

May also lead to endothelial dysfunction,

decreased NO production and increase

leukocyte adhesion

16

Explain metabolic syndrome as a risk factor for atherosclerosis.

Constellation of

HTN, elevated TG,

decreased HDL,

insulin resistance

and visceral obesity

Insulin resistance is

thought to promote

atherosclerosis

before overt DM

develops

17

Explain lack of physical activity as a risk factor for atherosclerosis.

Lack of physical activity

is risk factor for CVD

Exercise enhances

insulin sensitivity

Exercise increases NO

production

As little as 30 minutes of

brisk walking daily has

been shown to reduce

CV mortality

18

Explain estrogen state as a risk factor for atherosclerosis.

Before menopause women seem to be

protected from CV disease suggesting

estrogen may have atheroprotective effect

Studies such as HERS and WHI showed

excess CV risk from estrogen/progestin

replacement

19

Explain homocysteine as a novel risk biomarker for atherosclerosis.

1/5 patients with

atherosclerosis has none

of the traditional risk

factors

Elevated homocysteine

levels are associated with

increased CV risk and

may promote oxidative

stress, inflammation

and increased platelet

adhesiveness

Trials of B12 and folate (needed to break down homocysteine) supplements haven't showed to be clinically effective in reducing CV events.

20

Explain lp (a) as a novel risk biomarker for atherosclerosis.

Lp(a) is lipoprotein which

is structurally similar to

plasminogen and may

compete with its normal

activity thus increasing

thrombotic risk

Has been shown to

independently predict CV risk

Niacin decreases its levels

by 20%

Lack of clinical trials showing

reduced CV events

21

Explain CRP as a novel risk biomarker for atherosclerosis.

Elevated levels of C- reactive protein do

independently predict increased risk Of

MI, CVA, sudden cardiac death

Reflect inflammation and can be non-
specific

Trials such as JUPITER show that CRP

can be used to guide statin therapy and

affect outcomes