Chapter 26 Disorders of Blood Flow and BP Regulation Notes

**CHAPTER 26: DISORDERS OF BLOOD FLOW AND BP REGULATION** **[RISK FACTOR] [IN] [HEART] [DISEASE]** - age, gender body temp. - heart rate declines with age, more in men vs. Women 1. blood cholesterol 2. blood pressure 3. smoking/obesity 4. diabetes 5. genetics 6. male gender (befor...

**CHAPTER 26: DISORDERS OF BLOOD FLOW AND BP REGULATION** **[RISK FACTOR] [IN] [HEART] [DISEASE]** - age, gender body temp. - heart rate declines with age, more in men vs. Women 1. blood cholesterol 2. blood pressure 3. smoking/obesity 4. diabetes 5. genetics 6. male gender (before 70 yr. Old) - for each pound fat**,** there are an additional 300 km of blood vessels and the heart has to pump this extra distance **UNDERSTANDING BLOOD PRESSUR E- READ CHAPTER 26 PG 719** DYSLIPIDEMIA ------------ Refers to a condition of imbalance of lipid components in blood **Hyperlipidemia** is the EXCESS of lipids in blood **LIPIDS** - ; the hydrophobic fat-based core (**cholesterol, triglycerides**) and the **apoproteins** (B) combine to form a transport molecule called **lipoprotein** - **5 types of lipoproteins based on their densities; HDL, LDL, VLDL, IDL & Chylomicrons** - The apoproteisn determine the fate /metabolism of the lipoprotein - Lipoproteins are made in liver and duodenum. They begin with chylomicron made in by duodenal cells to transport dietary fat (triglycerides) and cholesterol that have been absorbed 1. **Chylomicrons** bring fats to muscle and adipose tissue. Residual cholesterol and protein in chylomicron is returned to LIVER and /or excreted in bile. 2. Liver makes VLDL & HDL 3. **VLDL/ IDL** are 25*%* cholesterol & large amount of endogenous triglycerides made by liver; they transports triglycerides made by the liver to the adipose 7 muscle cells for storage. When they drop off the triglycerides , they are now called IDL's which return to liver to remake VLDLs. Serve as main food source for body during starvation. A high fat diet promotes the production of **VLDLs**. In vascular system**, IDLs** are converted to LDL 4. **LDL** are 25% protein, 2% triglycerides, 55*%* cholesterol; most cells have receptors for these, they deliver cholesterol to the body as needed. Serve as primary transport for cholesterol. LDLs are removed from circulation by receptor- mediated endocytosis (70%) or scavenging via macrophages. most receptors are in hepatocytes - Once endocytosed, the vesicles fuse with lysosomes and the LDL is degraded with release of cholesterol into cytoplasm. - In other tissues (endothelium ) can control their uptake by receptor level modification - Scavenger LDL removal is via modified LDL receptor and is more directly related to patients plasma cholesterol levels - The macrophages in arterial walls can take up LDL and create an atherlerotic plaque 5. **HDL** are only 13% cholesterol; it removes excess cholesterol from the cells and brings it back to liver (bile) for elimination. (mechanism is unkn). Thus a high **HDL** valve is associated with a decreased risk of heart disease caused by plaques. Exercise, low alcohol , lipid meds, can increase am't of HDL **ETIOLOGY & PATHOGENESIS OF DYSLIPIDEMIA** - SERUM cholesterol elevations can be b/c of VLDL, HDL, or LDL = dyslipidemia factors contributing to increase : genetics, diet, medications , comorbid conditions & metabolic diseases. - Dyslipidemia is classified as PRIMARY or SECONDARY **PRIMARY** -- abnormal lipid =/or cholesterol levels independent of any disease or lifestyle problems; - **[FAMILIAM HYPERCHOLESTEROLEMIA]** -- is a type of primary ; autosomal dominant (heterozygous or homozygous ) mutation of chromosome 19 (short arm) ; LDL levels elevated to \~350mg/dl (heterozygous) and \~1000mg/dl (homozygous); most common in US is hetero.. 1/500 adults with hetero.. much more rare; for heterozygotes , elevated levels present from birth but symptoms are adult --onset ; most common symptom is **xanthomas (chol**. deposits around tendons) and **atherosclerotic vascular lesions.