Vascular disease and Atherosclerosis

Thoracic aortic aneurysms

- are more likely to occur in men than in women and in patients with chronic obstructive pulmonary disease (COPD).

Diagnosis of pulmonary embolism

-- can be difficult because the symptoms are nonspecific and may mimic many other diseases. • Pulmonary angiography is the gold standard test for diagnosis. Other tests may include oximetry and arterial blood gas analysis and imaging such as chest x-rays and ultrasonography. Treatment includes anticoagulants such as heparin and warfarin (Coumadin). • About 10- 15% of patients with pulmonary embolism die.

People with no LDL receptor

-- will have lots of LDL in their blood and will look muscular and healthy, but really LDL can't get into and out of cells as (as HDL) easily, so it's ruining their arteries • When arteries restrict, you're taking the same amount of blood as before and putting it through a smaller area, so the blood must move faster to get through at the same rate; thus, hypertension adds to the stress going on in the vessels *** The minute your doctor tells you to go on anti-hypertension medicine, do it

First step in atherogenesis

--is the formation of fatty streaks (pale yellow streaks that run along the intima from the focal accumulation of macrophages that take up fat and hold it in their cytoplasm.) •By 10 years of age, 10% of the aorta has fatty streaks through development. •Whether or not the fatty streaks develop into plaques depends, in part, on genetics and life style. -Almost all men age 25+ have some degree of atherosclerosis. -Fatty streaks do not develop into plaques in the thoracic aorta, but they do in the abdominal aorta (blood is slower and turbulence in branching areas). Prevalent in renal arteries and other areas of branching

Disorders of the vasculature: Of arteries

-Arteriosclerosis (structural defects): Accounts for more than half of the deaths in the US • Coronary artery disease • Peripheral vascular disease (like diabetes amputations) • Strokes • Aneurysms -& Hypertension • Blood pressure misregulation that leads to adverse structural alterations of the arteries

Risk factors in atherosclerosis- secondary or less clearly related factors

-Excessive (or no) alcohol use -Obesity -Inadequate exercise -Stress

Risk factors in atherosclerosis- major

-Hyperlipidemia - * especially w/ hypercholesteremia, where pt. has no/nonfunctioning LDL receptor and cholesterol is kept in the plasma Greatly incr. risk -- Chol. > 230; LDL > 130 -Genetic predisposition -Systemic hypertension - * hypertension will almost ALWAYS result in atherosclerosis because high pressure causes endothelial injury -Smoking -Male gender -Diabetes Mellitis

Aortic aneurysm cause

-related to multiple risk factors commonly found in pts. with thoracic and abdominal aneurysms. -risk factors include smoking, hypertension, atherosclerosis, bicuspid aortic valves, and genetic connective disorders (i.e. Marfan's Syndrome, and Ehlers-Danlos syndrome).

Lymphatic vessels

-run along side blood-carrying arteries and veins -have lymph nodes o Their walls are thinner than veins o They have valves and unidirectional flow

Theory example ctd. In hypertension caused by unilateral renal artery stenosis..

..the nonstenotic kidney becomes renin depleted but fails to prevent hypertension. The nonstenotic kidney mysteriously develops elevated intrarenal angiotensin II (ANG II) content. Rats chronically infused with ANG II exhibit a similar hypertensive process. The augmentation of intrarenal ANG II is due to receptor-mediated internalization and continued ANG II formation, which provide a hypertensinogenic stimulus. Thus, levels of Angiotensin II are the problem causing the hypertension. • Since Goldblatt's seminal experiment in 1934, renovascular hypertension has increasingly been recognized as an important cause of clinically atypical hypertension due to activation of the renin-angiotensin-aldosterone system (RAAS). Chronic kidney disease is also a consequence due to renal ischemia.

Sequelae of thrombosis

1. Resolution 2. Recanalization - pieces of thrombus attached to back wall; entire clot in vessel that you drilled holes through so more places have opened up where blood can flow through 3. Propagation - very bad 4. Infarction - thrombus in an artery; it breaks off and travels until it gets to a place where it gets caught; depending on where it gets caught... a. It can cause some trouble if it blocks an area that requires blood with no other pathway to get there, causing the whole area to die b. It can get caught in a small artery where there are other pathways to get there, like right before the capillaries, where the arteries branch quite a bit, and only cause infarction of a few cells 5. Thromboembolism

2 forms of hypertensive arteriOLOsclerosis Hyperplastic arteriolosclerosis

2. Hyperplastic arteriolosclerosis •The arteriole has an "onion skin" appearance. • malignant hypertension • leads to many more smooth muscle layers than five (~10) o Something has gone wrong to make to the muscle cells proliferate and add more layers around the artery, which squeezes shut the lumen and doesn't allow blood to go through o Can reverse itself with medication and not be a problem again

Diagnosis of Thrombophlebitis

: to determine whether superficial or deep vein thrombosis, ultrasound or venography with a contrast agent can locate a thrombus. Also, a blood test to check for D dimer levels. D dimer is a fibrin degradation product. It can be elevated in other conditions too, so although the test for D dimer is very sensitive, it's not very conclusive. It simply measures whether a fibrin degradation product is present in the blood, and suggests that a thrombus has recently been acted upon via fibrinolysis.

