PATHOLOGY - hypoxia, ischemia, shock, circulation

Hypovolemic shock

Causes -bleeding is the main cause (internal/external) -acute loss of over 20-30% of circulating blood -> Shock -decrease in body fluids due to excessive vomiting, diarrhea, sweating or burns Pathogenesis -lead to decreased blood volume -> hypoperfusion of tissues -> increased anaerobic glycolysis -> production of large amount of lactic acids. the lactic acidosis depresses myocardium, decreases peripheral vascular responsiveness to catecholamines and may be severe enough to induce coma. Clinical manifestations -hypotension, rapid weak pulse, cold and clammy skin, intense thirst, rapid respiration and restlessness or fatigue, urine decreased Types ★Hemorrhagic shock -loss of over 20% of circulating blood, shock will develop -after hemorrhage, the plasma protein loss is gradually replaced by the liver and the conc. of plasma proteins returns to normal within 3-4 days. -the increase in circulating EPO increase erythropoiesis, but it takes 3-6 days to restore RBC count to normal. ★Traumatic shock -develops due to severe damage to muscles and bones and there is bleeding into the injured areas. -the thigh muscle can accomodate 1L of extravasated blood. -example: Crush Syndrome -when pressures on tissues is relieved and they are once again perfused with blood, free radicals are generated which can cause further tissue destruction (reperfusion injury) -increased calcium in damaged cells can reacth toxic levels -large amounts of K enters blood circulation. -myoglobin and other products from reperfused tissues accumulate in kidney in which glomerular filtration is already reduced by hypotension and the tubules can become clogged, causing anuria. ★Surgical shock -due to combination in various proportions of external hemorrhage, bleeding into injured tissues and dehydration. ★Burn shock -loss of plasma from burnt surfaces and hematocrit rises, producing severe hemoconcentration. -there is also complex metabolic changes -for these reason and problems of easy infection of burned areas and kidney damage, the mortality rate when 3rd degree burns cover more than 75% of the body is close to 100%.

Chronic changes in BP - causes and consequences

Causes -cardiac abnormalities -renal artery stenosis, kidney disease -adenomas -> hyperaldosteronism, pheochromocytoma (endocrine dysfunction in general) (all causes secondary hypertension) Renal artery stenosis, Kidney disease -Renal disease is the most common cause of hypertension -most acute kidney disorders result in decreased urine formation, retention of salt and water and hypertension. -glomerulonephritis, acute renal failure and acute UT obstruction -hypertension also common in people with chronic pyelonephritis, polycystic kidney disease, diabetic nephropathy and end stage renal disease, regardless of cause. -in elderly, the sudden onset of secondary hypertension is associated with atherosclerosis of renal blood vessels. Renovascular hypertension -hypertension by reduced renal flow and activation of RAAS. -most common cause of secondary hypertension -Two types of renovascular disease: AS of renal a., fibromuscular dysplasia of renal a. -atherosclerosis of renal artery accounts for 70-90% of cases -fibromuscular dysplasia more common in women in 30s -genetics and increased risk with smoking, hyperlipidemia. -renal artery stenosis suspected in previosly normotensive person older than 50 and younger than 30 or in accerlerated hypertension -hypokalemia, abdominal bruit, absence of hypertension in family and duration of hypertension of less than 1 year -> renovascular hypertension Hyperaldosteronism -Primary hyperaldosteronism - adrenocortical hyperplasia, adenoma -excess mineralcorticoids, glucocorticoid (Cushings) tend to rise BP -hypertensionin 80% of Cushing patients -usually have hypokalemia (aldosterone) -CT, MRI scan to localize lesion, surgery, K sparing diuretics Pheochromocytoma -tumor of chromaffin tissue that release catecholamines -commonly in adrenal medulla or sympathetic ganglia -cause serious hypertensive crisis -continous release of catecholamines can cause headache, excessive sweating and palpitaions (nervous, tremor, pale, weak) -paroxysmal episodes of hypertension, sometimes dangerously high levels in 50% of patient, the other with sustained hypertension -measure urine catecholamines and metabolites, locate tumor by MRI or CT, surgery or catecholamine synthesis blockers

Acute changes in BP in systemic changes

Causes -drinking a lot of fluids -physical exercise -changes in body position (orthostatic hypotension) -acute hemorrhage -massive vasodilation Consequences -shock states -regulatory mechanisms Acute regulation -mechanisms that act over sec-min and are intended to correct temporary imbalances in BP (exercise, orthostatic) and also life threatening situations (hemorrhage) -the acute control of BP relies mainly on neuronal and humoral mechanisms Neural mechanism -the most rapid mechanism -control center for BP in reticular formation of medulla, pons where integration and modulation of ANS responses occur -this area contain vasomotor and cardiac control centers = Caridovascular center -transmit parasymp impulses to the heart through vagus and sympathetic impulses to heart and BV through SC and peripheral sympathetic nerves -sympathetic stimulation -> incr. HR, contractility, vasoconstriction -> increase peripheral vascular resistance. -ANS control intrinsic and extrinsic reflexes -Intrinsic reflexes: baroreceptor, chemoreceptor reflexes -Extrinsic reflexes: pain, cold Humoral mechanism -RAAS, ADH, catecholamines

Myocardial infarction - pathogenesis

-Hypoxia develops within 10 sec of decreased perfusion. -Cardiac cells remain viable for approx. 20 minutes under ischemic conditions -> irreversible changes - Myocardial infarction -pain is transient, last about 3-5 min, temporary ischemia has only reversible effects. -character of pains is sometimes mistaken for indigestion. -decreased contractility causes decrease stroke volume, BP -> activation of sympathetic system -> tachycardia -use of nitrates reduce coronary spasm, peripheral vasodilation decrease afterload and preload -> decreased oxygen demands. -B blockers decrease contractility and HR -> decrease oxygen consumption, prolonged diastole helps filling of coronary arteries -calcium channel blockers - influence vasospams and contractility

Unstable angina pectoris

-preinfarction, Cresando angina -advanced ischemia, unpredictable -the pain present randomly in all situations, not only during physical activity. -depression of ST segment -cause: vasospasm together with ulcerated atherosclerotic plaque which causes not only narrowing, but also attract thrombocytes. -a temporary thrombotic plaque formed that occludes the lumen of the coronary artery,but is almost immediately dissolved & perfusion restored -acute and dangerous situation, because you never know when the plaque will not be dissolved and myocardial infarction will occur. -nitroglycerin not helping, because the ischemic pain is temporary thrombotic occlusion.

Compensatory mechanisms in shock

1. Baroreceptor stimulate - SNS, Catechol, RAAS, ADH 2. Increase total peripheral resistance and HR - contractility increase cardiac output, BP, tissue perfusion 3. Renal blood flow - RAAS 4. Peripheral vasoconstriction increase central volume and vital organ blood supply 5. Respiratory rate increases to blow off excess CO2 Presentation of compensated shock -restlessness, anxiety -tachypnea - respiratory compensation to MAC -tachycardia (bradycardia in cardiogenic, neurogenic) -normal BP -pale, cool skin (cardiogenic, hypovolemic) -warm flushed skin (anaphylactic, septic, neurogenic) -weakness

Differences in compensation in shock

1. Sympathetic activation -Baroreceptors in aortic arch and carotid sinuses usually suppress the vasomotor center in the brain stem by sending a high frequency of action potential to it. In case of decrease in BP, the frequency is decreased and so is the suppression. - Constriction of veins - Constriction of splanchnic, skin, liver and renal arterioles to increase total peripheral resistance - diastolic BP -> Increase in HR and contractility -> Bronchodilation and increased ventilation 2. RAAS -In response to decreased blood flow and BP in kidneys, they will produce Renin. -The resulting aldosterone will provide fluid retention by kidneys and cleave angiotensin which acts as vasoconstrictor on veins, arterioles -> increasing venous return and total peripheral resistance - BP 3. ADH -released in response to increased osmolality (sensed by osmoreceptors in hypothalamus) and decreased circ. volume (sensed by baroreceptors in carotid bodies) -> Resorption of water -> Vasoconstriction -> Increased thirst 4. Reverse stress-relaxation of circulatory system - if circulatory system is filled with excess of blood, the resultant excess pressures throughout the system cause a slow stretch of essentially all vessels of the body, but especially the veins and venous reservoir such as liver and spleen. -therefor in effect, the circulatory system simply enlarges enough to make up for the increased blood volume. -when hemorrage occurs, the diameter of the vessels gradually shrink, especially the venous reservoirs such as liver and spleen, and in short time the size of circulatory system again more nearly fits the volume of blood that is available to fill it. This mechanism of stress relaxation and reverse stress relaxation begins to act within seconds, and it continues to act over a period of hours or even days, but most of the effect occurs within 20 min. -> Decrease capacity of vascular system -> Prevents peripheral pooling 5. Compartment shift -the hydrostatic pressure in capillaries is lost, so fluid is sucked into vessel. -there is a shift of interstitial fluid from interstitial space into vascular space.

