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CARDIOVASCULAR PATHOPHYSIOLOGY: DISORDERS OF BLOOD FLOW & BLOOD PRESSURE REGULATION MSPA 520 PATHOPHARMACOLOGY THERESA NEUMANN, PAC OBJECTIVES: • 1. Discuss the changes that occur in endothelial cells and vascular smooth muscle in response to vascular stress and injury. • 2. Differentiate atherosc...

CARDIOVASCULAR PATHOPHYSIOLOGY: DISORDERS OF BLOOD FLOW & BLOOD PRESSURE REGULATION MSPA 520 PATHOPHARMACOLOGY THERESA NEUMANN, PAC OBJECTIVES: • 1. Discuss the changes that occur in endothelial cells and vascular smooth muscle in response to vascular stress and injury. • 2. Differentiate atherosclerosis, calcific sclerosis and arteriosclerosis. • 3. Discuss the function of the five types of lipoproteins in terms of lipid transport and development of atherosclerosis. • 4. Describe the role of the low-density lipoprotein receptor in the removal of cholesterol from the blood. • 5. Describe the mechanisms involved in the development of atherosclerosis and the changes that occur in the vessels. • 6. Discuss the pathogenesis of essential hypertension and the changes that occur in the vessels and cardiac muscle as a result of essential hypertension. BLOOD VESSEL STRUCTURE & FUNCTION • Blood flow dependent on patent vessels & adequate perfusion pressures • Artery/arteriolar structural issues à lack nutrients to cells & accumulation of waste • Venous/venule structural issues à accumulation of cell waste • Closely titrated BP ensures efficient flow to/from all organs/tissues/cells • Too low à no nutrients • Too high à damage to vessels/tissues Diagram of a typical artery LAYERS OF BLOOD VESSELS • 3 layers (except capillaries) • Tunica externa (collagen/connective tissue) • Tunica media (smooth muscle cells in circumferential pattern) • Tunica intima (endothelial cells + connective tissue layer) • Capillaries = single layer of endothelial cells plus surrounding pericytes (similar to SMCs) • Artery vs. vein à SMC layer! microanatomy of the artery, vein, and capillary beds THE STRUCTURE AND FUNCTION OF THE BLOOD VESSELS ENDOTHELIUM & ENDOTHELIAL DYSFUNCTION • Continuous lining throughout the vascular system • Functions of endothelial cells: • • • • • • transfer of molecules across the vascular wall platelet adhesion and blood clotting (pro- and anti-coagulant factors) modulation of blood flow and vascular resistance (nitric oxide, endothelin) metabolism of hormones regulation of immune and inflammatory reactions (cytokines) VEGF & other growth factor production • Endothelial dysfunction = adaptations to various stimuli (e.g. inflammation, damage, hemodynamic factors, hypoxia, etc.) VASCULAR SMOOTH MUSCLE CELLS (SMCS) • Respond to neural and hormonal stimuli that diffuse into media layer • Constriction (sympathetic) or Dilation • Synthesize collagen, elastin, growth factors, and cytokines • Can be normal repair or pathologic (atherosclerosis) • Growth promoters = platelet-derived growth factor, thrombin, fibroblast growth factor, and cytokines (e.g. interferon gamma, interleukin-1) • Growth inhibitors = nitric oxide REGULATION OF SYSTEMIC ARTERIAL BLOOD PRESSURE • Systole = cardiac ejection of blood • Diastole = resting BP/ventricular filling • 70% of LVEF occurs in first third of systole • Dicrotic notch = pressure differential forcing aortic valve to close • Pulse pressure = difference between systolic and diastolic (~40mmHg) • Mean arterial pressure = avg pressure in arterial system over entire cardiac cycle (~90 – 100mmHg) • CO = HR x SV • MAP = CO x PVR MECHANISMS OF BP REGULATION • Acute Regulation: minute-to-minute adaptations; depends on neural* & humoral signaling • Neural = cardiovascular center in brainstem, ANS (sympathetic/parasympathetic), intrinsic receptors (baroreceptors & chemoreceptors), extrinsic receptors (pain, cold, emotion – hypothalamus) • Humoral = RAAS, vasopressin, adrenal epinephrine/norepinephrine • Long-Term Regulation: dependent on kidneys and volume control à dependent on sympathetic stimulation and volume setpoints • Circadian Variations