% of people who develop hyper plastic arteriOLOsclerosis

About 1% of people who have a history of high blood pressure develop this life-threatening condition. Risk factors are being male or being African-American. Medical conditions that cause it are kidney disease, scleroderma, spinal cord injuries, and adrenal gland tumors. Medications that may cause it are birth control pills, MAOIs and cocaine.

Response to injury as a hypothesis of Atherogenesis

Arterial endothelium is injured by altered hemodymanic forces (hypertension), harmful chemicals (nicotine, catecholamines, bacterial infection, hyperlipidemia, or mechanical trauma; endothelial membrane is disrupted, permeability is altered, and platelets, lipids and smooth muscle aggregate on the intimal layer. MACROPHAGES ADHERE TO THE WALL. Best hypothesis: when blood is in large arteries it is moving fast and hard and is splitting off into directions causing turbulence, which causes endothelial injury. Perpetuated by injurious agents being released and affecting adjacent endothelial cells.

Arteriosclerosis: affects and causes

Arteriolosclerosis •Affects small arteries (arterioles) •Luminal space narrowed because the walls are so thick •Uniform, glasslike appearance - hyaline •Compromises the ability to dilate •Causes downstream ischemia •Can be a cause of secondary hypertension: Restriction of artery in the kidney activates the renin-angiotensin system, which raises blood pressure

Arteriosclerosis: hardening of the arteries definition & 3 types

Arteriosclerosis is a reduction in normal flexibility and elasticity of arterial walls There are 3 types: 1. Arteriolosclerosis- Affects small arteries (arterioles) 2. Monckeberg's medial calcific sclerosis (will be question on the exam)- Affects medium sized arteries 3. Atherosclerosis (several questions on exam)- Affects large arteries

Progressive phase of Atherosclerosis of the renal artery

As the disease progresses (Panel B), there is progressive aortic atherosclerosis and severe unilateral renal-artery stenosis. The left kidney is smaller than the right, and there may be cortical thinning and asymmetry in renal blood flow. The serum creatinine concentration remains normal as long as the right kidney is normal, despite the loss of renal mass. The total glomerular filtration rate maybe normal (100ml per minute) or only slightly depressed owing to compensatory changes in the right kidney, but renal blood flow is decreased in the left kidney (35ml per minute).

Pathological effects of sustained, complicated primary hypertension Kidneys

A• Mechanism of injury: renin and aldosterone secretion stimulated by reduced blood flow • Potential pathological effect: retention of Na and H2O, leading to increased blood volume and perpetuation of hypertension B• Mechanism of injury: reduced oxygen supply, high pressures in renal arterioles • Pot. pathological effect: tissue damage compromises filtration, nephrosclerosis leading to renal failure

Balance between both making and dissolving a thrombus

Balance between making a thrombus (the thrombotic pathway - we want to avoid the consequences of bleeding out upon injury) - and dissolving the thrombus (thrombolytic pathway) -Require both -In fact, clotting activates the thrombolytic sequence -Constantly making small thrombi in the body In lung, 3x the thrombolytic activity > rest of the body

Capillaries' important points

Blood enters the capillary network as arterial blood and exits as venous blood Must have slow movement of blood for proper exchange Slow movement caused by branching of the arterioles (small arteries) and capillaries slows the blood flow to allow time for good exchange of gases and nutrients

Medications

Diuretics • Decrease fluid volume Vasodilators • Decrease total peripheral resistance (reflex stimulation of sympathetic outflow) Sympathetic inhibitors (especially beta blockers) • Reduce cardiac stimulation, decrease cardiac output • Reduce renin levels that result from vasodilators increasing sympathetic outflow (observed, unknown mechanism) • Reduce Na+ excreted, so increases plasma volume - need diuretic as part of therapy ACE inhibitors in specific populations • Diabetics • MI patients

Predisposing factors to thrombosis

Endothelial damage from hemodynamic stress (i.e. hypertension, arteriosclerosis, normal wear and tear, trauma, or surgery) Flow abnormalities from turbulence (varicose veins, tumors, aneurysms) Blood hypercoagulation (birth control pills, disease states, and some metastatic tumors)

Hyaline form of arteriOLOsclerosis is often from renal atherosclerosis

Goldblatt kidney - a constriction of the renal artery (from atherosclerosis) causes renal ischemia and renin release, resulting in a rise in blood pressure. The narrowing of the lumen decreases renal blood flow and GFR. The decreased GFR is sensed in the kidney as a low blood pressure, so renin is secreted and ultimately leads to up constriction of the arteries (and arterioles) to increase the blood flow in the kidney. However, this makes the blood pressure higher, and can exacerbate the problem, leading to a decrease in kidney function.