Embolism

Embolism =intravascular solid, liquid or gaseous mass that is carried by blood to a site distant from its point -majority derive from dislodged thrombus - thromboembolus -less common emboli: fat droplets, gas bubbles, AS debris, tumor fragments, bits of BM and amniotic fluid. -consequences are primarily infarction in downstream tissue or hypoxia, hypotension and RHF in pulmonary embolism. ★Thromboembolus -venous emboli lodge primarily in the lungs causing pulmonary thromboembolism -arterial emboli can travel anywhere causing systemic thromboembolism. Systemic thromboembolism -mostly arise from intracardiac mural thrombi -arteriolar embolization depends on the origin and common ones include LE, CNS, kidney, GIT, spleen. -consequences: depends on quality of occluded vessel, collateral supply and affected tissues vulnerability to anoxia. ★Fat embolism -soft tissue trauma, long bone fractures release microscopic fat globules into circulation. -occlude pulmonary and cerebral microvasculature. ★Amniotic fluid embolism -uncommon, serious condition of labour and immediate postpartum -entry of amniotic fluid into maternal circulation via tear in placental membrane. -mortality rate 80%, most common cause of maternal death ★Gas embolism -may occur during laporascope surgeries if air is pumped into abdomen. -classic in decompression sickness (sudden change in ATM) -nitrogen bubbles occur if diver ascend too quickly. -high pressure chamber.

Endothelial dysfunction syndrome

Endothelial dysfunction syndrome -Endothelial cells synthesize and release various factors that regulate angiogenesis, inflammatory responses, hemostasis, vascular tone and permeability. -EDS has been associated with a number of pathophys. processes -Oxidative stress appears to be a comon denominator underlying endothelial dysfunction in cardiovascular diseases. -However additional factors such as age, sex, salt intake, cholesterolemia, glycemia, smoking, hypertension and hyperhomocysteinemia are the mechanisms underlying the endothelial dysfunction. -Vascular endothelial cells line the entire circulatory system from the endocardium to the small capillaries. these cells have very distinct and unique functions which include fluid filtration, such as in the glomeruli of kidney, blood vessel tone, hemostasis, neutrophil recruitment and hormone traficking. EDS: imbalance between vasodilating and vasoconstricting substances produced by and acting on the endothelium. Stimuli/Causes: -hemodynamic stress and lipid metabolites - contributing to atheroscleoris -cytokines and bacterial product - contributing to septic shock -toxins from cigarette smoke and homocysteine - AS -oxidized LDL -diabetes -hypertension -mechanical denudation, immune complex deposition -irradiation or chemicals -> intima thickening and presence of high lipid diets, typical atheromas are produced -> ED -> atherosclerosis Endothelial reaction -rapid (minutes) - reversible and independent on new protein synthesis: histamine induced contraction. -slow (hours-days) - dependent on new gene expression, proteosynthesis Consequences -impaired endothelium dependent vasodilation -hypercoagulable states -leukocyte adhesion -increased endothelial permeability -lipid deposition -thrombosis (decreased smoothness of vessels) -hypertension (vasoconstriction due to endothelin and decreased NO) -atherosclerosis (inc. adhesive molecules and proinflammatory changes in endothelial cells) -heart failure

Causes and consequences of arterial hypertension

Hypertension - increase in blood pressure -Prehypertensive: 120-139/80-89 -Hypertension stage 1: 140-159/90-99 -Hypertension stage 2: >160/ >100 mmHg Patients can suffer from -Primary hypertension -Secondary hypertension -White coat syndrome: elevated office BP, normal home BP (12-18%) -Masked hypertension: normal office BP, elevated home BP (8%) Primary (essential) hypertension -Unknown cause, but risk factors are known -Nonmodifiable risk factors: - family history (50%), age related changes, race, insulin resistance and metabolic abnormalities: DM 2, hyperlipidemia, obesity -Modifiable risk factors: -high salt intake, obesity, excess alcohol consumption, intake of potassium, calcium, magnesium, obstructive sleep apnea Consequences - target-organ damage: long term effects of hypertension on other organ systems such as kidneys, heart, eyes and blood vessels. - major risk for atherosclerosis since it promotes, accelerate plaque formation and possible rupture. contribute to coronary heart disease, heart failure, stroke and peripheral artery disease. -increase workload on left ventricle, over time the left ventricle hypertrophies to compensate for increased work, major risk factor for coronary heart disease, cardiac dysrhytmias, sudden death and congestive heart failure since it cant pump properly. - chronic hypertension leads to nephrosclerosis -dementia and cognitive impairment -hypertensive retinopathy - thickening of intima, hyaline degeneration - may cause blindness Malignant hypertension -a small number of patients with hypertension develop and accelerated and potentially fatal form called malignant hypertension -usually in young black men, women with toxemia of pregnancy and people with renal and collagen diseases. -sudden, marked elevation in BP above 120 complicated by evidence of acute or rapidly progressive life-threatening organ dysfunction. -arterial spasm of cerebral arteries with hypertensive encephalopathy -vasoconstriction to protect brain, but these regulatory mechanisms are often insufficient to protect capillaries - cerebral edema often -swelling of optic nerve -> visual disturbance -headache, restlessness, confusion, stupor, motor and sensory deficits, in severe cases: convulsions and coma. -severe and prolonged malignant hypertension injure arteriole walls, intravascular coagulation and fragmentation of RBC -renal blood vessels particularly vulnerable to hypertensive damage and is probably the most important prognostic determinant -elevated blood urea nitrogen and serum creatinine, metabolic acidosis, hypocalcemia and protein urea (renal impairment)

Types of shock table

Hypovolemic, Cardiogenic -> cold and clammy Septic, Neurogenic, Anaphylactic -> warm and dry

Hypoxia

Hypoxia: low O2 in tissues Hypoxemia: low dissolved O2 in tissues -> cause stress reaction Types of hypoxia ★Hypoxic hypoxia: low dissolved O2 - in high altitude, respiratory muscle paralysis, COPD, restrictive lung disease, depression of respiratory shunt, arteriovenous shunt (congenital) ★Anemic hypoxia: low amount of Hb -anemias, CO poisoning ★ Circulatory (stagnant/ischemic) hypoxia: lower perfision -in distal parts: pale and ischemic (pain), proximal: cyanosis ★Histotoxic hypoxia: inability to utilize O2 in tissues - cyanide poisoning Acute hypoxia -depression of respiratory center, pathway obstruction, atelectasis etc. Chronic hypoxia -adaptation to high altitude or to respiratory and cardiac diseases Ischemia= combination of lower amount of oxygen (hypoxia), lower nutrients and build up of waste products in tissue due to lower perfusion.

Hypoxia causes and types

Hypoxia: low oxygen in tissues ★Hypoxic hypoxia Cause: low amount of o2 due to problems in ventilation, gas diffusion or blood perfusion in lungs Alveoli: low o2, pO2 low Blood: Hb amount same, decreased mtb in tissues -arterial blood: low o2, po2, amount of o2 -venous blood: low o2, amount of o2 -AV difference: same or lower Cyanosis possible due to high amount of Hb (erythropoiesis as compensation) Compensation: increased EPO, RBC, hyperventilation, Hb shift to left ★Ischemic hypoxia (circulatory) Cause: damage to arteries, heart failure, narrowing of vessels Alveoli: normal Blood: normal -arterial blood: normal -venous blood: lower pO2, amount of O2 (due to extraction) -AV difference: increased (due to extraction) Cyanosis: no, pale ★Stagnant hypoxia (circulatory) Cause: low venous output, thrombosis, right heart failure Alveoli: normal Blood: normal -arterial blood: normal -venous blood: lower pO2, lower amount of O2 (extraction) -AV difference: higher Cyanosis: YES (more time for reduction of Hb) ★Anemic hypoxia (transport) Cause: decreased amount of Hb or RBC, destruction of RBC, hemorrhage, CO poisoning Alveoli: normal Blood: low or normal Hb (if occupied by CO - normal) -arterial blood: normal pO2, low or normal Hb sat, low amount of O2 -venous blood: low pO2, low amount of O2 -AV difference: higher -Cyanosis: NO, pale ★Histotoxic hypoxia Cause: problem in tissues (fibrosis, necrosis), cyanide poisoning Alveoli: normal Blood: normal -arterial blood: normal -venous blood: increased pO2, increased amount of O2 -AV difference: decreased (low extraction) ★Ischemic + Anemic hypoxia always lead to increased extraction in tissues but no one knows why ★Cyanosis is blue discoloration of skin and mucous membranes. It depends on the amount of reduced Hb, normal Hb: 150g/l and at least 50 g/l must be reduced for cyanosis to occur. If you have higher amount of hemoglobin, it is easier to get cyanosis ★COPD is mainly problem with expiration, more air remains, less O2

Hypoxia, Ischemia - microscopic expressions

Hypoxia: lower oxygen in tissue or oxygen deprivation -interferes with aerobic oxidative phosphorylation -extremely important and a common cause of cell injury, death Ischemia -combination of hypoxia, lower amount nutrients and buildup of waste products in tissue due to lower perfusion. -due to impeded arterial flow or reduced venous drainage -common cause of hypoxia, but oxygen deficiency can also come from problems in respiration, or reduction in the blood capacity to carry oxygen (anemia, CO poisoning) Both in hypoxia and especially ischemia - cell damage occurs. -depending on severity of cell damage - reversible/irreversible -irreversible usually accompanied by inability to reverse MIT dysfunction and/or profound disturbance in membrane function. -cell death occurs by necrosis or apoptosis. 1. Cell swelling - as result of failure of energy dependent ion pumps in plasma membrane, leading to failure in maintaining ionic and fluid homeostasis. -hard to see in microscope, blebbing of cells, loss of microvilli -small clear vacoules within cell, fatty change - lipid vacoules -macroscopic pale, increased weight of organ 2. Cell death -if cell injury is too great the cell die by apoptosis or necrosis. -necrosis most common case in response to ischemia, hypoxia -in necrosis a series of changes result inability to maintain membrane integrity and the content leaks out - lysosome degrade cell and eventually kill it. -cell death from lack of oxygen -increased eosinophilia because of binding to denatured protein inside the cell and loss of basophila by cytoplasmic RNA. -the cell can look more glassy than normal due to loss of glycogen particles and when enzymes have digested the cytoplasmic organelles - moth eaten appearance. -myelin figures by damaged cell membranes -nuclear changes cause basophilia of chromatin to fade: 1. karyolysis because of DNase 2. pyknosis -shrinkage condensing and increased basophilia of DNA 3. karyohexis - pyknotic nucles get fragmented Ischemia is the most common form of cell injury in medicine. In hypoxia - energy generation through anaerobic glycolysis. 1. Failure in ion pumps -> cell swelling, influx of calcium (can lead to delirous effects, can activate catabolic enzymes that break down cell components, increase permeability of MIT - loss of function, pro-apoptotic proteins leak into cytoplasm that activate caspases) 2. Depletion of glycogen stores - accumulation of lactic acid 3. Reduction of protein synthesis After cell death: -replaced by large masses composed of phospholipids called myelin figures. -these are either phagocytosed by leukocytes or degraded further into FA and can later be calcified.