in BP à normal fluctuations in set points d/t time of day DISORDERS OF SYSTEMIC ARTERIAL FLOW ARTERIAL CONSIDERATIONS • 3 types of arteries: • Large elastic arteries (aorta & branches)à transport of blood, mainly • Medium-sized arteries (coronary and renal) à regulation of capillary blood flow • Small arteries & arterioles (tissues)à regulation of capillary blood flow • Arterial disease = impaired blood flow/faulty regulation • Ischemia = reduction in flow resulting in deficient O2 delivery • Infarction = area of ischemic necrosis in tissues • Common arterial causes = dyslipidemia, atherosclerosis, vasculitis, arterial disease of the extremities, and arterial aneurysms DYSLIPIDEMIA • Dyslipidemia = imbalance of lipid components of blood • Hyperlipidemia = excess lipids • Types: triglycerides, phospholipids, cholesterol • Lipoprotein = protein-lipid transport molecule • 5 Types Lipoproteins (based on density of molecule): • • • • • Chylomicrons VLDL IDL LDL HDL General structure of a lipoprotein. The cholesterol esters and triglycerides are located in the hydrophobic core of the macromolecule, surrounded by phospholipids and apoproteins. LIPOPROTEIN TRANSPORT • LDL removed by LDL receptors (~70%) or scavenger cells (~30%) • Liver (75% LDL receptors) – binding, endocytosis, fuse w/ lysosomes, degradation à free cholesterol • Scavenger cells (macrophages, monocytes) – phagocytosis à atherosclerosis • HDL à reverse transport of cholesterol • Brings cholesterol from tissues to liver à bile à fecal elimination PATHOGENESIS OF DYSLIPIDEMIA • Can be increase in any of lipid transport molecules • Multiple etiologies, not necessarily exclusive: • • • • • Nutrition Genetics Medications Comorbidities Metabolic diseases • Primary Dyslipidemia – genetics that lead to defective synthesis of certain apoproteins, a lack of receptors for lipids, defective lipid receptors, or defective handling of cholesterol by cells • Secondary Dyslipidemia – other health problems cause the lipid problem FAMILIAL HYPERCHOLESTEROLEMIA • Autosomal dominant disorder • Gene mutation (short arm of chromosome 19) coding for LDL receptor • Heterozygotes (1 in 500) • LDL ~ 350mg/dL • Adult signs/symptoms • Homozygotes (1 in 1 million) • LDL ~ 1,000mg/dL • Childhood signs/symptoms SECONDARY DYSLIPIDEMIA • Causes = dietary factors, obesity, metabolic changes/DM-2 • Obesity-related dyslipidemia à ↑ Triglycerides, ↑ LDL, ↓ HDL • Adipocytes à secretion of proinflammatory cytokines (adipokines) plus tissue macrophages à chronic low-grade inflammatory state • Hydrolysis of adipocytes release free fatty acids • High FFAs + inflammatory state à altered glucose metabolism and insulin resistance • Metabolic syndrome = ≥ 3 of following: • • • • Elevated fasting blood glucose ( or treatment for DM) Elevated blood pressure (or HTN treatment) Elevated waist circumference (per country-specific norms) Dyslipidemia (or current HLD treatment) • Others: hypothyroidism, nephrotic syndrome, obstructive liver disease • Med-induced: β-blockers, estrogens, protease inhibitors ATHEROSCLEROSIS • Type of arteriosclerosis • Formation of fibro-fatty lesions in intima of large- and medium-sized arteries • 3 Types Atherosclerosis: • Fatty streak • Fibrous atheromatous plaque* • Complicated lesion* https://www.youtube.com /watch?v=N33JsBeziEY VASCULITIS • Group of vascular disorders that cause inflammatory injury to the blood vessel wall, involving the endothelial cells and SMCs • Can be arteries, veins or capillaries – any organ or tissue • Etiologies à direct injury, infectious agents, immune processes or secondary to other disease states (e.g. SLE), cold, irradiation, mechanical injury, immune mechanisms, and toxins • Commonly classified based on etiology, pathology and prognosis • Common Classifications: • Small vessel vasculitis à small arteries (ANCA-assoc’d dz, only), arterioles, venules, & capillaries • Medium vessel vasculitis à medium- and small-sized arteries & arterioles • Large vessel vasculitis à aorta and its major tributaries • Leads to inflammation and necrosis