Blood pressure classification

Hypertension Systolic > 140 mmHg, Diastole >90 mmHg

Hypertension causes

Hypertension is Caused By: • Increased cardiac output • Increased arterial tension (peripheral resistance) • Increased blood plasma volume •When sustained, the vessels change permanently •The renin-angiotensin system becomes activated, resulting in various forms of angiotensin being in the blood stream. One of these forms promotes muscle cells in the tunica media to hypertrophy, as well as to proliferate, so the lumen becomes permanently narrowed. Cell number and extracellular matrix synthesis and deposition increased. •Drug therapy is absolutely required •In early stages there are no clinical manifestations except high blood pressure readings. The clinical manifestations that are seen later are the complications that damage tissues and organs outside the vascular system.

ideal cholesterol levels

Ideal cholesterol <200 LDL is low < 130 mg/100 mL HDH is high > 50 mg/100 mL (strive for >35)

2 forms of hypertensive arteriOLOsclerosis Hyaline arteriolosclerosis

In benign hypertension, hyaline (pink material) accumulates in the walls of small arteries and arterioles giving them a glass-like appearance The hyaline thickens the walls and narrows the lumen Typically seen in the kidney & generally occurs in the elderly, especially those with diabetes

Lymphatic system has capillaries and veins, but no arteries

In the area where arterioles and venules meet is the capillary network; there they are exchanging fluid, but they don't pick up all the fluid they let out. About 3 extra liters are deposited into the interstitium per day. Has evolved to become a washing or cleansing system.

Treatment for hypertension

Life style changes • Stop smoking • Reduce salt intake • Reduce stress

Lymph travels

Lymph comes up through lymphatic capillaries → Lymphatic vessels (or veins) → Through lymph nodes → Lymphatic veins drain into the right lymphatic duct and the thoracic duct. These drain lymph into the right and left subclavian veins.

Least prevalent form of arteriosclerosis

Monckeberg's medial calcific sclerosis is the least prevalent form of arteriosclerosis. Note the dark calcifications in the medial layer, and note that the lumen is NOT reduced in size. Thus, there are usually few clinical consequences. This type of arteriosclerosis is usually found in the elderly. Calcified arteries may be visualized on radiographs. Calcium deposits collect in the media of muscular arteries, particularly in pelvis and neck.

Most common anatomical location for different aneurysms

Most common anatomical location for an aortic aneurysm is in the abdomen and secondly in the descending thoracic aorta. Oftentimes, thoracic aortic aneurysms are found incidentally, however some patients may present with non-specific pain or other symptoms related to compression of other organs as a result of the expanding aneurysm. A common scenario which thoracic aortic aneurysms are discovered is on a plain chest x-ray or chest CT scan performed for another diagnosis.

Current Theories of Hypertension Pathogenesis

Note: when the CV system is affected, the kidneys are affected 1. An increase in blood volume 2. An increase in activity of sympathetic nervous system 3. Increased activity of renin-angiotensin-aldosterone system 4. Water and sodium retention by the kidneys a. Inherited defect -- i. Increased blood volume and ii. Increased Na+ → increased Ca++ 5. Hormonal inhibition of sodium-potassium transport across cell walls in the kidney and blood vessels (cell retention of sodium)

Stages of hypertension

Stage 1 mild-> 140-159 mmHg Stage 2 moderate-> 160-170 mmHg Stage 3 severe-> 180-209 mmHg Stage 4 very severe-> 210 + mmHg All stages are assoc. with an increased risk of atherosclerosis and CV disease. All req long term therapy Resulting changes can be reverse if not prolonged

Commentary for #2

The patient's apparent good health, and the indication that he had been drinking, might normally have resulted in his being sent home. However, in this case, the clinician's decision, based on many years of experience, was vindicated. Had the patient not been under close medical observation, the aorta might have ruptured, threatening his survival. Microscopic analysis of the excised segment of aorta showed evidence of medial necrosis, probably in response to the abnormally elevated pressures in the narrowed region. It was this damage that weakened the vessel wall, allowing the blood to gain access into the wall and begin its dissection.

Commentary for #1

The patient's rapid heart rate was compensation for the fall in cardiac output produced by the pulmonary occlusion. His chest pain was the result of right ventricular overload from the abrupt increase in resistance that the blocked pulmonary artery presented to it. Distention of the right pulmonary artery, which arose quickly as the blood supply of both lungs was being forced into it, also probably contributed to the pain. Inability to cope with such high demand caused backup of blood into the large veins of the systemic circulation, producing the observed neck vein distention. The "friction rub" heard over the lung was the result of infarction damage at the lung's surface, which produced a rubbing sound as it moved against the adjacent parietal pleura. The procedure to insert a caval filter was to have been done via the jugular vein. Such filters are able to block access of thromboemboli to the lung, at the same time allowing blood flow. The filters can be inserted with relative ease, avoiding full-blown surgery, and have been widely and successfully used. Had time permitted, such a filter would probably have spared this patient's life. Subsequent discussions with the family physician of the deceased revealed that in view of the man's history of varicose veins, he had provided his patient with a series of lower leg maneuvers intended to both promote venous flow in the fractured and immobilized leg. The patient's wife reported that her husband had not done the exercises, nor had he sought medical help for recent episodes of increased pain and swelling in the calf of his fractured limb.