Hypoxic hypoxia causes and consequences

Hypoxic hypoxia -inadequate pO2 in arterial blood -> hypoxemia Causes: -drowning, blocked airway -decreased pO2 in exterior air -reduced pulmonary blood supply (perfusion disorder) -impaired pulmonary gas exchange (diffusion disorder) -impaired oxygen transport and uptake by erythrocytes -hypoventilation, inadequate pulmonary minute ventilation (respiratory arrest or by drugs eg. opiates) -shunts in pulmonary circulation or right-left shunt in heart (shunts can be caused by collapsed alveoli that are still perfused or block in ventilation to an area of lung) -V/Q mismatch - usually due to pulmonary embolism -diffusion defects (pulmonary fibrosis) -decreased concentration of oxygen in inspired air. (high altitude) -seen in patients with COPD, neuromuscular diseases or interstital lung disease) Causes: 1. Changes in air components partial pressure 2. Disorders of ventilation/perfusion 3. Disorders of diffusion through alveolocapillary membrane (pneumocytes, basal membrane, endothelium) -Can be worsened by increase of diffusion pathway (due to edema) or decrease of diffusion area. Response -in most tissue -> vasodilation for greater perfusion -in lungs -> vasoconstriction -> redistribution of blood flow to alveoli with higher oxygen content. Ventilation/perfusion mismatch causes ★Pulmonary venous space: -develops when there is local decrease in ventilation and normal perfusion. -> decreased ventilation, normal perfusion ->PO2 decreased, PCO2 increased, V/Q ratio over 1 ★Dead space -develops when there is normal ventilation but local decreased or blocked perfusion ->normal ventilation, decreased perfusion ->PO2 increased, PCO2 decreased, V/Q ratio under 1 Compensation in V/Q mismatch -perfusion normal, ventilation increased - decrease pCO2 -> development of alveolar hypocapnia --> reflexive bronchoconstriction = hypocapnic bronchoconstriction --> increased V/Q ratio becomes normal (decrease ventilation, V/Q) -local decreased pO2 -> reflexive vasoconstriction = hypoxic vasoconstriction --> decreased V/Q ratio return to normal by decreased ventilation

Ischemia

Ischemia: -combination of lack of oxygen, lack of nutrient and buildup of waste products due to lower perfusion. -cells suffer and their function will be impaired, but not dead yet Infarction: -obstruction of the blood supply to organ or tissue, typically by thrombus or embolus, causing local death of the tissue. Infact: -small localized area of dead tissue resulting from failure of blood supply Arterial occlusion - thrombus or embolus Venous occlusion - mechanical compression of vein (especially in organs receiving blood via vascular pedicles that are twisted/constricted) ★Hemorrhagic infarction - commonly caused by occlusion of veins, RBCs enter the area of infarct or an artery occlusion of an organ with collaterals or dual circulation (brain, lungs, liver, GIT) ★Anemic infarction -caused by arterial occlusion (in heart, spleen, kidney) -infarction result in wedge shaped area of necrosis, apex being at the site of occlusion and the edged become inflamed and congested -type of necrosis: ischemic coagulative necrosis (in brain liquefactive) -white infarcts become hemorrhagic when re-perfused ★Myocardial infarct -coagulative necrosis of large myocardial area due to occlusion of the main trunks of coronary arteries. -occlusive thrombosis leads to absolute persistent ischemia and acute local hypoxia. ischemia leads to DNA and RNA damage resulting in synthesis of injurous peptides. -most severe damage is caused by reperfusion, where xanthine oxidase is interconverted to radical forming form, resulting in massive tissue damage -Subendothelial infarcts involve worsening of acute temporary relative ischemia, and produce multiple infarcts in the inner third of myocardium. -Transmural infarcts involve absolute persistant ischemia and influence all three layers of the heart wall -symptoms: angina, cardiogenic shock, later leukocytosis with left shift (high number immature WBC indicative for infection), increased temperature and ECG changes -complications: sudden cardiac death, pericarditis epistenocardia (inflammation after transmural), myocardial aneurysm, cardiac rupture, mitral insufficiency ★Anemic spleen infarct -coagulative necrosis resulting from loss of blood supply from splenal a. -wedge shaped infarct with their base on the capsule usually occur due to thromboembolic occlusion of splenic artery . -spotted spleen with multiple infarcts may result from arteritis of the splenic artery, hypertensive arteriolar necrosis, disseminated intravascular coagulation with intravascular microthrombi and sickle cell anemia with intracellular agglutination of cells. ★Anemic cerebral infarction -Liquefactive necrosis of a region of brain due to loss of blood supply in the main trunk of one of three cerebral arteries. -caused by insufficient collateral circulation or cerebral thromboembolism -Demarcation stage: liquefactive necrosis producing swelling -Absorption stage: macrophages migrate to necrotic area, break down myelin into lipid vacoules and turn cells into lipophages. -Result: liquefaction with whitish substance -> encephalomalacia -Cystic stage: tissue defect because of necrosis elimination by MØ. -Result: formation of cavity lined with glial and CT (postencephalic pseudocyst) -Total infarct: loss of supply from basal arteries or major cerebral a. producing absolute persistent ischemia in supplied areas. -Border zone infarct: compromised supply with acute temporary relative ischemia in most distal fields of the area supplied by 3 major cerebral a. leads to cortical softening and later necrosis and scarring. -Microinfarct: compromised blood supply with acute temporary relative ischemia in areas supplied by the minor cerebral arteries and arterioles. cortical softening mainly in cerebral medulla and basal ganglia. ★Brain stroke -syndrome of acute focal neurologic deficit from a vascular disorder that injures brain tissue. -can cause hemiparalysis and/or extrapyramidal symptoms and aphasia -Ischemic stroke: thrombi, emboli -Hemorrhagic stroke: by bleeding into brain tissue (vessel rupture due to hypertension, aneurysm, head injury etc) -stroke caused by cerebral infarction should be distinguished from two other kinds of stroke: cerebral hemorrhage, subarachnoid hemorrhage

Pulmonary hypertension, embolism

Pulmonary hypertension -elevation of pressure in pulmonary arterial system -occurs when mean pulmonary pressure reaches 1/4 of systemic levels (normal mean pulm. arterial pressure: 15 mmHg) -pulmonary hypertension is present when PMAP exceeds 25 at rest, or 30 mmHg at exertion. ★Primary hypertension -abnormal thickening of vessel wall increase resistance to blood flow ★Secondary hypertension -increase in pulmonary pressure associated with an underlying disorder, usually cardiac or pulmonary. 1. pulmonary venous pressure elevation -mitral valve stenosis, LVHF 2. increased pulmonary blood flow -result from increased flow through left-right shunt in congenital heart diseases such as atrial/ventricular septal defects or patent ductus arteriosus 3. pulmonary vascular obstruction -embolism, interstitial lung fibrosis 4. hypoxemia (pulm vessels constrict) -sleep apnea, high altitude Causes: 1.COPD/interstitial lung disease - hypoxia + parenchymal destruction - increased pulm. arterial resitance -> elevated pressure 2. Cor pulmonale -RHF resulting from lung disease or primary pulmonary hypertension Pulmonary embolism -almost all cases of pulmonary thromboembolism originate DVT -depending on size, it can occlude main pulmonary artery, lodge the bifurcation of right and left pulmonary arteries or pass into smaller, branching arterioles. -if the embolus passes through atrial or ventricular defect and enter systemic circulation it is called paradoxical embolism. -frequently multiple emboli occur -a patient with pulmonary embolus is increased risk for having more. Clinical features -most pulmonary emboli are small and clinically silent -a large embolus that blocks major pulmonary artery cause sudden death. -embolic obstruction of medium-sized arteries and rupture of capillaries cause pulmonary hemorrhage. -infarction doesnt occur, due to dual supply. -embolism to small end arteriolar pulm branches usually cause infarction. -multiple emboli occuring over time can cause pulmonary hypertension and RHF (cor pulmonale)

