Hypertension and Atherosclerosis 3/27/09

Describe role of components of RAAS (Renin-Angiotensin-Aldosterone System) control of BPo Indirect- making the adrenals secrete aldosterone (long term)o Direct- vasoconstriction increasing BP (short term)o Central role in BP regulationo Renin – from kidneys ^ from SNS stimulation or dec in BPo Angiotensin I – lung – ACE – Angiotensin II

Angiotensin I goes to the lung where ACE turns it into Angiotnesin IIo Angiotensin II short & long term BP regulation

Short Term is the vasoconstriction which immediately increases BP Long Term is that it stimulation of adrenals to spit out aldosterone Vasoconstrictor Stimulates aldosterone from adrenal cortex

Aldosterone increases sodium reabsorption (where Na goes, water follows) which keeps the water in your body which increases BP.

o Antidiuretic hormone or Vasopressin It makes the collecting tubule (duct) permeable to water. Ion pumps in the loop

of henle pump out NaCl into the kidney (out of the tubes). Where Na goes, water follows. If the collecting duct is permeable to water then the water can move out of the tubes back into the kidney (reabsorbed into the body). This concentrates the urine by keeping water out of it and lowers the osmolality of the stuff in the kidneys (blood).

Increases BP

Give numbers of normal, prehypertension, Stage 1, and Stage 2 hypertension from JNC7o All stages of hypertension are associated with increased risk for target organ disease

which includes MI (Miocardial Infarction or Heart attack), kidney disease, and stroke. They all need effective long term therapy. Once you’ve got it (hypertension), you have to treat it forever.

o Systolic Hypertension (even when it’s not accompanied with diastolic hypertension) is the most significant factor in creating target organ damage. You’re more likely to have MI’s, strokes and such if you have the high systolic numbers.

o Risk increases with age. HTN rates are higher in blacks than whites. (According to Fabry in clinicals, this is because Blacks have a slower GFR (Glomerular Filtration Rate). They can’t filter their shiz as quickly as everyone else, so the pressure in their blood vessels is higher.)

o Normal LESS THAN 120/80o JNC says Hypertension is any sustained BP over 140/90.

o Prehypertension Over 90% of these people will develop at least Stage 1 Hypertention 120-139 systolic 80-89 diastolic

o Stage 1 Hypertension 140-159 systolic 90-99 diastolic

o Stage 2 hypertension >160 systolic >100 diastolic

Define essential hypertensiono Primary Hypertension (Essential Hypertension) 90-95% of HTN Cases

Essential or idiopathic hypertension Chronic elevation of blood pressure without the presence of other

disease Genetic and environmental factors Affects 92% to 95% of individuals with hypertension

o Secondary Hypertension 5-10% of HTN Cases Caused by a systemic disease process that raises peripheral vascular resistance

or cardiac output.o Isolated systolic Hypertension

Elevations of systolic pressure are caused by increases in cardiac output, total peripheral vascular resistance, or both

o Complicated Hypertension Chronic hypertensive damage to the walls of systemic blood vessels Smooth muscle cells undergo hypertrophy and hyperplasia with fibrosis of the

tunica intima and tunica mediao Malignant Hypertension- type of secondary HTN

Rapidly progressive hypertension Diastolic pressure is usually >140 mm Hg!! Super Bad!

Describe (risk) factors associated with hypertension Factors Associated with HTN

Genetic predisposition - Family historyo Polygenic (many genes responsible). Genes that control for

Renal sodium excretion, insulin and insulin sensitivity, the genes that control the activity of the RAAS, and associated with cell membrane transport, and sympathetic nervous response to neurogenic hormones.

Advancing ageo The older you get the more at risk you are

Gendero Men greater risk before age 55o Women more than men after 55 after menopause

Raceo Blacks more than everyone else, as mentioned earlier

Dietary sodium intakeo High dietary NAo Low dietary intake of K, Ca, and Mg

Glucose intoleranceo Insulin sensitivity plays a role in HTN

Cigarette smokingo Smoking increases risks of HTN

Obesityo The fatter you are the more at risk you are

Heavy Alcohol intakeo The more you drink the more at risk you are

o Treatment For HTN

Discuss hyperlipidemia and its role in atherosclerosiso From what I can understand, hyperlipidemia is lots of fat floating around in your blood.

