Nurs 6501 Midterm Exam Review Guide (Weeks 1-6) Cellular Processes and the Genetic Environment ALL ANSWERS 100% CORRECT AID GRADE ‘A’

1. Describe cellular processes and alterations within cellular processes. Movement. Muscle cells can generate forces that produce motion. Muscles that are attached to bones produce limb movements, whereas those that enclose hollow tubes or cavities move or empty contents when they contract. For example, the contraction of smooth muscle cells surrounding blood vessels changes the diameter of the vessels; the contraction of muscles in walls of the urinary bladder expels urine. Conductivity. Conduction as a response to a stimulus is manifested by a wave of excitation, an electrical potential that passes along the surface of the cell to reach its other parts. Conductivity is the chief function of nerve cells. Metabolic absorption. All cells take in and use nutrients and other substances from their surroundings. Cells of the intestine and the kidney are specialized to carry out absorption. Cells of the kidney tubules reabsorb fluids and synthesize proteins. Intestinal epithelial cells reabsorb fluids and synthesize protein enzymes. Secretion. Certain cells, such as mucous gland cells, can synthesize new substances from substances they absorb and then secrete the new substances to serve as needed elsewhere. Cells of the adrenal gland, testis, and ovary can secrete hormonal steroids. Excretion. All cells can rid themselves of waste products resulting from the metabolic breakdown of nutrients. Membrane-bound sacs (lysosomes) within cells contain enzymes that break down, or digest, large molecules, turning them into waste products that are released from the cell. Respiration. Cells absorb oxygen, which is used to transform nutrients into energy in the form of adenosine triphosphate (ATP). Cellular respiration, or oxidation, occurs in organelles called mitochondria. Reproduction. Tissue growth occurs as cells enlarge and reproduce themselves. Even without growth, tissue maintenance requires that new cells be produced to replace cells that are lost normally through cellular death. Not all cells are capable of continuous division. Communication. Communication is vital for cells to survive as a society of cells. Pancreatic cells, for instance, secrete and release insulin necessary to signal muscle cells to absorb sugar from the blood for energy. Constant communication allows the maintenance of a dynamic steady state. 2. What is the impact of the genetic environment on disease? Genetic diseases caused by single genes usually follow autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance. The recurrence risk for autosomal dominant diseases is usually 50%. Germline mosaicism can alter recurrence risks for genetic diseases because unaffected parents can produce multiple affected offspring. This situation occurs because the germline of one parent is affected by a mutation but the parent's somatic cells are unaffected. Skipped generations are not seen in classic autosomal dominant pedigrees. Males and females are equally likely to exhibit autosomal dominant diseases and to pass them on to their offspring. Penetrance may be age-dependent, as in Huntington disease and familial breast cancer. Most commonly, parents of children with autosomal recessive diseases are both heterozygous carriers of the disease gene. In this case, the recurrence risk for autosomal recessive diseases is 25%. Males and females are equally likely to be affected by autosomal recessive diseases. The frequency of genetic diseases approximately doubles in the offspring of first-cousin matings. In each normal female somatic cell, one of the two X chromosomes is inactivated early in embryogenesis. X inactivation is random, fixed, and incomplete (i.e., only part of the chromosome is actually inactivated). It may involve methylation. Gender is determined embryonically by the presence of the SRY gene on the Y chromosome. Embryos that have a Y chromosome (and thus the SRY gene) become males, whereas those lacking the Y chromosome become females. When the Y chromosome lacks the SRY gene, an XY female can be produced. Similarly, an X chromosome that contains the SRY gene can produce an XX male. X-linked genes are those that are located on the X chromosome. Nearly all known X-linked diseases are caused by X-linked recessive genes. Males are hemizygous for genes on the X chromosome. X-linked recessive diseases are seen much more often in males than in females because males need only one copy of the gene to express the disease. Fathers cannot pass X- linked genes to their sons. Skipped generations are often seen in X-linked recessive disease pedigrees because the gene can be transmitted through carrier females. Recurrence risks for X- linked recessive diseases depend on the carrier and affected status of the mother and father. A sex-limited trait is one that occurs in only one of the sexes. A sex-influenced trait is one that occurs more often in one sex than in the other. Congenital diseases are those present at birth. Most of these diseases are multifactorial in etiology. Multifactorial diseases in adults include coronary heart disease, hypertension, breast cancer, colon cancer, diabetes mellitus, obesity, AD, alcoholism, schizophrenia, and bipolar affective disorder. It is incorrect to assume that the presence of a genetic component means that the course of a disease cannot be altered—most diseases have both genetic and environmental aspects. 