Disorders of blood pressure regulation

Regulation of blood pressure is both - vasomotor (vasomotor center in brain stem - can be reset to increased BP during stress) -volemic (dependent mainly on GF in kidney and RAAS, partially influenced by ANP) Acute regulation -mechanism that act in sec-min, intended to correct temporary imbalances in BP (exercise, orthostatic) and also in life-threatening situations (hemorrhage) -relies on neuronal and humoral mechanisms ★Neural mechanism -most rapid mechanism by cardiovascular center -baroreceptors: pressure-sensitive in carotid and aortic sinuses -chemoreceptors: sensitive to monitor oxygen, CO2, H+ located in carotid bodies and aortic bodies and regulate ventilation -extrinsic factors as cold and pain ★Humoral mechanisms -RAAS, ADH, catecholamines -RAAS: in response to increase in SNS or decrease in BP, volume or sodium concentration -ADH: in response to decreased volume and BP, increased osmolality and SNS. released from posterior pituitary. -Catecholamines: in response to SNS induce vasoconstriction, increased HR and cardiac contractility Disorders ★SIADH ★Ectopic hormone producing tumors -Small cell carcinoma of lung ★Conns, Cushings ★Adenoma ★Pheochromocytoma

SIRS - Systemic inflammatory response syndrome

SIRS -inflammatory state affecting the whole body, frequently a response of immune system to infection but can also arise from other causes such as trauma by surgery etc. -serious condition related to systemic inflammation, organ dysfunction, and organ failure. -subset of cytokine storm, in which there is abnormal regulation of various cytokines. -SIRS is also closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection. Causes -infectious or noninfectious -trauma, burns, pancreatitis, ischemia, hemorrhage -other: complications of surgery, adrenal insufficiency, pulmonary embolism, complicated aortic aneurysm, cardiac tamponade, anaphylaxis, drug overdose ★Adult SIRS criteria Manifestaions: -body temp less than 36 or greater than 38 -heart rate greater than 90 bpm -tachypnea with greater than 20 breaths per minute or arterial pCO2 less than 32 mmHg -WBC count less than 4000 cells/mm3 or greater than 12 000 or presence of greater than 10% immature neutrophils (band forms) If 2 or more criteria are met with or without evidence of infection, patients may be diagnosed with SIRS Patients with SIRS + acute organ disfunction = Severe SIRS ★Pediatric SIRS criteria -HR greater than 2 standard deviation above normal for age with absence of pain, drugs. -or unexplaned elevated HR in more than 30min-4h -Body temp less than 36, greater than 38.5 (mandatory for SIRS kids) -Respiratory rate greater than 2 standard deviations for age -WBC count elevated or depressed for age or >10% band neutrophils Complications -acute lung injury, acute kidney injury, shock, MODS (more than 2 organs failing) Treatment -treatment to underlying problem -IV fluids to replace hypovolemia

Secondary hypertension - types, causes

Secondary hypertension -BP elevation due to another underlying disorder -can be corrected or cured by surgery or medical treatment -tends to occur in people under 30 and over 50 years -most common causes: kidney disease, adrenal cortical disorders, pheochromocytoma and coarctation of the aorta. -oral contraceptive agents can also be a cause ★Renal hypertension -hypertension caused by reduced renal flow and activation of RAAS -2 major types of renovascular disease: 1. atherosclerosis of proximal renal artery 2. fibromuscular dysplasia on renal arteries and branches Diagnosis: -asses renal function, RAAS, perfusion studies. - CT, MRI, US, renal angiograph for definite diagnosis Treatment -angioplasty, revascularization, ACE inhibitors (careful! may cause impaired renal function) ★Disorders of adrenocortical hormones -primary hyperaldosteronism - hyperplasia or adenoma -Cushings ★Pheochromocytoma -tumor of chromaffin tissue in adrenal medulla or symp. ganglia ★Coarctation of aorta -narrowing of aorta -in infants, may die within first year ★Oral contraceptive -in young women, very rare. -estrogen and progesteron cause sodium retention

Sepsis

Sepsis -life threatening condition that arise when the body´s response to infection causes injury to its own tissues and organs. -caused by immune response triggered by an infection (pathogen or its own toxins) -most commonly the infection is bacterial (fungi, virus, parasite) -common location for primary infection: lungs, GIT, UT (brain,skin) -risk factors: young or old age, weakened immune system (cancers, diabetes), major trauma or burns. -gram negatives used to be the main cause, but now more than 50% of cases are caused by gram positives (most often staph). -other common: strep. pyogenes, e coli, pseudomonas, klebsiella -fungal accounts for 5% of severe sepsis and septic shock (Candida) Signs and symptoms -typically fever, low body temperature, rapid breathing, elevated HR, confusion and edema. -early signs: rapid HR, decreased urination and high blood sugar -later signs: confusion, MAC, low BP, higher CO, coagulation dysfunction Pathophysology -sepsis is caused by a combination of factors related to the invading pathogens and the state of the immune system of the host. -early phase of sepsis is characterized by excessive inflammation (sometimes resulting in cytokine storm) -may be followed by prolonged period of decreased functioning of the immune system -either of these phases may prove fatal. Microbial factors -Bacterial virulence factors, such as glycocalyx and varios adhesins -allow colonization, immune evasion and establishment of disease in host. -Gram neg. bacterias lipid A (endotoxin) -I-response of host -sepsis -Gram pos. bacterias lipoteichoic acid - IR -Bacterial exotoxins that acts as superantigens can also cause sepsis -superantigens simultanously bing MHC and T cell receptors in absence of antigen presentation. the forced receptor interaction induce the production of cytokines by T cells. -Many microbial factors that can cause typical septic inflammatory cascade: PAMPS- in LPS, flagellin of gram neg, muramyl dipeptide in peptidoglycan of gram pos. -PAMPS are recognized by toll-like receptors of innate immune system, which can be membrane bound or cytosolic. -can cause a series of intracellular signaling cascades Host factors -cytokines such as TNF, IL-1, IL-6 may activate procoagulation factors in the cells lining vessels, leading to endothelial damage. -the damaged endothelial surface inhibit anticoagulant properties as well as antifibrinolysis, which lead to intravascular clotting, the formation of blood clots in small blood vessels and multiple organ failure. -a systemic inflammatory response syndrome may occur in patients without the presence of infection, fex. in those with burns, polytrauma or initial state in pancreatitis and chemical pneumonitis. -the low BP seen in those with sepsis is the result of various processes: including excessive production of chemicals that dilate blood vessels such as NO, a deficiency of chemicals that constrict blood vessels such as vasopressin and activation of ATP sensitive potassium channels. -in those with severe sepsis and septic shock, the sequence of events leads to a type of circulatory shock known as distributive shock.

Phases of hypovolemic shock (compensation)

★ Compensatory phase (Non progressive phase) -aims to maintain BP by vasoconstriction and to gain fluid into circulation -activation of SNS -> vasoconstriction on arteries and some veins, increased HR -activation of RAAS and secretion of ADH -capillaries has low hydrostatic pressure but increased oncotic pressure, this causes the water from interstitium into vessels which helps the increase of volume Characteristics: normal BP, peripheral vasoconstriction, tachycardia, increased ADH, RAAS and SNS After a while the body can´t compensate any longer due to lack of energy (low ATP) and tissues and organs starts giving up. eg. vasoconstriction -> water goes into interstitium again, development of microthrombi in kidney or lungs -> organs start to fail ★Decompensatory phase (progresssive phase) -multi organ dysfunction syndrome (MODS): more than 2 organs fails Characteristics: low BP, respiratory stress, oliguria, disorders of consciousness, metabolic acidosis. ★Irreversible phase (refractory phase) -there is no longer any response to vasopressive drugs, and even if you would manage to restore blood volume, the CO remains depressed, no matter what you do - the patient will die -precapillary sphincters are now open, bur postcapillary sphincters remain closed, this causes blood flow into capillaries and stay there -cerebral ischemia depress vasomotor and cardiac discharge, causing BP to fall and make the shock even worse. this in turn causes further reduction in cerebral blood flow. -myocardial blood flow is reduced in severe shock causing myocardial failure, make the pump action less effective which also makes the shock worse and further decreases myocardial blood flow Characteristics: breakdown of cellular membranes, cellular death, release of intracellular enzymes, thromboplastic effect, blood clotting, ischemic damage, necrosis in tissues -pulmonary damage with development of ARDS is a common cause of death.

Consequences of acute and chronic bleeding

★Acute bleeding -acute loss of significant blood volume Causes -trauma, nosebleeds -depend on volume loss, rate of bleeding, site of hemorrhage Consequences -loss of intravascular volume which if massive can lead to cardiovascular collapse, shock and death -depends on rate and if its internal or external -if patient survives: rapid restored flow by intravascular shift, erythropoiesis (takes 5 days) -significant bleeding involve RBC, WBC, platelets -compensation: RAAS, SNS: catechol, ADH, AG2, aldosterone -reticulocytosis -early recovery: accompanied by thrombocytosis resulting from platelet production -after 3-6 weeks (time depends): RBC concentration return to normal ★Chronic bleeding -induces anemia only when the rate of loss exceeds the regenerative capacity of BM or when iron reserves are depleted. -internal bleeding does not lead to iron deficiency (iron recycled) -external bleeding leads to hypochromic, microcytic anemia due to depletion of iron stores. Causes -GIT carcinoma, menstrual bleeding, chronic peptide ulcer Consequences -microcytic, hypochromic (iron def) anemia -chronically increased EPO due to tissue hypoxia -blood volume should be normal because of compensatory mechanisms.