** **TREATMENTS:** - *Statins* - inhibit enzyme HMG-CoA reductase resulting in the inhibition of cholesterol synthesis in liver and reduces VLDL as well as triglycerides and increase HDL levels. - *Colestipol* binds with bile acids and impair their absorption and reduce enterohepatic ciculation and reutilization of bile acids. It also decreases the absorption of dietary cholesterol. - *Fibrates* increase HDL level and decrease triglyceride levels. - Cholesterol absorption inhibitors (*ezetimibe):* Inhibits absorption of cholesterol from the small intestine: dietary (from food) and also promotes cholesterol excretion along with bile. - *Niacin* (Nicotinic acid) decreases the production of VLDL and triglycerides in the body, and raises HDL-cholesterol. **SECONDARY** -- this dyslipidemia is Caused by health problems and behavioral problems; causes (obesity, metabolic diseases like DM II; mechanism of action (cause and effects are not fully understood , but **obesity related dyslipidemia e**levates triglycerides, LDL and cholesterol with decreased HDL. Stimulated adipocytes release inflammatory cytokines (adipokines). Also fat tissue contains increased macrophage activity **= together this creates a state of systemic inflammatio**n. Also free fatty acids in blood are elevated (hydrolytic activity of fat cells). Free FA & systemic inflammation = disrupted glucose metabolism = insulin resistance = DM II. Whether or not the tissue insulin resistance comes before the DM or vise verda -- not clear. *Dyslipidemia associated with insulin resistance (DM II) -- called **metabolic syndrome** (characterized in 1988). Consensuses statement defines the [presence of \>3 of these] : elevated fasting glucose; elevated blood pressure ; elevated waist circumference (abdominal fat tha tis country specific); dyslipidemia (increased triglycerides & chol. Decreased HDL)* - Hardening or stiffening of arteries due to formation of **fibro-fatty lesions** -- can occurs in ICA, vertebral /basilar arteries, corona, y abdominal aorta , thoracic, femoral or popliteal arteries - Risk factors include: high LDL, high BP, smoking, diabetes, obesity, sedentary lifestyle ; some genetics factors for atherosclerosis ( altered lipoproteins) , family history, age, sex (men at greater risk vs pre-menopausal women b/c of protective estrogens but equalizes out in post- menopausal women) ; smoking (cigarette toxins enter blood and damage endothelial cells which begins process of lesion formation ) - DMII and hypertension are BOTH risk factors; separate each one alone increase **2x** change of lesion formation; together increases **8x;** if you add hyperlipidemia -- increase is **20x** for lesion formation of athersc. - High levels of C-reactive protein (CPRP- an acute inflammatory protein) in blood is marker for plaque formation (CRP is also present in lesions) - High levels of homocysteine (derived from protein metabolism which is normally metabolized). High blood levels inhibits anticoagulants and is associated with endothelial damage. People born with **homocystinuria** (genetic defect in metabolism) have increased risk for early development of plaque - Hyperlipidemia -- correlates with increased LDL and increased uptake via vascular macrophages. **PATHOGENESIS** - ***Development of plaques:*** steps include - ***Endothelial cell injury --***smoking, elevated LDL, immune and mechanical stress mechanisms cause endothelial damage with adhesion of monocytes/platelets to injury site - ***Migration of inflammatory cells-*** endothelium secrete adhesion molecules binding other WBCs which emigrate into the tunic intima. Monocytes become macrophages and engulf LDLs which are then oxidized (they become foam cells) - ***Lipid Accumulation and Smooth Muscle Proliferation --*** excessive accumulation of foam cells leads to lesion progression ; macrophages release growth factors leading to proliferation of SMCs and elaboration of the ECM within vascular wall; - ***Plaque Structure --*** plaque matures to an accumulation of macrophages, SMCs, ECM (collagen & elastic fibers) , WBCs. [there is a superficial FIBROUS CAP] (SMCs & ECM); [immediately below and to side (SHOULDER region )] are macrophages, SMCs and lymphocytes; [below cap is a CENTRAL CORE] (lipid foam cells with fatty debris that becomes necrotic); - ***Rupture or ulceration of the central core b/c of the unstable fibrous cap leads to hemorrhage and possible thrombolytic occlusion of lumen*** **CLINICAL MANIFESTATIONS:** it begins