3. Explain how healthy cell activity contributes to good health and how its breakdown in cellular behavior and alterations to cells lead to health issues. Cells adapt to their environment to escape and protect themselves from injury. An adapted cell is neither normal nor injured—its condition lies somewhere between these two states. Adaptations are reversible changes in cell size, number, phenotype, metabolic activity, or functions of cells. 1 However, cellular adaptations are a common and central part of many disease states. In the early stages of a successful adaptive response, cells may have enhanced function; thus, it is hard to differentiate a pathologic response from an extreme adaptation to an excessive functional demand. The most significant adaptive changes in cells include atrophy (decrease in cell size), hypertrophy (increase in cell size), hyperplasia (increase in cell number), and metaplasia (reversible replacement of one mature cell type by another less mature cell type or a change in the phenotype). Dysplasia (deranged cellular growth) is not considered a true cellular adaptation but rather an atypical hyperplasia. Injury to cells and to extracellular matrix (ECM) leads to injury of tissues and organs ultimately determining the structural patterns of disease. Loss of function derives from cell and ECM injury and cell death. Cellular injury occurs if the cell is “stressed” or unable to maintain homeostasis in the face of injurious stimuli or cell stress. Injured cells may recover (reversible injury) or die (irreversible injury). Injurious stimuli include chemical agents, lack of sufficient oxygen (hypoxia), free radicals, infectious agents, physical and mechanical factors, immunologic reactions, genetic factors, and nutritional imbalances. Cell injury and cell death often result from exposure to toxic chemicals, infections, physical trauma, and hypoxia. 4. What are the roles genetics plays in disease processes? See answer for question 2. 5. What is the relationship of how cells are involved in disease processes? Common biochemical mechanisms are important to understanding cell injury and cell death regardless of the injuring agent. These mechanisms include adenosine triphosphate (ATP) depletion, mitochondrial damage, accumulation of oxygen and oxygen-derived free radicals, membrane damage (depletion of ATP), protein folding defects, DNA damage defects, and calcium level alterations. Examples of cell injury are (1) ischemic and hypoxic injury, (2) ischemia-reperfusion injury, (3) oxidative stress or accumulation of oxygen-derived free radicals–induced injury, and (4) chemical injury. Altered cellular and tissue biology can result from adaptation, injury, neoplasia, accumulations, aging, or death. Knowledge of the structural and functional reactions of cells and tissues to injurious agents, including genetic defects, is key to understanding disease processes. Cellular injury can be caused by any factor that disrupts cellular structures or deprives the cell of oxygen and nutrients required for survival. Injury may be reversible (sublethal) or irreversible (lethal) and is classified broadly as chemical, hypoxic (lack of sufficient oxygen), free radical, unintentional or intentional, and immunologic or inflammatory. Cellular injuries from various causes have different clinical and pathophysiologic manifestations. Stresses from metabolic derangements may be associated with intracellular accumulations and include carbohydrates, proteins, and lipids. Sites of cellular death can cause accumulations of calcium resulting in pathologic calcification. Cellular death is confirmed by structural changes seen when cells are stained and examined with a microscope. The most important changes are nuclear; clearly, without a healthy nucleus, the cell cannot survive. The two main types of cell death are necrosis and apoptosis, and nutrient deprivation can initiate autophagy that results in cell death. Altered Physiology 6. Evaluate cellular processes and alterations within cellular processes. Injury to cells and their surrounding environment, called the extracellular matrix, leads to tissue and organ injury. Although the normal cell is restricted by a narrow range of structure and function, it can adapt to physiologic demands or stress to maintain a steady state called homeostasis. Adaptation is a reversible, structural, or functional response to both normal or physiologic conditions and adverse or pathologic conditions. For example, the uterus adapts to pregnancy— a normal physiologic state—by enlarging. Enlargement occurs because of an increase in the size and number of uterine cells. In an adverse condition, such as high blood pressure, myocardial cells are stimulated to enlarge by the increased work of pumping. Like most of the body's adaptive mechanisms, however, cellular adaptations to adverse conditions are usually only temporarily successful. Severe or long-term stressors overwhelm adaptive processes and cellular injury or death ensues. Altered cellular and tissue biology can result from adaptation, injury, neoplasia, accumulations, aging, or death. Knowledge of the structural and functional reactions of cells and tissues to injurious agents, including genetic defects, is key to understanding disease processes. Cellular injury can