Shock classification

★Cardiogenic shock -heart fails to pump blood sufficiently to meet bodys demands. -causes: infarctions, arrytmias, cardiomyopathies, valve disease ★Hypovolemic shock -loss of blood/plasma volume -causes: hemorrhage, burns, trauma, severe vomiting, diarrhea, sweat -acute loss of 15-20% (1L) of circulatory volume -> shock -low cardiac output ★Distributive shock Septic shock -62% of all shock cases -due to microbial infection (most often Gneg. + Gpos, fungi) -it doesnt have to be systemic bacteremia, inflammatory response to local extravascular infections can also induce shock -> cytokines -> peripheral vasodilation Neurogenic shock -fall of sympathetic tone (PNS take over) -anesthetic accident or SC injury -> loss of vascular tone and peripheral pooling of blood -the problem is that baroreceptor reflex cant help maintaining adequate blood flow because vasomotor center is not functioning and therefor cant signal an increase in cardiac output Anaphylactic shock -type 1 hypersensitivity (IgE) -> release of histamine -> acute widespread vasodilation and bronchoconstriction ★Obstructive shock -result from mechanical obstruction of blood flow through the central circulation (great vessels, heart or lungs) -capacity is normal: 5L, volume is normal: 5L -pulmonary embolism (DVT, thrombus) is the most common cause -other causes: tumor in heart, cardiac tamponade, dissection of aorta that produce hematoma protruding into aortic lumen, pneumothorax

Ischemia and stasis

Ischemia: combination of lower amount of oxygen, lower amount of nutrients and buildup of waste products in tissue due to low perfusion. -in contrast to hypoxia alone (anaerobic glycolysis), ischemia compromise delivery of substrates for glycolysis. = not only aerobic compromised, but also anaerobic compromised after glycolytic substrates are deprived. -ischemia tend to cause more rapid and severe cell and tissue injury than hypoxia alone -Ischemia due to narrowing (atherosclerotic plaque) of the artery and increased metabolic demands can occur anywhere in the body. -Fex. claudification seen in femoral artery narrowing; patient is able to walk a certain distance and the the ischemic pain forces to stop. If he rests, the pain subsides. But you cant stop a beating heart.... -Lactate is produced during ischemia -> metabolic acidosis -> histiotoxic hypoxia. -in DM we can get microangiopathy - basal membrane of vessels gets thicker(glc and protein deposits) and diffusion is problematic ->ischemia Causes of ischemia -blockage of flow, edema (mechanical compression), immobility (compression), vasospasm, atheroma after intraplaque hemorrhage, compression of vessels (edema, tumor), vessel twisting, low circulatory volume, shock. Consequences of ischemia -hypoxia, decreased nutrient delivery, decreased waste removal, lactic acidosis, decreased ATP production (lysosomal swelling,(necrosis) MIT swelling, apoptosis may occur instead)

Development of ECG changes in heart ischemia

Ischemic coronary disease -represent insufficient perfusion of myocardium via coronary arteries -the insufficiency can be absolute or relative -absolute: decreased volume of perfused blood, usually atherosclerotic -relative: normal/increased but inadequate volume of perfused blood relative to myocardial O2 demands - myocardial hypertrophy, anemia -characteristic Angina Pectoris - pain behind sternum, irradiating to neck, arms and scapula due to myocardial hypoxia. Etiology ★Absolute insufficiency of coronary arteries -atherosclerosis in coronary arteries -vasospasms, embolisation, congenital abnormality of coronary arteries -hypotension, hypovolemia, aortic valve insufficiency ★Relative insufficiency of coronary arteries -myocardial hypertrophy -anemia, hypoxemia, polyglobulia -significant tachycardia (short coronary filling during short diastole) -physical activity, fever, hyperthyroidism (myocardial demands increased) ★Types of angina pectoris -Stable angina pectoris -Unstable angina pectoris -Prinzmetal angina pectoris

Organs in irreversible stage of shock

Lung: -ARDS (Acute resp. distress sy) - wet lung: pulm edema -"shock lung" - diffuse alveolar damage due to sepsis or trauma Kidney -cortical anemia, tubular ischemia Brain -prolonged edema -> anoxic encephalopathy Adrenals -more pink because of decreased lipids, medullary hemorrhage especially in septic shock Liver -centroacinar ischemia, necrosis, fatty change GIT -hemorrhagic enteropathy Lymphoid tissue -necrosis of follicular centers Heart -coagulative necrosis, subendocardial hemorrhage, contraction band necrosis

Long term complications of systemic hypertension

Phases of arterial hypertension 1. increased BP without any subjective problems and organ changes 2. presence of some organ changes - LV hypertrophy, changes in retinal vessels, glomerular pathology, nephrosclerosis 3. organ changes with failures of organs - LV failure, hypertensive encephalopathy, intracerebral bleeding (stroke), retinal hemorrhage, kidney failure, aortic aneurysm. Consequences ★Target organ damage -when symptoms occur, they are usually related to long-term effects of hypertension on organs like kidney, heart, eyes, BV. ★Major risk for atherosclerosis -since it promotes and/or accelerate plaque formation and possible rupture. it contribute to atherosclerotic cardiovascular disorders such as coronary heart disease, HF, stroke, peripheral artery disease. -depends on extent of risk factors: obesity, smoking, hypercholesterolemia, genetics ★Left ventricle hypertrophy -hypertension increase work load of LV. major risk for coronary heart disease, cardiac dysrhytmias, sudden death and congestive HF ★Nephrosclerosis -chronic hypertension can cause kidney damage ★Dementia and cognitive impairment -occur more commonly in persons with hypertension. -major risk factor for ischemic stroke, intracerebral hemorrhage -narrowing and sclerosis of small arteries in brain ★Hypertensive retinopathy -through a set of microvascular changes -the eye of person with hypertension will initially have increased vasomotor tone -> generalized arteriolar narrowing -as hypertension persists, AS changes become worse and include media wall hyperplasia, intimal thickening and hyalin degeneration -these long term changes can cause more severe arteriovenous nicking and may cause blindness. -if there is acute rise in BP, hemorrhages, microaneurysms and hard exudates can manifest.

Anemia - pathogenic classification

Anemia: =reduction in oxygen-transporting capacity of blood -usually caused by decrease in RBC mass -can result from bleeding, increased RBC destruction or decreased RBC production. -leads to hypoxia in tissues -diagnosed based on hematocrit and Hb concentration Morphology -Microcytic anemia (iron deficiency, thalassemia) -Macrocytic (folate or vit B12 deficiency) -Normocytic anemia with abnormal shape (hereditary spherocytosis, sickle cell disease) Clinical manifestation -Acute: shortness of breath, organ failure, shock -Chronic: -pale, fatigue -with hemolysis: jaundice, gallstones -ineffective erythropoiesis: iron overload, heart/endocrine failure -if severe and congenital: growth retardation, bone deformities due to reactive BM hyperplasia. ★Anemia of blood loss -acute blood loss exceeding 20% -hypovolemic shock is the threat rather than anemia -hemodilution (infusion) starts at once, achieve effect after 2-3days -normocytic and normochromic (Hb levels normal), but too few -with chronic blood loss, the iron stores are depleted. -iron is essential for Hb and erythropoiesis, lead to chronic anemia of underproduction. ★Hemolytic anemia -caused by accelerated RBC destruction due to RBC defect or extrinsic factors (acquired) -1. decrease in RBC life span (less than 120 days) -2. compensatory increase in erythropiesis -3. retention of products of degraded RBC -iron. -erythropoiesis may keep up with hemolysis. -associated with erythroid hyperplasia in BM, increased reticulocytes -in severe: extramedullary hematopoiesis in liver, spleen, LN Intravascular hemolysis: -can result from mechanical force (defected heart valve) or biochemical/physical agents that damage RBC membrane. -lead to Hb-emia, Hb-uria, hemosiderinuria. Extravascular hemolysis -more common, by macrophages of spleen and liver. -often associated with jaundice, sometimes bilirubin rich gallstones Examples of common hemolytic anemias -Hereditary spherocytosis (AD - defect in RBC membrane) -Sickle cell anemia (AR - mutation of beta globin) -Thalassemia (AR - mutation in alfa or beta globin)

Anemic hypoxia causes and consequences

Anemic hypoxia -caused by reduction of oxygen carrying capacity of blood -can be due to decrease in total Hb or altered Hb contents (not able to bind O2) -arterial pressure is normal, but oxygen content of blood is reduced. Hemoglobin -binds to 1,34 ml O2/ 1g Hb -Oxyhemoglobin, Deoxyhemoglobin, Carbaminohemoglobin (CO2), Carboxyhemoglobin (CO), Myoglobin -98% O2 binds to Hb, 2% diluted in plasma -Cyanosis: bluish discoloration due to deoxyhemoglobin(>50g/l) -Normal: 135-175 g/l in men, 120-168 g/l in women -Left shift of dissociation curve: increased affinity to Hb -Right shift: decreased affinity to Hb Causes -vitamin B12 and folate deficiency lead to megaloblastic anemia -hemolytic anemia (abnormal breakdown of RBC) -decrease in body iron conent -CO poisoning has increased aff. to Hb, and low O2 to tissues -Kidney failure -> decreased EPO -Sulfhemoglobin, Methemoglobin: not able to bind O2 -medications: aspirin, sulfonamides, nitrites -bleeding -decreased production (iron deficiency, B12, folate deficiency) -increased degradation (sickle cell anemia) -decreased affinity to O2 (CarboxyHb- CO poisoning -cherry red) (Methemoglobin - iron in Fe3+ state) Consequences/Response -In most tissues: hypoxia response -> vasodilation (inc. perfusion) -In lungs: vasoconstriction (hypoxic pulmonary vasoconstriction) -> redirect blood flow to alveoli with higher oxygen content (in this case it doesnt help much, since it is the carrying capacity that is the problem) - Increased CO can lead to palpitations -hyperventilation, production of EPO, production of RBCs Hypoxic injury effects 1.Reduced activity of ATP- driven Na/K pump -> accumulation of Na+H2O and diffusion of K out of cells. -> acute cellular swelling (water and other metabolites) 2. Increased anaerobic glycolysis - decr. ATP, incr. AMP -> AMP stimulate phosphofructokinase to generate ATP from glycogen -> depletion of glycogen stores -> reduced staining of carbs (histo) 3. Low pH and low ATP cause ribosomes to detach from RER and polysomes to dissociate to monsomes -> reduction in proteosynthesis 4. Fatty change - lipid vacoules in cytoplasm of hepatocytes, myocardial 5. Oxygen deprivation -> generation of reactive oxygen species -> cause damage to membranes, protein denaturation, damage to carbohydrates and nucleic acids 5. Hypoxia may lead to atrophy of cells due to loss of cell substance. 6. Coagulative necrosis characteristic for hypoxic death of cells in all tissues except brain (Liquefactive necrosis)