insidiously and becomes evident \~20-40yrs old. Fibrous plaques in Americans begin to appear in 30's. Plaques produce their effect thru: narrowing of vessel walls leading to ischemia & sudden vessel obstruction b/c of rupture or hemorrhage; thrombosis or emboli formation ; aneurysm **formation due to weak vessel walls** **ANEURYSMS** - Abnormal local dilation of blood vessels -- mostly in aorta & branches; classified as to location , anatomical features - TWO types -- **TRUE** (the dilation consist of the entire wall of vessels ) & **FALSE** (results from a bulge in wall due to blood leaking from a tear of the inner wall) - **BERRY** aneurysm -- true aneurysm occurs in circle of Willis ; occurs at bifurcation ; small, spherical dilation of vessel - **FUSIFORM** -- true aneurysm involving entire circumference of vessel wall, begins slowly then enlarges; found in thoracic /abdominal aorta - **SACCULAR** -- true aneurysm that extends over part of circumference of vessel -- saclike - **DISSECTING aneurysm**- false aneurysm resulting from tear in intima creating blood cavity. - **RISK factors**: congenital defects; trauma; infections; atherosclerosis. - **Tension on wall** = pressure X radius -- therefore increases with increasing radius or dilation **Clinical Manifestations**: can be asymptomatic Aneurysm of Thoracic aorta: back and neck pain, dyspnea, brassy cough due to pressure on trachea, difficulty in swallowing, distention of neck vein and edema of face and neck - Life threatening -- involves hemorrhage into a vessel wall with blood filled cavity. - Most common in aorta close to aortic valve and thoracic aorta distal to the origin of subclavian artery - Abnormal diffuse dilatation of veins.; Lower limbs- common - Congenital or acquired - Since there are no valves in inferior vena cava and common iliac veins, blood in abdominal veins must be supported by valves in external iliac and femoral veins. - When intraabdominal pressure increases as during pregnancy, stress on saphenofemoral junction is increased. - Hormones may have effect on smooth muscles of veins contributing to venous dilatation and valvular incompetence. - extra pressure allows pooling of blood and forces fluids into surrounding tissues - nearby tissue is inflamed and tender **VENOUS THROMBOSIS (DVT**) - Thrombus can develop in superficial (more innocuous a condition ) or deep veins - deep vein thrombosis (DVT) common in lower extremities - DVT is a serious disorder complicated by pulmonary embolism. **Diagnosis, Treatment** - Most patients are asymptomatic but when symptoms present -- pain, swelling and deep muscle tenderness depending upon the veins involved. -Exercising legs and wearing support stockings to improve venous flow - -5 -- 20° elevation of the leg prevents stasis. -Avoid body positions that favor venous pooling -Anticoagulant therapy (heparin and warfarin)- initial treatment is injection then switched to oral or subQ -surgical treatment only in selected cases when patient is at risk of developing pulmonary embolism **CHRONIC VENOUS INSUFFICIENCY (CVI)** - Improper functioning of the vein valves in the leg, causing swelling and skin changes. - Normally, the vein valves keep blood moving back toward the heart. - It is a condition where the veins cannot pump enough oxygen-poor blood back to the heart. - Physiologic consequences of DVT (most common cause) or valvular incompetence or both. - In valvular incompetence, valves become damaged, allowing the blood to leak backward. Unidirectional blood flow through valves as well as muscle pumps are ineffective. - Venous insufficiency leads to tissue congestion, edema, and impairment of tissue nutrition. **Etiology :** Symptoms include varicose veins, swelling, or skin color changes on the affected leg. If the condition progresses, leg ulcers can form. **People may experience:** Pain areas: in the leg; Skin: darkening of the skin, discolored and thick skin on legs, swollen blood vessels in the skin, or varicose veins Also common: swelling in extremities **Treatment : consists of devices and activity modifications;** compression stockings, elevating the legs, and moisturizing the skin to prevent cracks. In some cases, surgery may be needed to improve blood flow. (Endovenous laser