Hypertension

There is a systemic hypertension and organ specific hypertension (kidney) • Hypertension causes increased hemodynamic force that will injure the endothelium → → → atherosclerosis!!!

Disorders of the vasculature: of arteries AND veins

Thrombosis • Hemodynamic disorder that alters vessel structure

Thrombosis differences from clots:

Thrombosis is a Hemodynamic Disorder, But a thrombus is different from a clot in three ways: -It never forms outside of a vessel -It is attached to the vessel wall (and if it detaches it becomes an embolism or a thromboembolism) -The components of a thrombus are organized differently than a clot (more organization)

Thrombosis without initial blood flow abnormalities

Two types Arteries (fast flow: platelets & sm. amt of fibrin) • Faster blood flow disallows formation of terrible thrombus Vein (slow flow: get platelets, lots of fibrin & coagulated blood cells) • Slow flow allows for formation of a much bigger thrombus (feet long) -Thrombus is an aneurysm. -Thrombosis: occurring with turbulent blood flow, layers of platelets and RBCs become trapped by fibrin

Disorders of the vasculature: Of veins

Varicose veins Thrombophlebitis

Case Study #1 --Auscultation- medical diagnosis procedure: listening to the sounds from the heart, lungs and other organs with a stethoscope

While convalescing at home following a work-related foot fracture, a 57 year old brick layer felt weak and faint, and then suffered a severe episode of labored breathing and crushing pain over his left chest. He was rushed to the hospital, where he complained of dizziness and persistence of his chest pain. On exam, he was found to be pale with a rapid heart rate, reduced blood pressure, and distended neck veins. His ECG produced no evidence of myocardial infarction, but signs of some right ventricular strain were present. Auscultation of the left lung revealed a "friction rub" over the left lung. He was also febrile, with a temp of 38.8oC. He reported a history of varicose veins and a recent worsening of calf pain while recuperating from his fracture. His left calf was swollen, tender, warm and edematous. He also stated he had no history of heart trouble and had recently had a general physical exam by his family physician, who declared him to be "in the pink," apart from minor problems such as his varicose veins. His chest pain and breathing difficulties continued and IV heparin therapy was instituted on the basis of a presumed pulmonary embolism. Quickly obtained radiographic and radioisotope scans confirmed a massive occlusive embolism in the left pulmonary artery, blocking all blood flow to the left lung. Vasoconstriction therapy to support his blood pressure was started and a more aggressive anticoagulation regimen was quickly instituted. Because of the threat of further emboli forming in the leg veins, it was decided to insert a filter in the inferior vena cava, but as the patient was being prepared for the procedure, he abruptly developed a sharp pain in his right chest, gasped repeatedly for breath, and died before any intervention could reverse the situation. Autopsy findings confirmed the complete occlusion of the left pulmonary artery that presumably produced the patient's initial attack. The occluding mass was formed of a coil of gelatinous thrombus. A similar coil was found blocking the right pulmonary artery. It appeared that a long thrombus initially detached from its site of formation in the popliteal vein, reaching the right ventricle. It was then driven into the left pulmonary artery, producing the initial attack. A second, large mass of embolus, presumably from the same leg vein, was found coiled in the right pulmonary artery, where it completely blocked all lung access to the pulmonary vasculature. A small fragment of embolus, wedged within the right ventricle's floor, testified to the passage of the larger masses through the chamber en route to the lungs. An infarcted area of the left lung was also found, verifying the lung sounds and ECG indications of pulmonary infarction. (In this extreme case, the initial massive occlusion induced the ischemic damage, but because the lung is also supplied by the bronchial arteries, infarction due to a pulmonary embolism is unusual.) The infarction was also likely the cause of the elevated temperature. Examination of the left leg revealed pronounced varicosities in the deep calf veins and in the popliteal and great saphenous veins, with residual thrombi at several points in the vessels.

Case Study #2

While driving with his girlfriend, a 24 year old man said that he felt "kinda funny and dizzy" and that his vision was blurred. At the woman's insistence, he surrendered the wheel, and she drove to a nearby hospital emergency room. The physician on duty examined the man and found him to be in excellent health, but with mildly elevated blood pressure. When questioned about the aroma of alcohol detected on his breath, the man reported having "only a beer of two," which his girlfriend verified. He was admitted to the hospital for overnight observation. During the night he complained of feeling ill and having blurred vision, chest and abdomainal pain, and tingling in the feet. His ECG showed tachycardia, and was grossly abnormal. His legs were cool. No femoral pulse could be found. A CT scan was ordered and indicated a dissecting hematoma of the aorta, distal to the ductus arteriosus. The patient showed signs of circulatory shock as he was prepared for emergency surgery. During the procedure the presence of a 5 cm dissecting hematoma (clot in an aortic aneurysm) was verified. It was removed and replaced by a Dacron graft. The aorta was somewhat narrowed distal to the point of dissection. This region was removed and replaced. The postoperative period was uneventful and the patient recovered fully.