Anemic and hemorrhagic infarct

Anemic infarct/ white infarct -Tissue necrosis due to persistent loss of blood supply from a terminal artery. After 6 h, the tissue area appears yellow. -The complete necrotic center is surrounded by peripheral hemorrage. -The necrosis is surrounded by an edematous area due to exudative inflammation. -The lesion triggers the wound healing process, and the necrotic area is organized by granulation tissue and heals with scarring. -Organs with end-arterial circulations. Usually form wedge shaped infarcts. -Coagulative necrosis (liquefactive - brain) Heal with fibrosis. Commonly affect heart, kidney, spleen. Hemorrhagic infarct -Tissue necrosis due to persistent occlusion of terminal artery with slight, insufficient residual blood supply. -In tissues with dual blood supply, venous obstruction, loose tissues (lung) where blood can collect, previously congested tissue and when flow is reestablished. -Sources of residual blood supply: - Arterial occlusion - Collateral circulation - Retrograde venous blood flow due to increased venous pressure - Anatomic regions with double vascular supply - Venous occlusion - Venous thrombosis prevents drainage of blood. This produces tissue ischemia with necrosis and locally increased blood pressure that leads to bleeding into tissue.

Arteriosclerosis

Arteriosclerosis -thickening, hardening and loss of elasticity in artery walls. -gradually restrict blood flow to tissues and may lead to several quite serious health conditions. -these lesions generally begin in tunica intima and often affect other parts of the vessel wall as well. -these lesions affect arteries. Subtypes: ★Arteriolosclerosis -only affects small arteries and arterioles -most commonly associated with hypertension or DM. Hyaline arteriolosclerosis -thickening of walls of arterioles by homogenous pink hyaline. -associated with hypertension, DM, some drugs and kidney patho. -in hypertension: afferent arteriole is affected -in DM: both afferent and efferent arterioles are affected, more leaky to to plasma proteins -> nephropathy, retinopathy, neuropathies. -these lesions are due to leakage of plasma components across endothelium and excessive ECM production by smooth muscle cells. -hyaline arteriosclerosis is a major characteristic of Benign nephrosclerosis. Hyperplastic arteriosclerosis -thickening of vessel walls by thickened smooth muscle, associated with malignant hypertension. -histologically marked by onion skin, concentric laminated thickening of walls of arterioles with luminal narrowing. -these changes are accompanied by fibrinoid deposits and vessel wall necrosis, especially in kidneys. -hallmark of malignant nephrosclerosis. ★ Atherosclerosis -thickening of arteries due to build of atherosclerotic plaques consisting of lipid-laden macrophages (foamy cells), T cells, cholesterol clefts, smooth muscle cells, TAG and possibly calcifications if lesion is older. -lesion may be covered in a fibrous cap, stabilising it, consisting of ECM rich in collagen, elastic fibres and proteoglycans. -quite common to find a necrotic core, and peripheral neovascularisation. -these lesions may rupture, resulting in atherosclerotic thrombus -thrombi may travel to distal sites causing ischemia and infarction. -another possible complication is intraplaque hemorrhage, which may extend the plaque or cause rupture, or formation of aneurysm -another possible complication is stenosis eg. in renal artery -most common sites of atherosclerosis are abdominal aorta, coronary, popliteal and internal carotid and circle of willis. -chronic inflammatory response of arterial wall to endothelial injury Nonmodifiable risk factors: old age, male, family history Modifiable risk factors: DM, dyslipoproteinemia, hyperlipidemia, smoking, increased CRP, vitamin B6 deficiency, iodine deficiency and hypothyroidism.

Local circulation failure

Circulatory failure -inability of cardiovascular system to supply the cells of the body with enough oxygenated blood to meet their metabolic demands -can be systemic (shock) or local. Causes of local circulatory failure: -thrombosis, emboli, tumors, AS, local edema (pressure on cells and capillaries), local hemorrhage, diabetic micro and macroangiopathy, torsion of vessels, hypotension, dissecting aortic aneurysm. Result of circulatory failure is hypoxia, ischemia and necrosis. Infarction -area of ischemic necrosis caused by occlusion of vascular supply. -pulmonary infarction is common clinical complication -bowel infarction is often fatal -ischemic necrosis of distal extremities (gangrene) causes substantial morbidity in diabetics. Causes -arterial thrombosis or embolism underlies majority of infarcts. -venous thrombisis can also cause infarction, however the more common outcome is simply congestion. usually occur in organs with single efferent vein (testis, ovaries) White infarct - (anemic) occur in organs with end-arteriole supply and affect solid organs: spleen, heart and kidneys. -solidity of tissue limit amount of nutrients that can flow into area of ischemic necrosis. Red infarct (hemorrhagic) occurs in organs with dual supply, generally affect lungs and other loose organs that allow the blood to collect in the infarct zone. In most findings of infarct - ischemic coagulative necrosis. In brain ischemic tissue injury - liquefactive necrosis. Factors that influence infarct development: 1. anatomy of vascular supply -organs with dual supply less prone 2. rate of occlusion - slowly developing occlusion less likely 3. tissue vulnerability to ischemia - neurons:3-4min, myocardial cells:20-30min, fibroblasts:hours 4. hypoxemia - abnormal low oxy content increase likelihood

Compensation and adaptation to hypoxia

Clinical signs of hypoxia -tachycardia (SNS) -increased pulmonary ventilation (hyperventilation, dyspnea) -paleness of skin and mucous membranes (in anemia, ischemia) -cyanosis (in case of increased deoxyHb in hypoxic, stagnant) -decreased skin temp (in peripheral ischemia due to SNS) -increased fatigue -decreased physical performance, mental performance -pain (acidosis) Compensatory mechanisms in hypoxia -hyperventilation (due to reaction of peripheral chemoreceptors) -increased release of 2,3-DPG from tissue cells, decreased affinity of O2 to Hb -> release of O2 -increase of RBC number (erythropoietin) Adaptation to hypoxia -eg. in high altitude adaptation in humans -people living in Tibet, Andes and Ethiopia have acquired ability to survive at extremely high altitudes -> irreversible, long term physiologic responses associated with physiologic and genetic changes particularly in regulation of oxygen respiration and blood circulation Tibetian highlanders -inhale more air with each breath and breath more rapidly than people at sea level. -better oxygenation at birth, enlarged lung volumes throughout life and a higher capacity for exercise -sustained increase in cerebral blood flow & slightly lower Hb conc. -higher levels of No -> vasodilation -> enhance blood circulation Andeans -higher Hb value than lowlanders -if they spend some weeks in lowland, their Hb will normalize -increased oxygen level in Hb -> able to carry more oxy -> more effective transport of oxygen in their body while breathing -develop enlarged residual lung volume and its associate increase in alveolar area, which is supplemented with increased tissue thickness and moderate increase in RBC Climbing Mount Everest -stay at base camp for 2w -> experience over 2g/dl increase in Hb -> able to evade hypoxia and mountain sickness -increased erythropoiesis -> increased RBC ->increased uptake of O2

Compensation and adaptaion in various systems

Compensation -increase in size or activity of one part of organism or organ that makes up for the loss or dysfunction of another. -Examples: hypertrophy of kidney as another removed, hypertrophy of liver as one part is removed. -pH changes compensation mechanisms - MAC -> respiration (Kussmaul breathing) -> hyperventilation - MAL -> hypoventilation - RAC, RAL -> kidney compensation -low oxygen -> breathing (hyperventilation) - in sports men - higher need of oxygen -> tachycardia Adaptation -reversible changes in number, size, phenotype, metabolic activity or functions of cells in response to changes in environment. -Physiolologic: represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (hormone-breast, uterus enlargement) -Pathologic: responses to stress that allow cells to modulate their structure and function and thus escape injury, such adaptations can cause several distinct forms. -Continous interactions between organisms & external environment -Body tries to keep constant internal environment irrespective of external environment parameters via adaptive mechanism (thermoregulatory) -Any change of external environment require resetting of regulatory mechanisms to keep homeostasis -Each adaptation mechanism is limited. Adaptation capacity -represent adaptability of the body -can be expressed as a range of external environment parameters within which the particular organism can keep homeostasis -very individual, depend on genetics, age, functional reserve of the body systems responsible for the adaptation to a change, lifestyle -extreme changes of external environment or failure of adaptation mechanism -> change in internal environment -> disease -border changes of external environment leading to survival only od individuals with best adaptation -high external temperature require thermoregulatory response based on peripheral vasodilation -> decrease BP - to keep adequate BP require increased minute volume, people with chronic heart failure do not have sufficient heart reserve -> collapse (fainting) Examples -hypertrophy - cardiac enlargemend with hypertension -hyperplasia - benign prostatic hyperplasia -atrophy - lipomatous atrophy in skeletal muscle -metaplasia -Barrets esophagus -dysplasia (abnormal growth) - CIN -hypoplasia (streak ovary in turners) Adaptation pathophysiology -central pCO2 sensor in long lasting high pCO2 -low O2 -> EPO -hyperplasia of heart