treatment and Sclerotherapy) **BLOOD PRESSURE AND ITS REGULATION-Lecture 4** **[Blood Pressure: is]** the *hydrostatic pressure* of the blood exerted on the vessel. It is highest in the large aorta and is generated by the contraction of the ventricles. It is generated by the contraction of ventricles. As blood leaves the larger vessels to the smaller vessels, the BP drops progressively at a distance from the left ventricle increases. BP continues to drop as blood enters systemic venules (16 mmHg), and then veins b/c these vessels are farthest from the left ventricle. Finally BP reaches 0 mmHg as blood flows into the right ventricle. Blood always FLOW DOWN a PRESSURE GRADIENT so if there is no pressure difference there is no flow. BP also depends on the volume of liquid in the vessel. If there is a change in the volume of \>**10%,** the BP changes. Smaller amounts can be compensated for by homeostatic mechanisms. The converse is also true. AP.png **[Inter- Arterial pressure (from brachial artery)] -- shows sharp rise to 120mmhg during systole (ejection phase) ; then downward deflection and dicrotic notch (when the ventricular pressure falls below aortic pressure slamming shut the SV which THEN leads to rise in inter-aortic pressure due to recoil in large arteries. As the ventricles relax and blood flows to the peripheral arteries during diastole , the arterial pressure falls** **[MAP (90-100mmHg in adults]**) - is the measure of the average pressure in the arterial system during systole and relaxation. - Serves a good indicator of tissue perfusion and it determined by 60%of the diastole pressure and 40% of systole pressure -- diastole pressure accts for more b/c a greater fraction of cardiac cycle is spent in diastole - MAP is function of CO and PVR **[Mean arterial blood pressure (MABP) is the average BP in arteries, and is equal to:]** 80. \+ 1/3 (120 -- 80) == 93 mm Hg CO = MAP / R (resistance) **or** **MAP = CO (SV x HR) X R** (if the CO rises (due to an increase in heart rate or stroke volume) than the MAP rises so long as the resistance remains the same), and the reverse is true also. MAP decreases from 93 mmHg to 35 mmHg as blood passes from arteries thru capillaries where the pressure fluctuations disappear. **The body maintains BP by (1) adjusting CO to compensate for changes in PVR (2) adjust PVR to comp for changes in CO** **[Regulation of Blood Pressure]** **ACUTE REGULATION** [**Neural Regulation***: occurs via 3 kinds of receptors/ registers* ;] the **cardiovascular center** in the medulla/pons helps regulate heart rate and SV. It also controls neural, hormonal, and local negative feedback systems that regulate BP, contractility (force of contraction) of the ventricles, and blood vessel diameter. Some of the CV's center's neurons stimulate the heart, some inhibit the heart (HR decreases with parasym vagal stimulation ) while some control vessel diameter. - The ANS control of BP is mediated thru circulatory reflexes (intrinsic and extrinsic ) : extrinsic sensors are found outside CV system (pain or temperature receptors then channeled thru the hypothalamus/limbic system (emotions can change HR/BP) ). Intrinsic sensors are the baro and chemoreceptors - **baroreceptors** - specialized nerve cells in the wall of the carotid artery (carotid sinus) and the arch of the aorta. - Any *increase in BP results in the stretching* of the walls and the stimulation of the baroreceptors. This signal is sent to the brain, which responds accordingly *(decrease in heart rate).* - If there is a decrease in BP then the negative feedback loop *results in the release of Epinephrine/NE.* The baroreceptor reflexes send impulses to the CV center to help regulate BP. When BP falls, the baroreceptors are stretched less, and they send nerve impulses at a slower rate to the CV center. - Moving from a **lying to standing** position decreases BP and blood flow in the head and upper part of the body. The **baroreceptor reflexes,** counteract the drop in pressure resulting in increase in HR and sympathetic vasoconstriction to increase PVR These are the baroreceptor triggered reflexes : a. **[the carotid sinus reflex]**- initiates from the carotid sinuses in the walls of the carotid arteries near the branching points in the