be caused by any factor that disrupts cellular structures or deprives the cell of oxygen and nutrients required for survival. Injury may be reversible (sublethal) or irreversible (lethal) and is classified broadly as chemical, hypoxic (lack of sufficient oxygen), free radical, unintentional or intentional, and immunologic or inflammatory. Cellular injuries from various causes have different clinical and pathophysiologic manifestations. Stresses from metabolic derangements may be associated with intracellular accumulations and include carbohydrates, proteins, and lipids. Sites of cellular death can cause accumulations of calcium resulting in pathologic calcification. Cellular death is confirmed by structural changes seen when cells are stained and examined with a microscope. The most important changes are nuclear; clearly, without a healthy nucleus, the cell cannot survive. The two main types of cell death are necrosis and apoptosis, and nutrient deprivation can initiate autophagy that results in cell death. Cellular aging causes structural and functional changes that eventually lead to cellular death or a decreased capacity to recover from injury. 7. Analyze alterations in the immune system that result in disease processes. Inappropriate immune responses are misdirected responses against the host's own tissues (autoimmunity); directed responses against beneficial foreign tissues, such as transfusions or transplants (alloimmunity); exaggerated responses against environmental antigens (allergy); or insufficient responses to protect the host (immune deficiency). Allergy, autoimmunity, and alloimmunity are collectively known as hypersensitivity reactions. Mechanisms of hypersensitivity are classified as type I (IgEmediated) reactions, type II (tissue-specific) reactions, type III (immune complex–mediated) reactions, and type IV (cell mediated) reactions. Type I (IgE-mediated) hypersensitivity reactions are mediated through the binding of IgE to Fc receptors on mast cells and cross-linking of IgE by antigens that bind to the Fab portions of IgE. Cross-linking causes mast cell degranulation and the release of histamine (the most potent mediator) and other inflammatory substances. Histamine, acting through the H1 receptor, contracts bronchial smooth muscles, causing bronchial constriction; increases vascular permeability, causing edema; and causes vasodilation, increasing blood flow into the affected area. Histamine with H2 receptors results in increased gastric acid secretion and a decrease of histamine released from mast cells and basophils. Histamine enhances the chemotaxis of eosinophils into sites of type I allergic reactions. Atopic individuals tend to produce higher quantities of IgE and to have more Fc receptors for IgE on their mast cells. Ex: seasonal allergic rhinitis. Type II (tissue-specific) hypersensitivity reactions are caused by five possible mechanisms: complement-mediated lysis, opsonization and phagocytosis, neutrophil-mediated tissue damage, antibody-dependent cell-mediated cytotoxicity, and modulation of cellular function. Ex: Graves disease, autoimmune thrombocytopenic purpura, and autoimmune hemolytic anemia. Type III (immune complex–mediated) hypersensitivity reactions are caused by the formation of immune complexes that are deposited in target tissues, where they activate the complement cascade, generating chemotactic fragments that attract neutrophils into the inflammatory site. Neutrophils release lysosomal enzymes that result in tissue damage. Intermediate-sized immune complexes are the most likely to have severe pathologic consequences. Immune complex disease can be a systemic reaction, such as serum sickness, or a localized response, such as the Arthus reaction. Ex: SLE, serum sickness. Type IV (cell-mediated) hypersensitivity reactions are caused by either cytotoxic T lymphocytes (Tc cells) or lymphokine producing Th1 cells. 16. Typical allergens include pollen, molds and fungi, certain foods (milk, eggs, fish, peanuts), animals, certain drugs, cigarette smoke, and house dust. Clinical manifestations of allergic reactions usually are confined to the areas of initial intake or contact with the allergen. Ingested allergens induce gastrointestinal symptoms, airborne allergens induce respiratory tract or skin manifestations, and contact allergens induce allergic responses at the site of contact. Ex: Contact sensitivity to poison ivy and metals, contact/atopic dermatitis. SLE is a chronic, multisystem, inflammatory disease and is one of the most serious of the autoimmune disorders. SLE is characterized by the production of a large variety of autoantibodies. Occurs more often in women, age 20-40, and blacks. Hyperacute graft rejection (preexisting antibody) is immediate and rare, acute rejection is cell mediated and occurs days to months after transplantation, and chronic rejection is caused by inflammatory damage to endothelial cells as a result of a weak cell-mediated reaction. Red blood cell antigens may be the targets of autoimmune or alloimmune reactions. The most important of these, because they provoke the strongest humoral immune response, are the ABO and Rh systems. DiGeorge syndrome (congenital thymic aplasia or hypoplasia) is characterized by complete or partial lack of the thymus (resulting in depressed T-cell immunity) and the parathyroid glands (resulting in hypocalcemia) and the presence of cardiac anomalies. SCID is a total lack of T-cell function and a severe (either partial or total) lack of B-cell function. SCID can result from mutations in critical enzymes (ADA deficiency, PNP deficiency), in cytokine receptors (X-linked SCID, JAK3 deficiency, IL-7 receptor deficiency), or in antigen receptors (RAG-1/RAG-2 deficiencies, CD45 deficiency, CD3 deficiency, ZAP-70 deficiency). Other combined defects may result from deficiencies in antigen-presenting molecules (bare lymphocyte syndrome), cytoskeletal proteins (WAS), or DNA repair (ataxia-telangiectasia) 8. Identify racial/ethnic variables that may impact physiological functioning. Will list these with individual disease processes. 