Cyanosis

Cyanosis: bluish discoloration of skin caused by typically highly reduced hemoglobin (deoxyhemoglobin) or rarely higher levels of hemoglobin derivatives like Methemoglobin or Sulfhemoglobin. -Threshold: 50g/l reduced hemoglobin (normal 130-160g/l) ★Central cyanosis -typically seen in hypoxic hypoxia -central: eg. tongue, mucous membranes -due to poor oxygenation of blood in the lungs, typically in hypoventilation, COPD or pulmonary embolism, shunt, valve problems -low partial pressure of oxygen in air can also be a key cause. -in case of normal temp, metabolic state, no presence of centralization, it is the intraoral bluing that discriminate between central and peripheral (not color of fingers or toes) -if tongue is blue (central cyanosis), he will also show signs of peripheral -> main problem is with oxygenation of blood ★Peripheral cyanosis -bluish discoloration seen peripherally, on extremities (fingers, toes) or perorally, on tip of nose and on ear lobes. -typically seen in stagnant hypoxia -no problem with oxygenation of blood -caused by slower blood flow in peripheral tissues and thus increased extraction of O2 by these tissues. -can also occur due to Raynauds phenomenon (white fingers in episodes) or local venous obstruction (DVT, compression etc) ★Cyanosis in methemoglobinemia -presence of ferric form of Hemoglobin. -blood looks more brown(depend on the degree,the higher,the browner) -transport function of Hb is impaired - thus O2 capacity reduced. -Methemoglobinemia can be congenital (several enzymatic defects) or acquired (commonly caused by intake of nitrates in children under 6mths) -Skin color is more bluish-brown than disting blue in cyanosis due to more reduced Hb. -typically cited under causes of central cyanosis.

ECG in acute ischemia of heart

Diagnostics ★ECG -can be normal in absence of pain -should be performed during attack of angina pectores or during exertion (bicycle ergometry) -includes transient segment ST segment depression and T wave inversions (subendocardial ischemia) or ST elevation (Prinzmetal angina) ★Radioisotope imaging with thallium 201 -ischemic area displayed as "cold spot" in the scan ★Coronary angiography -most precise examination prior to by-pass surgery, percutaneous transluminal coronary angioplasty (PTCA-balloon dilation catheter is used) or stents. ECG -ST depression: temporary depression of ST segment during the attack of angina pectoris. After the attack, the ST depression normalizes -ST elevation: typical for acute heart infarction, the necrosis is permanent thus the elevation does not normalize. (it can normalize after several days) -Typical transmural infarction wave "Pardee wave" is a very high ST elevation with a tent T wave.

Causes and consequences of venous hypertension -portal

Portal vein -supplies blood and O2 to liver from GIT (1L/min) -normal BP: 5-10 mmHg Portal hypertension -pressure in in the portal vein at least 5mmHg higher than in IVC -result from functional obstruction to blood flow from any point in the portal system -mechanism: vasodilators; cytokines (TNF alpha) may play a role in stimulating endothelial vasodilators such as NO, prostacyclin as well as nonendothelial vasodilators (glucagon) -these molecules may affect pressure and flow in the splanchnic vasculature, leading to hypertension. Causes -if vessels in liver are blocked due to liver damage, blood cant flow properly through liver -> portal hypertension -hypertension can lead to large, swollen veins (varices) within esophagus, stomach, rectum or umbilical area. -varices can rupture and bleed, resulting in potentially life threatening complications. -most common cause is thrombosis in portal vein, blockage of veins that carry blood from the liver to heart, schistosomiasis, focular nodular hyperplasia seen in HIV or unknown cause. -Budd Chiari syndrome: occlusion of hepatic veins that drain liver leading to ascites, hepatomegaly and abdominal pain. -Cirrhosis: replacement of normal tissue by scar tissue, due to alcohol abuse, drug abuse, Hep B and C, non-alcoholic fatty liver. Symptoms: -onset of portal hypertension may not always have specific symptom -main symptoms: -GI bleeding (black stool or blood in stool, bloody vomiting due to esophageal varices), caput medusae -Ascites -Encephalopathy, confusion, forgetfulness due to poor liver function -reduced levels of platelets or WBC -gynecomastia due to low liver function -> low breakdown of estrogen -> breast in men Diagnosis -ascites or dilated veins or varices in physical examination -lab tests, x-ray, endoscopy

Prinzmetal´s angina pectoris

Prinzmetal´s angina pectoris -transmural ischemia, unpredictable -exclusively at rest caused by vasospasm (even without atherosclerosis) -frequently at night in REM sleep - hyperactivity of SNS, influx of calcium, prostaglandins and thromboxane -angiography of the coronary artery looks pretty normal -interestingly in many cases - ST elevation -typically seen in women, cause is probably vasospasm -STEMI (ST Elevation Myocardial Infarction) -NSTEMI (Non ST elevation myocardial infarction)

Septic shock

Septic shock goes under distributive shock. -when a bacteria, either from an infection or from our normal flora, enters the blood, they can cause a cytokine storm -> dysregulate everything and also vessel tone (vasodilation) -eg. gram neg -> release endotoxin (lipid A) -> activate NOS -> extreme vasodilation. In septic shock: - preload ↓ - cardiac output ↑ ->↓ - afterload ↓ - skin/temperature is dry and warm Septic shock -serious medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. -primary infection most commonly by bacteria (fungi,virus,parasite) -it may be located anywhere, most commonly in lungs,brain, UT, skin or abdominal organs. -can cause multiple organ dysfunction syndrome and death -frequently people with septic shock are cared for in intensive unit -most commonly affects children, IC, elderly as their immune system cannot deal with infection so effectively as healthy adults. -mortality rate approximately 25-50%. Causes -result of systemic response to infection -infectious causes: sepsis may be present, but septic shock occur without sepsis. -appendicitis, pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancreatitis, necrotizing fasciitis, MRSA and mesenteric necrosis. Symptoms -sepsis: disruption in HR, RR, temp and WBC count -severe sepsis: end-organ dysfunction: kidney failure, liver dysfunction, altered mental state or heart damage -Septic shock: even worse + BP cant be maintained with IV alone -tachypnea, WBC count significant low/high, tachycardia, fever or hypothermia, end organ dysfunction Treatment -IV fluids, early ATB administration, early therapy, rapid source of identification and control, support of major organ dysfunction

Shock states

Shock -acute drop in blood pressure or systemic hypoperfusion. -vital functions of the body are depressed due to severe and acute reduction in cardiac output and effective circ. blood volume -> hypoperfusion, metabolic acidosis and decreased oxygenation to tissues. -perfusion is the process delivering blood to capillary bed in tissue Main consequences of shock -low cardiac output -hypotension -impaired tissue perfusion -cellular hypoxia Inadequate perfusion -> hypoxia, anabolic mtb, activation of inflammatory pathway -> death at cellular level -> vital organ dysfunction -> death Shock gives rise to systemic hypoperfusion and decreased return to heart regardless of underlying pathology. -can be caused by reduced cardiac output or reduced effective circulating blood volume. -leads to hypotension, impaired tissue perfusion and cell hypoxia -initially reversible hypoxic and metabolic effects become irreversible tissue injuries as shock persists.

Stages of shock

Shock involves three general stages -unless it is massive and rapidly lethal ★Nonprogressive stage (Compensated) -reflex compensatory mechanisms are activated to maintain perfusion of vital organs. -neurohormonal mechanisms helps maintain CO, BP -these include baroreceptor reflexes, release of catecholamines, activation of RAAS, ADH release and generalized sympathetic stim. -centralization of circulation -> blood to heart and brain -> normal BP, peripheral vasoconstriction, tachycardia, increased ADH, RAAS and SNS. -Baroreceptor reflex, catecholamine release, RAAS, ADH, SNS -tachycardia, peripheral vasoconstriction -> normal BP -renal fluid conservation -> hypoperfusion-> aldosterone secretion *paradoxical polyuria can occur in kidney failure* -reduced central venous pressure -> reduced CO -> reduced arterial pressure -> activation of central and peripheral receptors - baroreflex -> SNS -> ADH, Cardiac effects, vasoconstriction -> Catecholamines -> increase HR, vasoconstricion -> Vasoconstriction of skin, GIT, kidney -> vasoconstriction to kidney-> RAAS -> retention -> central receptor: ADH -vasocontriction -> increase BP(hydrostatic pressure) ->water into BV -dilation of cerebral and coronary arteries to maintain blood flow P ★Progressive stage (Decompensated) -tissue hypoperfusion, worsening circulatory & metabolic imbalance -> decreased BP, bradycardia, repiratory stress, oliguria, MAL, disorders of conciousness -Widespread hypoxia -> anaerobic glycolysis -> Lactic acidosis -> dulls vasomotor response -> dilation or arterioles, blood pooling in microcirculation. -Lowered CO, anoxic injury of endothelium with subsequent DIC, tissue hypoxia -> vital organs start to fail -Acute hypoxia -> damaged endothelium -> coagulation cascade -> formation of fibrin -> DIC -Release of glucose from cell -> hyperglycemia -Sick cell syndrome: water and electrolyte disturbance (Na/K pump)

Stable angina pectoris

Stable angina pectoris -classic -when you reach a certain level of exercise, you get angina pectoris and it is stable in its manifestation. same physical load start stably the angina attack, and if you stop exercising, the pain stably disappear. -also caused by emotional stress. -stable depression of ST segment during angina pectoris attack, normalizes after attack. -stably respond to nitroglycerine (vasodilator) Cause: -narrowing of lumen in coronary artery over 60%. -at rest: no pain, because sufficient supply to myocardium -in exercise: pain, because of metabolic demands not able to keep up -if keep exercising -> can end up with myocardial infarction -most common cause is atherosclerotic plaque (also stable) -can occur any where in the body such as in the femoral artery with claudification causing narrowing.