neck. Blood stretches the walls of the sinus, which stimulates the baroreceptors., which sends these impulses to the CV center. b. **[The aortic reflex]** -- is found in the wall of the ascending aorta and the arch of the aorta and regulates systemic BP - **chemoreceptors -** located in the carotid bodies (at the bifurcation of carotids), detect changes in the O2, CO2, H+ ion levels in the blood, and send signals to the brain to regulate ventilation & they communicate with CV centers to **induce vasoconstriction** (detects acidity or hypoxia, and detects hypercapnia or excess CO2). Signals are also sent to the respiratory center in the brain to adjust the rate of breathing affects blood chemistry. - There is a response also when BP drops leading to low O2 and high H+/CO2. -- **leads to vasoconstriction** - **In COPD people** , they may develop pulmonary hypertension due to hypoxic response of chemoreceptors - **In sleep apnea** there is a rise in BP during hypoxemia during apneic periods - **proprioceptors --** monitor movements of joints and muscles and provide input to the CV center during physical activity. Their activity accounts for the rapid increase in heart rate at the beginning of exercise. **Hormone Regulation :** [ ] occurs via (1) **altering CO (2) changing vascular resistance (3) adjusting total blood volume** 1. [rennin-angiotensin-aldosterone] (RAA) system. When blood volume falls, or blood flow to kidneys decreases, JG cells in kidney release ***rennin***. Rennin and ***angiotensin-converting-enzyme*** (ACE) act to produce active hormone -- **angiotensin II** which raises BP as follows: (a) angiotensin II is a potent vasoconstrictor that raises vascular resistance (b) it stimulates secretion of aldosterone which increases Na+ reabsorption from kidneys indirectly increasing blood volume & BP 1. [Epinephrine & Norepinephrine]. These, released by adrenal medulla increase CO by increasing heart rate and force of heart contraction; they vasoconstrict arterioles and veins in skin and abdominal organs and cause vasodilation of arterioles in cardiac and skeletal muscle, helping to increase blood flow to muscle thru exercise. 1. [antidiuretic hormone (ADH]). One of the actions of this hypothalamus-produced hormone called *vasopressin* is to vasoconstrict which increases BP 1. [Atrial natriuretic peptide (ANP]). Released by atrial heart cells, it lowers BP by causing vasodilatations by promoting loss of salt and water in urine reducing blood volume [*Autoregulation* - Local response:] autoregulation at the level of the capillary bed occurs via vasodilatation or vasoconstriction, and is important in times of increased demand like physical activity 1. 1. **LONG TERM REGULATION** - short term regulation of BP etc., loses its effectiveness over time. Long term (weekly daily etc) is enhanced by kidney in response - When the body contains **excess ECM fluid** b/increased water intake or salt retention (which leads to water retention)- this leads to rise in atrial pressure (which has a direct effect on CO and an indirect effect on PVR) and the resultant **increase in rate of kidney excretion of water** (pressure diuresis) and salt (pressure diuresis) **HYPERTENSION (HT)** **Classified as primary or secondary; refers to sustained condition of elevation of BP within arterial circulation** **Etiology Primary HT** - - **Gender & Age Related: (**Systolic pressure in new born: 50; 10 days of age: 78; adolescence 120); prevalence for hypertension is greater in men vs women (younger adults) -  Link between insulin resistance and hypertension: What is the evidence from evolutionary biology? \| Diabetology & Metabolic Syndrome \| Full Text - - **Insulin resistance and Metabolic abnormalities:** insulin mediated increase in sympathetic activity is directed at increasing metabolic rate for burning calories, but doesn't work In Type II diabetes, because of insulin resistance. Insulin stimulates growth of smooth muscles which increase PVR. Insulin also stimulates kidney to retain water and Na+. - **Obesity:** Fat distribution may be a critical indicator of hypertension risk than actual over weight. - Waist to hip ratio is used, as **abdominal fat seems to be more insulin resistant** than fat deposits over buttocks and