When you’re scavenger cells try and eat the fat floating around, it causes atherosclerosis. Read the next outcome for more detail about this process. All the stupid lipid information is at the end of the outline.

State the pathophysiology of atherosclerosis (and discuss the role of chronic inflammation)o Atherosclerosis

Form of arteriosclerosis (see extras at end of outline). Thickening and hardening is caused by accumulation of lipid-laden macrophages in the arterial wall.

Plaque development (fibro-fatty or stiff and fatty plaques) in the intima (lining) of large and medium sized arteries. Produces decrease in blood flow due to narrowing of the lumen. And vasculitis (inflammation of the blood or lymph vessels) occurs in multiple vessels and produces inflammation of the vessel wall and is a common pathway for vessel and tissue injury in a number of diseases, including atherosclerosis. Inflammation is the culprit!

Progression Inflammation of endothelium

o Endothelium gets leaky (permeable) and fat gets into the tunica intima from the blood.

Cellular proliferationo Smooth muscles cells from the tunica adventitia say WTF?

Who’s in here? I’m going to make more of me to go check it out. Macrophage migration

o Macrophages are like I’ll eat these lipid bitches who are going where they aren’t supposed to.

LDL oxidation (foam cell formation)o Macrophages eat the lipid bitches and become foam cells. The

foam cells release growth factors (cytokines) that encourage artherosclerosis

Fatty streak Fibrous plaque Complicated plaque

Relate atherosclerosis to Risk factors, CAD, PAD, aneurysm, and thrombosis

o Risk Factors of CAD and Atherosclerosis Hyperlipidemia

Lipids get into the vascular endothelium White blood (macrophages) cells eat the lipids and become à foam

cells (a combo of fat and macrophage). WBCs and vascular endothelium release growth factors that promote

plaque formation. Plaques block the arteries

Three types of lesionso Fatty streaks- little yellow streaks. Thin, they line inside the

intima. They are present as early as the first year of life. Occurs regardless of geographic setting, gender, or race. They don’t know that the fatty streaks are precursors to the plaque.

o Fibrous lesion- basic lesion of clinical atherosclerosis. Accumulation of intra and extracellular lipids. Proliferation of vascular smooth muscle cell leads to scar tissue formation. This scar tissue then becomes the plaques that cause the damage. Inflammation causes the shit. As the lesions increase in size, they squish the lumen which reduce laminar flow which leads to thrombus (blood clot)

o Complicated lesion- because of the little lumen and slowed blood flow, clots form (thrombus)

Age Men > 45 y/o Women > 55 y/o or women with premature menopause without

estrogen therapy Family History

If pt family has had MI before 45 y/o in male relative or before 64 y/o in a female relative. Has to be close relative, mother, sister, dad, brother, etc.

Cigarette Smoking Hypertension

Above 140/90 or they already have been diagnosed with HTN. Diabetes Mellitus Negative Risk factors is a High HDL! If you have this you are less likely to get

atherosclerosis.o PAD (Peripheral Arterial Disease)

Atherosclerotic disease of arteries that perfuse limbs, usually lower limbs. Intermittent claudication- pain with walking. It’s the primary symptom. They get

calf pain caused by ischemia of the gastrocnemius muscle (because when you’re walking it requires the most oxygen, so you notice the lack of oxygen there first)

o CAD (Coronary Artery Disease) This is classified as any vascular disorder that narrows or occludes the coronary

arteries. So no shit, since atherosclerosis causes narrowing, it’s the most common cause. Both CAD and PAD are narrowing of the vessels (mostly caused by atherosclerosis). They are just different because of the location of the narrowing.

o Aneurysm Aneurysms represent an abnormal localized dilatation of an artery due to a

weakness in the vessel wall. As the aneurysm increases in size, the tension in the wall of the vessel increases, predisposing it to rupture. Most common in the aorta.