Veins • Important points

o Medial layer (tunica media) is not prominent nor abundant, makes recoil not as good o Vein recoil is not as quick as artery recoil after distention (it's easy to stretch out a vein). Veins and arteries travel in pairs. The vein's size will often look larger than the artery's because is stretched out. o Valves regulate the one way flow of blood (prevent backflow). They are folds of the tunica intima, i.e. endothelial outcroppings folded back on themselves. o For deep veins in the legs, muscle contractions assist the blood flow back to the heart. • Important for people who have just had surgery to get up and walk to get blood moving, or stuff will accumulate in veins and form thrombi • Surface, outer parts of legs, looser veins called varicose veins

Thrombophlebitis

o Signs and symptoms include warmth, tenderness and pain in the affected area, redness, and swelling • Venous inflammation, most often caused by local infection

Preventative

principle therapeutic approaches to intravascular thrombosis and embolism; anticoagulation and anti platelet therapies limit coagulation and thrombosis: fibrinolytic therapy promotes the formation of pasmic and its suppressing effects

Artery

pronounced medial layer rectifies pulsative flow of blood from the heart high pressure

During exchange in lymphatic system

substances flow from capillaries out to the cells (and vice versa). The outflow of fluid exceeds what is reabsorbed by up to 3 liters/day (extra). This fluid accumulates in the interstitium with the cells and gets recirculated by lymphatic vessels. Lymphatics help maintain sufficient blood volume.

Thromboembolism

thrombus in a vein; blood travels from smallest vein to largest vein (vena cava); thrombus breaks off in a smaller area and can travel all the way up through all the veins to the heart; thrombi in the veins can get very large, so they usually can't get into the pulmonary trunk from the heart, so the blood is stopped there, causing extreme pain (no oxygen because not getting blood in some section of lung, so lung cells die, and often the patient will die)

Veins

unidirectional flow of blood collapsed lumen thinner walls low pressure

Degenerative aortic aneurysms most common type

which are found in the aging population. The aortic wall undergoes changes that involve reduction in the structural framework and strength of the aorta. As the diameter of the aorta increases and the wall thickness decreases, the aortic wall stress increases resulting in a higher probability of rupture or dissection.

The hypotheses suggest intervention for:

• 1 and 4: diuretics • 2: inhibitors of the sympathetic nervous system • 2 and 3: vasodilators

Primary hypertension

• 50-70 million people affected • Also called essential or idiopathic hypertension • >140/190 systolic/diastolic

Deep Vein Thrombosis → Thromboembolism

• A venous thromboembolism reaching the lung is also called a pulmonary embolism. Deep vein thrombosis is the most common cause. • Pulmonary embolism: A thrombus obstructing the pulmonary artery or a branch of it leading to the lungs.

Atherosclerosis at the intima

• Activation of monocytes • Migration of smooth muscle cells into the intima • Smooth muscle cell mitosis • Synthesis and deposition of extracellular matrix

Arteries and Veins travel together

• After we get out of the aorta and before we get into the vena cava (inside the tissues), arteries and veins run side by side. This makes sense because their whole purpose is to bring stuff to the capillaries and take stuff away from the capillaries, where exchange is happening. • Medial layer of the artery is much thicker than that of the vein, making the vein look like its collapsed whereas the artery keeps its shape

Risk Factors of DVT

• Age over 40 • Pregnancy • Family history • Clotting disorders • Recent major surgery • Estrogen hormone therapy • Immobility

Adhesion and Rolling

• Any time the basement membrane underneath an artery becomes exposed, things can sneak through • Platelets grab onto the slightest separation between the endothelial cells to sneak in; white blood cells have receptors on them to bind things on endothelial cells to then sneak in

Three morphological types of arteriosclerosis

• Arteriolosclerosis (affects small arteries, aka arterioles) • Medial calcific sclerosis (affects medium arteries) • Atherosclerosis (affects large arteries and is the most important)

basement membrane

• Basement membrane is acellular, and contains type IV collagen, laminin and proteoglycans • Not a lot of muscle (tunica media) around a vein; difference between vein and an artery • Adventitia is mostly fibroblasts with some collagen in it

Complications of Atherosclerosis Involve Vessel Wall Damage

• Calcification • Hemorrhage • Tunica media destruction • Ulceration

Systemic hypertension

• Caused by a systemic disease process that raises peripheral vascular resistance to cardiac output (such as renal vascular disease associated with arteriolosclerosis)

2 Serially Connected Systems

• Continuum of sizes: o Starting at heart o Large arteries o Medium arteries o Small arteries o Capillaries o Small veins o Medium veins o Large veins o Return to heart • In order to have good exchange in the capillaries, you need slow speed of blood running through them