Thrombosis

Thrombosis =pathologic formation of intravascular blood clot -can occur in artery or vein, most common DVT of leg below knee Three major factors for thrombosis (Virchows triad) 1. Endothelial injury 2. Stasis of turbulent blood flow 3. Hypercoagulability of blood ★Endothelial injury -disrupt the protective function of endothelial cells, increasing the risk for thrombosis. Protective mechanisms of endothelial cells -block exposure to subendothelial collagen and underlying tissue factor -produce prostacyclin and NO (vasodilation and inhibit platelet aggr) -secrete heparin-like molecules (increase antithrombin) -secrete tissue plasminogen activator (cleaves fibrin) -secrete thrombomodulin (redirect thrombin to activate protein C which inactivate factor 5,8) -endothelial cell injury may be result from atherosclerosis, vasculitis, trauma, burns and high levels of homocysteine (vitB12, folate def) ★Stasis of turbulent blood flow -blood flow normally continous, laminar where platelets found mainly in centre of vessel lumen, separated by endothelium by slower moving layer of plasma. -turbulence contributes to thrombosis -stasis is a major factor in development of venous thrombi -immobilization, cardiac wall dysfunction(arrytmia, MI), aneurysm ★Hypercoagulability -alteration of coagulation cascade that predispose persons to thrombus production. -inherited or acquired conditions - recurrent DVT, DVT at young age -excessive procoagulant proteins or defective anticoagulant proteins increase risk of thrombus formation Examples -Protein C,S inactivate factor 5,8 - if def: more coagulation -inherited mutated factor 5 - lack cleavage site for Protein S,C -inherited mutated protrombin gene -increase thrombin -oral contraceptive - estrogen increase prod. of coag. factors Morphology -thrombi: lines of Zahn (pale platelet and fibrin layers with rbc layer) -thrombi in heart chambers or in aortic lumen: mural thrombi -abnormal myocardial contraction or endomyocardial injury promotes cardiac mural thrombi -ulcerated AS plaque and aneurysm promote aortic mural thrombi Red thrombi - due to stagnant blood flow (fibrin + cells) veins in leg White thrombi - occur in flowing blood (fibrin+WBC+platelets) aorta Mixed (lines of Zahn) - cells + fibrin + WBC, white/red - common form Hyaline thrombi: red homogenous material(fibrin + platelets)capillary

Anemic hypoxia - types of anemia, its compensation

Types of anemia ★Anemia of blood loss -acute blood loss, chronic blood loss ★Hemolytic anemia -hereditary spherocytosis -hemolytic disease due to RBC enzyme defects: Glc-6-P dehydrogenase deficiency -sickle cell anemia, thalassemia syndromes -paroxysmal noctural hemoglobinuria -immunohemolytic anemia -hemolytic anemia resulting from trauma to RBC ★Anemias of diminished erythropoiesis -megaloblastic anemia -iron deficiency anemia -anemia of chronic disease -aplastic anemia -pure red cell aplasia -other forms of bone marrow failure Compensation -Hyperventilation to get more oxygen -Production of EPO -Production of RBC

Causes and consequences of venous hypertension -systemic

Venous pressure -gravitational pressure (caused by weight of blood to RA) -dynamic pressure (caused by forceful muscle contraction) -if perforating vein fails, high pressures elicited by contractions are transmitted to the superficial system causing dilation of superficial veins. progressive valvular failure may occur later. -if proximal valves become incompetent at sapheno-femoral junction, muscular contraction pressure is supplemented by weight of static column of blood from the heart. this column becomes a barrier. blood flowing from femoral vein spills into saphenous vein and flow distally, as it refluxes through progressively incompetent valves, it is returned through the perforators to the deep veins, from where it goes back to the femoral vein and start over again (origin of hyperteinsion) Central venous pressure -pressure in the right atrium -determined by balance of heart pumping blood out of the right atrium and flow of blood from the large veins into RA -normally 0 mmHg - can be as high as 20-30 mmHg -more vigorous heart contraction cause lower CVP -less heart contractions -> higher CVP -factors increasing CVP: increased blood volume, increased peripheral pressure, dilation of arterioles, decreased right ventricular function, skeletal and respiratory pumps. Venous hypertension Causes: -breaking of valves of legs and pelvis -> venous hypertension causing varicose veins -capillary proliferation - extensive capillary permeability Systemic venous hypertension Causes: -chronic myocardial failure (RHF elevate RA pressure and CVP) -tricuspid insufficiency (elevate RA pressure and CVP) -chronic salt and water retention (both art + ven pressure) -tone of venous circulation (contraction of smooth muscle cells in veins respond to catechol, AG2, endothelin 1 -> increase BP) Consequences -increased hydrostatic pressure distributed within central veins that include jugular, subclavian and vena cavae. -in absence of valves the vessels cant be protected against SVH -SVH accounts for an increase in hydrostatic pressure and transcapillary fluid -> accumulation in interstitial space -> ascitis -Hepatic and splanchnic congestion: Liver sinusoids that has bad control of proteins and fluids moving in and out when hepatic venous pressure rises. -In other organs capillaries are similar to the rest of the body, but when the hydrostatic pressure is too high in SVH -> filtration

Acute organ failure

★Heart failure -condition where the heart pump is unable to meet metabolic requirements of tissues for blood. Causes: -myocardial disease: cardiomyopathy, myocarditis, MI -valvular disease: stenotic valves, regurgitation -congenital heart defects -pericardial disorders: pericarditis, cardiac tamponade -increased pressure work: hypertension -increased volume work: arteriovenous shunt, hypervolemia -increased perfusion work: thyreotoxicosis, pheochromocytoma Consequences -reduced flow to kidneys causing kidney failure if left untreated -valve dysfunction -arrytmias -liver damage - buildup of fluid that puts pressure on liver, can lead to scarring. ★Respiratory failure Causes: 1) Extrinsic: -normal lung, but decreased minute ventilation -depression of respiratory center -neuromuscular diseases (myasthenia gravis, multiple sclerosis) -chest disorders, injuries 2) Intrinsic: -COPD -massive pulmonary edema -extensive pneumonia -ARDS Consequences -restlessness, anxiety, sleepiness, loss of consciousness -rapid and shallow breathing -racing heart -irregular heartbeats (arrhythmias) -profuse sweating ★ Renal failure -loss of kidneys ability to clear blood of toxic substances leading to accumulation of nitrogenous wastes in blood. Causes -heart failure -hypovolemia (hemorrhage, dehydration, loss of fluid) -circulatory shock -decreaed renal perfusion due to vasoactive mediators -drugs -acute renal disease - glomerular disorder (acute Gnephritis) -acute tubular necrosis -ureteral obstruction, bladder obstruction Consequences -decreased EPO production -no RAAS -no reabsorption, filtration -accumulation of waste

Regulation of perfusion and its disorders

★Perfusion in lungs -pulmonary perfusion depends on gravity -smallest in apical zone (better ventilation than perfusion) - largest in basal zone (better perfusion than ventilation) -while standing the blood flow to the upper lung is less than the base -while lying the blood flow to posterior portion exceeds anterior portion -pulmonary vessels are highly sensitive to alveolar oxygen levels and undergo marked vasoconstriction when exposed to hypoxia. (<60mmHg) -at very low levels, the local flow may be almost abolished. -in Regional hypoxia (atelectasis),vasoconstriction is localized to a region. in this case vasoconstriction leads blood flow away from hypoxic region -when alveolar hypoxia no longer exist, restored blood flow -Generalized hypoxia (high altitude, chronic lung disease) cause vasoconstriction throughout the lung -prolonged hypoxia can lead to pulmonary hypertension and increased workload on the right heart, causing Cor Pulmonale. -a low pH have similar effect, producing similar effect particularly when alveolar hypoxia is present (eg. during circulatory shock) -physiologic shunt: due to insufficient ventilation cant provide oxygen-needs. usually result from destructive lung disease that impairs ventilation, or from heart failure that interferes with blood flow through lungs -VQ ratio regulation -reduction of blood flow ->bronchoconstriction -> air redistribution -obstructed bronchioles -> vasoconstriction -> blood redistribution -high pO2 -> dilation of arterioles. low pO2 -> constriction of arterioles -high pCO2 -> dilation of arterioles. low pCO2 -> bronchoconstriction -mismatch caused by atelectasis (V, but no Q), COPD ★Perfusion in tissue -perfusion occurs via capillaries in systemic circulation where arterioles and sphincters can regulate perfusion through specific tissues, organs. -different hormones and endothelial factors can regulate contraction and dilation of arterioles and sphincters. -vasopressin, angiotensin 2, endothelin, noradrenalin (vasoconstrictors) -bradykinin, substance P, ANP (vasodilators)