The two most common causes of aortic aneurysms are atherosclerosis and degeneration of the vessel media.

Aortic Dissection Aneurysm- is a false aneurysm because of tearing in the lining of the vessels that allows blood to enter the vessel wall causing it

o Thrombosis ?

Extras from the lecture Artery Structure

o Tunica intima: endothelium Food and 02 pass into tissues Wastes and CO2 pass from tissues into blood Creates compounds that cause vasodilation or vasoconstriction Creates growth factors that can stimulate smooth muscle Forms a smooth lining of the blood vessels that resists clot formation Creates compounds to promote clot formation in injured areas Table 17-1 Endothelial Cell Properties and Functions

Major Properties Associated Functions/FactorsMaintenance of a selective permeability barrier Controls the transfer of small and large molecules

across the vessel wallRegulation of Thrombosis Elaboration of prothrombogenic molecules (von

Willebrand factor, plasminogen activator) and antithrombotic molecules (prostacyclin, heparin-like molecules, plasminogen activator)

Modulation of Blood flow and vascular reactivity Elaboration of vasodilators (nitric oxide, prostacyclin) and vasoconstrictors (endothelins, angiotensin-converting enzyme)

Regulation of cell growth, particularly smooth muscles cells

Production of growth-stimulating factors (platelet-derived growth factor, hematopoietic colony-stimulating factor) and growth-inhibiting factors (heparin, transforming growth factor-β)

Regulation of inflammatory/immune response Expression of adhesion molecules that regulate leukocyte migration and release of inflammatory and immune system mediators (e.g., interleukins, interferons)

Maintenance of the extracellular matrix Synthesis of collagen, laminin, proteoglycansInvolvement in lipoprotein metabolism Oxidation of VLDL, LDL, cholesterol

o Tunica media: smooth muscleo Tunica adventitia: collagen and elastic fibers

Participates in atherosclerotic process Patho of HTN (I DON’T KNOW WHERE THIS GOES OR IF WE HAVE TO KNOW IT)

o Adducin Adducin is membrane skeletal protein. Helps determine cell shape and

movement. Reacts with sodium/potassium pump===it’s a regulator for the pump.

Mutations effect spp / increase in re-absorption of sodiumInflammation effects it also. See slide above

Arteriosclerosis

o Chronic disease of the arterial system Abnormal thickening and hardening of the vessel walls Smooth muscle cells and collagen fibers migrate to the tunica intima Atherosclerosis is just this because of lipid-laden macrophages and the

development of plaque

Lipid and Cholesterol Crapo Lipoproteins: because lipids are insoluble in plasma, they are encapsulated by special

fat-carrying proteins called lipoproteins for transport in the blood. 5 types

Based on density o The more protein, the higher the density (HDL’s, the good

cholesterol)o The more lipid, the lower the density (LDL’s, the bad

cholesterol) You want more Protein than Fat in your body!

o Cholesterol 2 Sources

Exogenouso Dietary intake

Endogenouso Something or other

o Lipid Transport in the Body HDL

High-density lipoproteins (“good cholesterol”) are made in the liver They go out to the peripheral tissues and pick up lipid Then they carry it back to the liver

IDL’s (Intermediate Density Lipoproteins): dietary lipids are absorbed as cholymicrons. Then your adipose (fat) and muscle cells suck out the lipids from the cholymicrons. The left over bits of the cholymicrons (sans lipids) are IDL’s.

IDLs become low-density lipoproteins (“bad cholesterol”) These can deliver fat to the liver and to other tissues LDL receptors are necessary for the liver to take them up Some LDLs are taken up by scavenger cells like macrophages

o The amount of LDL removed by the scavenger cells (macrophages) is directly related to blood cholesterol levels

o When there is a decrease in LDL receptors (or there is too much LDL for all the receptors to deal with) the amount of LDL removed by the scavengers is increased.

Different Types of Plaqueso Stable

Have thick fibrous caps Partially block vessels Do not tend to form clots or emboli

o Unstable Have thin fibrous caps Plaque can rupture and cause a clot to form May completely block the artery The clot may break free and become an embolus