of blood vessels walls CLASSIFICATION OF THE VASCULITIDES GIANT CELL TEMPORAL ARTERITIS • Most common vasculitis • Focal, inflammatory condition of medium- to large-arteries • Predominantly aortic arch arterial branches: superficial temporal, vertebral, ophthalmic and posterior ciliary arteries • “older adults”, 2:1 F:M ratio • Auto-immune component à multinucleated giant cell invasion of vessel wall leading to inflammation and transmural necrosis • Complications = blindness, thoracic aortic aneurysms • Associated with polymyalgia rheumatica (PMR) • “Peripheral Vascular Diseases” (PVD) ARTERIAL DISEASES OF THE EXTREMITIES • Same disease process as other arterial diseases --> flow obstruction leading to ischemia, ischemic pain, impaired function, tissue infarction and necrosis • Specific conditions: • • • • Acute arterial occlusion Atherosclerotic occlusive disease Thromboangiitis obliterans Raynaud disease/phenomenon ACUTE ARTERIAL OCCLUSION • Sudden blockage of blood flow in artery, most commonly d/t embolus or thrombus (can be arterial vasospasm or trauma/mechanical) • Emboli (thrombus, fat, air, amniotic fluid) à dislodges and flows until vessel narrows à lodges and obstructs • Thrombus (not embolic) à formation on vessel wall with propagation until obstructs lumen • Most commonly due to enlarging atherosclerotic plaque that sustains erosion or rupture of fibrous cap, stimulating clotting cascade ATHEROSCLEROTIC OCCLUSIVE DISEASE • More commonly in LE arteries – “arteriosclerosis obliterans” • Same risk factors as atherosclerosis: tobacco smoking, DM, HLD/dyslipidemia • Superficial femoral and popliteal = most common • Lower leg vessels => tibial, common peroneal, pedal vessels • “Intermittent claudication” = angina in the leg (ischemic pain with exertion) • Other signs = atrophic changes in skin (thinning, hair loss), shrinking muscles • Dry gangrene results when complete obstruction • ABI interpretation THROMBOANGIITIS OBLITERANS • “Buerger disease” • Inflammatory (vasculitis) disorder of mediumarteries causing thrombus formation • Plantar and digital arteries of foot/lower leg, usually • Can affect hand/arm arteries • Can extend to adjacent veins and nerves • Segmental thromboses due to acute and chronic inflammation • Commonly heavy smokers < 35yrs of age; can be seen with chewing tobacco, too • Nicotine triggers toxic rxn in endothelial cells • Genetic predisposition?? (seen in certain ethnic groups) REYNAUD DISEASE & PHENOMENON • Functional disorder due to intense vasospasm of the arteries/arterioles in fingers (and less commonly toes) • 3 – 5% of population, F>>M • Reynaud Disease (primary) = vasospasm w/o demonstrable cause • Reynaud Phenomenon (secondary) = associated w/ other diseases known to cause vasospasm (e.g. previous vessel injury, occupational trauma/vibrating tools, collagen disease, neurologic disorders, chronic arterial occlusive disorders) • Vasospasm => excessive vasoconstrictor response to stimuli (cold, emotional stress) ANEURYSMS • Abnormal localized dilatation of a blood vessel (artery or vein) • 2 structural forms: • True aneurysm = small, spherical dilation of vessel at bifurcation (e.g. berry, fusiform, saccular) • False aneurysm = “pseudoaneurysm” – localized dissection/tear in inner wall of artery with formation of extravascular hematoma, enlarging vessel • Etiologies: congenital defects, trauma, infections, atherosclerosis lead to weakness in vessel wall, allowing progressive dilatation with increasing intraluminal pressures at risk for rupture AORTIC ANEURYSM AND DISSECTION • Aortic aneuryms à involve any part of aorta; multiple aneurysms can be present • Most common etiologies = atherosclerosis and degeneration of vessel media • High incidence in men > 50yrs who smoke tobacco • Aortic dissection à acute, life-threatening condition – hemorrhage into vessel wall that extends longitudinally along vessel axis, separating layers • >95% show transverse tear in intima and internal media • Most dissections involve ascending aorta followed by descending thoracic aorta (past