Atherosclerosis at the endothelial surface

• Damage to cells • Permeability to LDL (cholesterol) • Adherence and entry of monocytes into the intima

Renin-Angiotensin-Aldosterone System (steps)

• Decreased blood flow in kidney stimulates renin release → • Renin converts angiotensinogen to angiotensin I → • Vascular endothelial cell ACE converts angiotensin I to angiotensin II → 1. Constriction; rise in blood pressure 2. Increased permeability of endothelial cells 3. Increased signaling to SMC to proliferate and to hypertrophy 4. Increased release of aldosterone ( Bad because once permeable, lipids and monocytes slip between the cells) → • Stimulates reabsorption of Na+, increasing plasma volume → • BLOOD PRESSURE RISES

Important Points about Arteries

• Elastic material is in the medial layer • Internal and external elastic membranes in medium arteries (hidden in large arteries and not prominent in small arteries) • Diffusion gets oxygen and nutrients from lumen to the inner layers of cells • If far from lumen, need vasa vasorum (vessels of the vessels) to nourish the outermost cells in medial layer • Much less elastic tissue in the smaller arteries • Internal and external elastic membranes to prevent blood coming out of heart from flowing right out of vessel

Architecture of a Capillary Wall

• Endothelial cells are flat epithelial cells that have tight junctions, which can be modified to let things through. They always sit on a basement membrane (outside). Basal side of the epithelium is facing out; apical side is facing the lumen, so nuclei can bulge into lumen. Some capillaries are only 1 cell in diameter (3-4 micrometers). Blood cells march through the capillary in single file; slow so that gas and nutrient exchange is good. Below is a capillary 2 cells in diameter.

An Example of Theory 2 An increase in activity of the sympathetic nervous system

• Goldblatt kidney is when one renal artery becomes blocked. This can be due to a thrombus in the renal artery preventing blood flow. The resulting sustained hypertension is sometimes referred to as Goldblatt hypertension. If the hypertension has not existed long, removal of the kidney can cure it. • Goldblatt kidney is a condition where constriction of one of the renal artery causes ischemia in the kidney and the release of renin. This is named for Harry Goldblatt who was intrigued by observations of physicians Robert Tigerstedt and Per Bergman in the late 1890s that kidneys and blood pressure were related. They suggested that the kidneys produced a soluble protein, which they named renin (from renal) that triggered a rise in blood pressure. Goldblatt was able to develop a model of hypertension in dogs to investigate this by partially constricting one of the renal arteries. He published the results in 1934.

Deep Vein Thrombosis (DVT)

• Happens when a thrombus forms in a deep vein (far from skin surface) • It most commonly happens in the deep veins of the calf, and can spread up to the deep veins in the thigh • Rarely, it can develop in other deep veins, for example in the arm • Thrombophlebitis in the deep veins (i.e. DVT) is a significant risk for thromboembolism because muscle contractions can dislodge a thrombus

Hypertensive crisis symptoms

• Headaches, especially pulsating headaches behind the eyes that occur early in the morning • Visual disturbances • Nausea • Vomiting

For Years, Hypertension Will Cause No Clinical Symptoms...

• However, if blood pressure rises quickly and severely high (i.e. 160/100 or higher), it may lead to hypertensive crisis • Over time, untreated high blood pressure can damage organs, such as the heart, kidneys, or eyes. This will ultimately lead to clinical manifestations such as chest pain, cardiovascular problems, stroke, pulmonary edema, kidney failure, eye damage (retinopathy).

Cross section of atherosclerosis

• If you take a coronary and cut it in sections and then line up the sections, there will be regions where the atherosclerosis has made the vessel wall much thicker versus areas where it isn't so bad. Some areas have a cross section where it looks like it is dividing the vessel in half.

LDL

• LDL is floating around in blood and is used by cells to make new membrane • When the cell takes it up on the LDL receptor, it takes it in and uses it, and whatever is leftover is bound as HDL (high density lipoprotein) • HDL is sent to the liver to be disposed of • Want to keep LDL level in bloodstream as low as possible • When LDL cholesterol gets inside, it becomes oxidized which attracts more cells coming in, and activates them to become foam cells • Once atheroma starts, it perpetuates itself by causing more damage by releasing cytotoxic things • When endothelial cell dies and separates from its neighbor, more stuff can come in

Varicose veins - twisted superficial veins Vein disorders

• Lack of muscle support in the veins; veins spread out from increased venous pressure (from standing, pregnancy, etc.) • Valve function is compromised • Thrombosis can result, but generally, this is not a step toward thromboembolism

Malignant hypertension

• Less than 5% of cases • Rapidly progressive hypertension • BP can be up to 220/140 • Diastolic can go above 140 mmHg • Immediate hospitalization needed • Can cause cerebral edema, stroke, <3 failure, death

Important things to consider in atherosclerosis:

• Lumen becomes constricted, so the blood is not going through as easily as it should be going through • Caused by the plaques that start out as fatty streaks and become hardened • End up with the lack of being able to do stretch and recoil because of the hardness that gets established in the arteries