legs, causes more glucose intolerance, chronic kidney disease dyslipidemia. - 10lb wgt reduction produces decrease in BP - [Mechanism of action] ? **LEPTIN adipocyte-derived hormone** acts on hypothalamus to increase BP thru SNS - Large levels of free FA in obese people, causes SNS activation (vasoconstriction) - **Excess Alcohol Consumption, Stress, Sedentary life style, Tobacco (inflammatory changes from toxins in vascular contribute to atherosclerosis = HT** ) - **Sleep apnea- normal nocturnal "dipping of BP" is disrupted b/c of apnea** **Etiology : Secondary HT** Tends to be seen in \>30yr -50yr olds. Can be attributed to drug abuse (cocaine, amphetamines; hormones like Erythropoietin). Most cases have to do with renal disease or adrenal disease - Renal HT: renal disease resulting in decreased urine formation/output can cause HT (acute renal disorders -- glomerulonephritis, acute renal failure or Tubal obstruction , chronic pyelonephritis, poly cystic disease & ESRD or diabetic nephropathy) - **Renovascular HT** -- is HT caused by reduced renal blood flow and activation of RAA (release of renin -- AGII = vasoconstriction & increased PVR) and the release of aldosterone (increases slat retention ). One or both kidneys can be affected, and the unaffected kidney suffers the effects of high BP**; causes include ( artherosclerosis of RA and fibromuscular dysplasia - noninflammatory vascular disease in renal branches; common in women 30-50yrs)** - **Adrenal Disorders:** primary hyperaldosteronism (hyperplasia or adenoma) leads to excess glucocorticoids and raises BP - **Oral Contraceptives-** mechanism might be via increased tissue volume (b/c hormones cause Na+ retention) -- not a permanent consequence **Clinical Manifestations:** - target organs include: heart, eyes & kidney for both primary and secondary HT - **atherosclerosis, coronary artery diseases, stroke, heart failure**; increases risk for atherosclerosis b/c of endothelial damage - **Left ventricular hypertrophy** leading to ischemic disease, cardiac arrhythmias & congestive heart failure b/c of increased afterload (pressure in peripheral circulatory system) ; as it hypertrophies, it become less efficient and can fail totally - **Retina:** Retinopathy, thickening of retinal capillaries (narrows lumen) ; increased HT can then cause hemorrhages, microaneurysms and hard exudates 9not reversible after a certain pt) - - - - **Kidney damage : glomerular HYPOperfusion which can then cause gomerulosclerosis +/or tubuointerstitial fibrosis** **Treatments:** - **Diet-** - **Medication-** - Diuretics (thiazides ) -- NA & Cl are not reabsorbed in the DCT and this results in increased excretion of ions - Beta blockers -- blocks clels response to NOR & EPI -- especially in heart & kidney arteries - ACE inhibitors- stops RAA system increase in BP via conversion of AGI to AGII - Ca+ channel blockers- Inhibition of Calcium channels; Reduces: Contractility of myocardium & Tone in vascular smooth & muscles including coronary artery & - reduces activity of SA node - It is the abnormal drop in pressure upon standing for a while; drop in systolic (20mmHg) and diastolic (10mmHg) after 3 min standing - When jumping up from reclined position, 500-7700ml blood drops to lower extremities leading to decreased central volume and arterial pressure ; normally carotid baroreceptors sense decreased pressure and (RAA) kick in feedback mechanisms via ANA etc; also with movement of leg muscles and the muscle pump -- venous return is enhanced. - **Aging --** increased tendency towards arterial pressure instability. Postprandial BP decreases in older person after high carbohydrate meal -- (glucose mediated impairment of baroreceptoreflex sensitivity and increased blood flow to GI tract organs (due to GI tract hormones) - **Reduced blood volume** -- excessive use of diuretics, excessive diaphoresis, vomiting, diarrhea and loss of fluid - **Bed rest and impaired mobility** -- promotes a reduction in plasma volume, decrease in venous tone, and failure of peripheral vasoconstriction and weakness of skeletal muscles that supports veins - **Drug induced** - **Disorders of autonomic** N.S. -- Diabetic neuropathy, injury to spinal cord, cerebral vascular accident interrupts sympathetic outflow. -