9. What is the impact of patient characteristics on disorders and altered physiology? Will list with individual disease processes. 10. What is the association of genes in the development of disease? Genetic diseases caused by single genes usually follow autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance. Pedigree charts are an important tool in the analysis of modes of inheritance. Recurrence risks specify the probability that future offspring will inherit a genetic disease. For single-gene diseases, recurrence risks remain the same for each offspring, regardless of the number of affected or unaffected offspring. The recurrence risk for autosomal dominant diseases is usually 50%. Germline mosaicism can alter recurrence risks for genetic diseases because unaffected parents can produce multiple affected offspring. This situation occurs because the germline of one parent is affected by a mutation but the parent's somatic cells are unaffected. Skipped generations are not seen in classic autosomal dominant pedigrees. Males and females are equally likely to exhibit autosomal dominant diseases and to pass them on to their offspring. A gene that is not always expressed phenotypically is said to have incomplete penetrance. Penetrance may be age-dependent, as in Huntington disease and familial breast cancer. Variable expressivity is a characteristic of many genetic diseases. Most commonly, parents of children with autosomal recessive diseases are both heterozygous carriers of the disease gene. In this case, the recurrence risk for autosomal recessive diseases is 25%. Males and females are equally likely to be affected by autosomal recessive diseases. Consanguinity is sometimes present in families with autosomal recessive diseases, and it becomes more prevalent with rarer recessive diseases. Carrier detection tests for an increasing number of autosomal recessive diseases are available. The frequency of genetic diseases approximately doubles in the offspring of first-cousin matings. In each normal female somatic cell, one of the two X chromosomes is inactivated early in embryogenesis. X inactivation is random, fixed, and incomplete (i.e., only part of the chromosome is actually inactivated). It may involve methylation. Gender is determined embryonically by the presence of the SRY gene on the Y chromosome. Embryos that have a Y chromosome (and thus the SRY gene) become males, whereas those lacking the Y chromosome become females. When the Y chromosome lacks the SRY gene, an XY female can be produced. Similarly, an X chromosome that contains the SRY gene can produce an XX male. X-linked genes are those that are located on the X chromosome. Nearly all known X-linked diseases are caused by X-linked recessive genes. Males are hemizygous for genes on the X chromosome. X-linked recessive diseases are seen much more often in males than in females because males need only one copy of the gene to express the disease. Fathers cannot pass X-linked genes to their sons. Skipped generations are often seen in X-linked recessive disease pedigrees because the gene can be transmitted through carrier females. Recurrence risks for X-linked recessive diseases depend on the carrier and affected status of the mother and father. A sex-limited trait is one that occurs in only one of the sexes. A sex-influenced trait is one that occurs more often in one sex than in the other. 11. What is the process of immunosuppression and the effect it has on body systems? Disorders resulting from immune deficiency are the clinical sequelae (results) of impaired function of one or more components of the immune or inflammatory response (e.g., B cells, T cells, phagocytes, complement). An immune deficiency is the failure of these mechanisms of self-defense to function at their normal capacity, resulting in increased susceptibility to infections. A primary (congenital) immune deficiency is caused generally by a genetic anomaly, whereas a secondary (acquired) immune deficiency is caused by another illness, such as cancer or viral infection, or by normal physiologic changes, such as aging. Acquired forms of immune deficiency are far more common than the congenital forms. Concepts and Alterations of Cardiovascular and Respiratory Disorders 12. Common diseases and disorders that impact the Cardiovascular system, racial/ethnic variables, and patient characteristics. Varicose vein: refers to a condition in which venous blood has pooled, producing distortion of the veins, leakage, increased intravascular hydrostatic pressure, and inflammation (Fig. 33.1). Varicose veins result from incompetent valves, venous obstruction, muscle pump dysfunction, or a combination of these conditions. The increase in venous hydrostatic pressure is associated with an increase in transforming growth factor beta (TGF-β) and basic fibroblast growth factor (bfgf) in vessel walls resulting in permanent remodeling of the vessels. An altered ratio of prostacyclin to thromboxane A2 with potential for clotting also occurs. 