Pathological effects of sustained, complicated primary hypertension Coronary arteries

• Mechanism of injury: accelerates atherosclerosis (coronary artery disease) • Potential pathological effect: myocardial ischemia, myocardial infarction, sudden death

Pathological effects of sustained, complicated primary hypertension Aorta

• Mechanism of injury: high arterial pressure, weakened vessel wall • Potential pathological effect: dissecting aneurysm

Pathological effects of sustained, complicated primary hypertension Heart, Myocardium

• Mechanism of injury: increased workload combined ith diminished blood flow through coronary artieries • Potential pathological effect: left ventricular hypertrophy, myocardial ischemia, right heart failure

Pathological effects of sustained, complicated primary hypertension Brain

• Mechanism of injury: reduced blood flow and oxygen supply, weakened vessel walls • Potential pathological effect: transient ischemic attacks, cerebral thrombosis, aneurysm, hemorrhage

Pathological effects of sustained, complicated primary hypertension Eyes (retina)

• Mechanism of injury: reduced blood flow, high aerial pressure • Potential pathological effect: retinal value sclerosis. exudation, hemorrhage

Pathological effects of sustained, complicated primary hypertension Arterial vessels of lower extremities

• Mechanism of injury: weakened vessel wall • Potential pathological effect: intermittent claudication, gangrene

Hypertension risk factors

• STRESS • family history • Advanced aging • Cigarette smoking • Obesity • Heavy alcohol consumption • Gender: men < 50 and women > 50 • High dietary sodium intake • Low dietary intake of potassium, calcium and magnesium

Benign hypertension

• Stably controlled for years • Greater than 95% of cases

Symptoms: Deep Vein Thrombosis → Thromboembolism

• Sudden shortness of breath (dyspnea-a serious sign of airway problems) • Chest pain that often mimics a heart attack (may be sharp and stabbing or aching and dull). Pain worsens with exertion, but does not go away when at rest. • A cough that produces bloody or blood-streaked sputum. • Excessive sweating. • Rapid heartbeat (tachycardia) • Lightheadedness or fainting

Symptoms of Deep Vein Thrombosis

• Tenderness/redness in affected area • Pain and swelling in affected area • Fever • Rapid heart beat • Joint pain and soreness

Atherogenesis

• The lesion in atherosclerosis, the atheroma, is different than the lesion in other types of arteriosclerosis • Starts out with a fatty streak; we all have cholesterol in our blood that we need for our cells. It travels through the blood as LDL on its way to the cells. The top of the aorta is very well protected; so small injury of the endothelium doesn't cause accumulation. In the middle and lower regions of the aorta, there is enough slowing down of the blood and areas where the blood branches off that it causes turbulence, which can disturb the endothelium. LDL can get captured and accumulate, and as the blood rushes through it can injure the endothelial cells and make an opening. The LDL can get through the opening and into the interstitium of the tunica intima, and as it gets elevated, the tunica media, which can become very compromised. The plaques are called atheroma. o Atheroma = singular form of word; Atheromata = plural

Structure of a Small Artery (Arteriole)

• The wall blends into surrounding tissue. There are about 5 or fewer layers of smooth muscle around a small artery. • Muscle cell nuclei are directional, go around in a circle → make it strong and elastic

Thrombophlebitis: Sometimes is localized in superficial veins

• Thrombi that form in the superficial veins, which lie just under the skin, are known as superficial phlebitis. These superficial thrombi are different than deep venous thrombi and are much less serious. When a superficial vein is affected, a red, hard, and tender cord may be present just under the surface of the skin.

Progression of Atherosclerosis

• Turbulence injures the endothelium • Macrophages enter the intima and take up lipids and become foam cells • Also endothelial damage exposes the basement membrane, favoring platelet adhesion • Platelets release growth factors that stimulate smooth muscle cells (SMCs) to proliferate (muscle cells don't generally proliferate, so they have to dedifferentiated to be more like fibroblasts) • These SMCs take up lipid particles, and become foam cells. They can enter the intimal layer, reducing the medial layer. • They can ultimately make collagen (crunchy, not something you want in arteries) as they swell with lipid, so that they develop fibrous areas. Calcification can occur.

Thrombophlebitis: Most often in deep leg veins

• When a deep vein is affected, the leg may become swollen, tender, and painful, most noticeably when standing or walking. There may also be fever. However, many people with deep vein thrombosis have no symptoms.