subclavian origin) • Etiology = conditions that weaken or cause degeneration of elastic and SMC layers of vessel (e.g. HTN* and age-related); also assoc’d with connective tissue disorders/Marfan’s syndrome, pregnancy, congenital defects (aortic valve, coarctation), cardiac surgery-related DISORDERS OF SYSTEMIC VENOUS CIRCULATION VENOUS DISEASE • Veins = low-pressure, thin-walled vessels that rely on muscles and pressure changes (abd/thorax) to promote return flow to heart; valves prevent retrograde flow • Legs contain superficial and deep vessels, connected by communicating vessels • Designed to be “storage” area for blood • Subject to stasis and venous insufficiency • Common venous problems: • Varicose veins • Venous insufficiency • Venous thrombosis The skeletal muscle pumps and their function in promoting blood flow in the deep and superficial calf vessels of the leg. VARICOSE VEINS • Dilated, tortuous veins of LE à lead to venous insuffiency • Primary – originate in superficial saphenous veins • Secondary – originate in deep veins d//t DVT*, congenital or acquired AV fistulas, congenital venous malformations, pressure-induced (pregnancy, tumor) • Prolonged exposure to increased hydrostatic pressures in leg veins (prolonged standing, obesity, tumors, pregnancy, etc.) causes valvular incompetence, leading to retrograde flow and worsening pressures and volume; capillaries leak à interstitial edema CHRONIC VENOUS INSUFFICIENCY • Pathophysiologic effects of persistent venous hypertension on structure and function of the venous system of the LE • Multifactorial (see previous slide); add inflammatory processes and endothelial dysfunction • Once veins are insufficient, normal flow is disrupted • High pressures and retrograde flow leads to collection of toxic metabolites, inefficient delivery of needed oxygen and nutrients • Necrosis of fat deposits, skin atrophy, hemosiderin deposits from RBC degradation (brown pigment) • Later stages => stasis dermatitis, stasis ulcers due to loss of nutritional support, fat degradation, tissue necrosis; can become secondarily infected due to breaches in skin integrity VENOUS THROMBOSIS • “Thrombophlebitis” = presence of thrombus in a vein with inflammatory response involving vessel wall • Can be superficial (SVT) or deep veins (DVT) • Virchow’s triad**: stasis of blood, hypercoagulability, vessel wall injury • Stasis = blood pooling (immobility, varicosities/venous stasis) • Hypercoagulability = genetic, marantic/neoplastic, estrogen, pro-inflammatory state • Vessel injury = surgery, trauma, infection, other inflammation • ~50% asymptomatic • Symptoms range from leg pain/swelling, fever/malaise, complications (e.g. PE) DISORDERS OF BLOOD PRESSURE REGULATION HYPERTENSION • Sustained condition of elevated BP within arterial circuit • Primary risk factor for cardiovascular disease • Leading cause of worldwide morbidity and mortality • Either primary (essential) or secondary hypertension • Primary = clinical presence of hypertension w/o evidence of causal condition; much of this is theoretical • Secondary = hypertension d/t identifiable condition that, if corrected, resolves HTN PRIMARY (ESSENTIAL) HYPERTENSION Non-Modifiable Risk Factors • Age • Gender & Race • Family History & Genetics Modifiable Risk Factors • Dietary Factors (salt) • Dyslipidemia • Tobacco Use • • • • Alcohol Consumption Fitness Level Obesity Insulin Resistance & Metabolic Abnormalities • Obstructive Sleep Apnea SECONDARY HYPERTENSION • Renal hypertension (glomerulonephritis, ARF, urinary tract obstruction, pyelonephritis, polycystic kidney disease, renal artery stenosis, renal artery hyperplasia) à triggers RAAS • Disorders of adrenocortical hormones – salt/water retention (hyperaldosteronism, Cushings) • Pheochromocytoma - tumor of chromaffin tissue in adrenal gland – release of catecholamines • Coarctation of the aorta - narrowing of aorta creating resistance to flow à UE hypertension; LE have lower pressures • Oral contraceptives – proposed mechanism is salt/water retention à volume expansion QUESTIONS??