Atherosclerosis: affects

•Affects large arteries •A main feature of atherosclerosis is the presence of atheromatous plaques that harden over time •The lumenal area becomes reduced, sometimes severely reduced •This is the form of arteriosclerosis that is MOST prevalent in the US and other countries with Western diets

Aneurysm: complication of atherosclerosis

•Atherosclerosis changes the intimal and medial tunics, but can develop to injure the whole vessel wall. •Clinical symptoms -Pain from pressure of a large volume of blood on the surrounding organs -Dysphagia (difficulty swallowing) -Dyspnea (shortness of breath) -Back pain •Less than 6 cm rarely ruptures •80% of larger ones rupture •Mortality: 5% pre-rupture & 50% post-rupture

Clinical Manifestations of atherosclerosis

•Atherosclerotic lesions generally cause no symptoms until 60% of the tissue's blood supply is occluded (if plaque formation is slow, collaterals may develop) •Early manifestations - transient ischemic events associated with exercise or stress •Later manifestations - CAD, infarction, stroke, hypertension from loss of stretch and recoil and decreased lumenal size (it seems to work both ways): Hypertension → atherosclerosis Atherosclerosis → hypertension •^ big difference - note that atherosclerosis leading to hypertension is a much later sequela of atherosclerosis (very far downstream - 90% occlusion). • With hypertension as the primary disorder, atherosclerosis is an early sequel, not a later one; you must treat it right away.

Structure of a Medium Artery

•Except for the largest of the medium arteries, the arterial walls blend into the surrounding tissue •The tunica media (tunica muscularis) is the most prominent layer There is less elastic material present compared to the aorta; this allows the interior and exterior elastic membranes to be seen clearly However, the amount of elastic material is a relative thing - there is still a lot of it present for stretch and recoil, to rectify the pulsatile flow of blood

Complications of Thrombophlebitis

•If thrombophlebitis is in a superficial vein, serious complications are rare •If the thrombus occurs in a deep vein, the risk of serious complications is great • Pulmonary embolism (potentially life-threatening) • Damage to valves in the leg veins • Permanent vein obstruction if many episodes of deep vein thrombosis have occurred

Goals in Management of Atherosclerosis

•Intervention, if necessary (acute ischemia) -Like coronary bypass •Removal of causes of vessel damage and prevention of lesion progression -Smoking cessation -Control of hypertension -Control of diabetes -Exercise -Diet to reduce LDL cholesterol: desired levels of Cholesterol less than 200 mg/dl, LDLs less than 130 mg/dl and HDL more than 35 mg/dl -Medication to reduce LDL cholesterol if diet alone does not work

Lymphatic System

•Location where another kind of capillary is found • Lymphatics help us to prevent a lot of disease and prevent us from having legs full of water • Contains: Water, Protein too large to be reabsorbed (mostly albumin) & Foreign substances • Lg. immunological function. In nodes, foreign substances are phagocytized before they can get into the blood stream

Lymphatic capillaries and veins

•Lymphatic capillaries are "blind" and have thinner vessel walls than those of veins that carry blood. They reabsorb the extra fluid (easily because of thin walls) and bring it through the lymphatic veins, up through the lymph nodes, and back into the bloodstream. •Lymphatic veins have valves, like blood carrying veins, to keep unidirectional flow. •There are lymphatic capillaries and veins. There are no lymphatic arteries - think of the direction that they carry lymph - towards the heart, like veins.

Capillaries

•Made up of just the endothelial layer and its basement membrane •1. Arteriole with muscle around it When it's cold outside, we want to be able to clamp down on arterioles to let less blood go through so we don't lose a lot of temperature. When it's hot outside, they can be more relaxed and open and blood can flow through superficial arteries easily. •2. Arterioles are connected to capillaries; blood runs through capillaries into the veins and is brought back up to the heart

Monckeberg's Medial Calcific Sclerosis - RARE! - KNOW THIS.

•Occurs mostly in people over 50 •Affects medium sized arteries, mostly of neck, pelvis, and limbs Femoral, tibial, radial, and ulnar arteries •Characterized by focal radiologic calcifications in the tunica media •Muscle tissue degenerates •The lumen is NOT narrowed -shape is not changed •Does not usually have clinical manifestations •Causes pulselessness - no stretch and recoil of artery because medial layer is compromised

Types of aneurysms -All are possible sequela of atherosclerosis

•True aneurysms: all 3 tunics of the wall bulge out together -Saccular vs. fusiform •False aneurysm: blood contained by a clot; shaped like saccular but no bulge •Dissecting saccular aneurysm - blood is contained by the adventitia (not as strong as medial layer - prone to breakage - patient could die)

Early phase of Atherosclerosis of the renal artery

(Panel A), there is mild atherosclerosis of the perirenal abdominal aorta and normal renal function. Renal blood flow, renal mass, and the serum creatinine concentration are normal. The dimensions of the kidneys are normal, and there is no cortical atrophy. The total glomerular filtration rate (100ml per minute) and the glomerular filtration rate in each kidney (50ml per minute) are normal.

Advanced phase of Atherosclerosis of the renal artery

(Panel C), there is bulky atherosclerotic plaques in the perirenal aorta and severe bilateral renal-artery stenosis. Both kidneys are small, and there is marked cortical thinning and irregularity. Loss of more than 50% of renal mass is usually associated with an elevation in the serum creatinine concentration (ischemic nephropathy), which may not be reversible. The total glomerular filtration rate (30ml per minute) and the glomerular rate in each kidney (15ml per minute) are depressed.