2 Risk factors for developing varicose veins include gender (women are at a much higher risk), pregnancy, increased weight, increased age, leg trauma, sitting or standing for long periods of time, and family history. Symptoms include visible distended veins; itching, burning, or throbbing around lower leg veins; and muscle cramping or pain in the lower legs. DVT: Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). DVT is a blood clot that remains attached to a vessel wall, usually in a single side of a lower extremity. A detached thrombus is a thromboembolus. Venous thrombi are more common than arterial thrombi because flow and pressure are lower in the veins than in the arteries. 5 Three factors (termed the triad of Virchow) promote venous thrombosis: (1) venous stasis (associated with immobility, obesity, prolonged leg dependency, age, congestive heart failure [CHF]), (2) venous intimal damage (related to trauma, venipuncture, IV medications), and (3) hypercoagulable states (from inherited disorders, smoking, malignancy, liver disease, pregnancy, oral contraceptives, hormone replacement, hyperhomocysteinemia, antiphospholipid syndrome). 6 Virtually everyone who is hospitalized is at significant risk for DVT, especially those with orthopedic trauma or surgery, spinal cord injury, age older than 60 years, and obstetric/gynecologic conditions. Individuals with malignancy (especially ovarian and pancreatic cancer), and women who are pregnant are also at significant risk. The most common heritable hypercoagulable states are abnormal factor V Leiden and prothrombin gene variant 20210A, both of which predispose patients to DVT. Accumulation of clotting factors and platelets leads to thrombus formation in the vein, often near a venous valve. Inflammation around the thrombus promotes further platelet aggregation, and the thrombus grows proximally. Most thrombi eventually dissolve without treatment, but untreated DVT is associated with a high risk of thromboembolization of a part of the clot from the leg traveling to the lung resulting in a pulmonary embolism7 (see Chapter 36). In up to one-third of individuals with DVT, persistent venous outflow obstruction may lead to post-thrombotic syndrome (PTS) characterized by chronic, persistent pain; edema; and ulceration of the affected limb. 8 Clinical manifestations of DVT are often absent. If a symptom is present, it is typically pain. Other signs of DVT include unilateral leg swelling, dilation of superficial veins, calf tenderness, and skin that is mottled or cyanotic. Superior vena cava syndrome (SVCS): is a clinical manifestation of progressive compression of the superior vena cava (SVC) that leads to venous distention in the upper extremities and head. The leading causes of SVCS are nonsmall cell lung cancer, small cell lung cancer, and lymphoma. Nonmalignant causes of SVCS include thrombosis; infection, such as tuberculosis or histoplasmosis; mediastinal fibrosis; cystic fibrosis; and retrosternal goiter. Pacemaker wires, central venous catheters, and pulmonary artery catheters also can lead to SVCS. The most common clinical manifestations of SVCS include edema and venous distention in the face, neck, trunk, and upper extremities. More rarely, cyanosis may be observed. Individuals may complain of dyspnea, dysphagia, hoarseness, stridor, cough, and chest pain. Central nervous system (CNS) edema may cause malaise, headache, visual disturbances, vertigo, awareness or memory disorders, and impaired consciousness. The skin of the face and arms may become purple and taut, and capillary refill time can be prolonged. Respiratory distress may be present because of edema of bronchial structures or compression of the bronchus by a carcinoma. Hypertension (HTN): is consistent elevation of systemic arterial blood pressure. Hypertension was defined in 2014 as a sustained systolic blood pressure (SBP) of 140 mmHg or greater or a diastolic blood pressure (DBP) of 90 mmHg or greater. 18 In 2017 hypertension was redefined as a SBP of 130 or greater or a DBP of 80 or greater. Hypertension is caused by increases in cardiac output, total peripheral resistance, or both. Cardiac output is increased by any condition that increases heart rate or stroke volume, whereas peripheral resistance is increased by any factor that increases blood viscosity or reduces vessel diameter (vasoconstriction). Hypertension is the most common primary diagnosis in the United States—approximately one in three adults older than 20 years of age has hypertension; this increases to nearly two in three in those older than age 60. In individuals younger than age 45, the prevalence of hypertension is higher in men than in women; from ages 45 to 65 prevalence is the same in men and women; and after age 65 the prevalence of hypertension is greater in women than in men. 5 The prevalence of HTN is higher in blacks and in those with diabetes. Genetic predisposition to hypertension is polygenic, including polymorphisms associated with renal sodium excretion, insulin and insulin sensitivity, activity of the sympathetic nervous system (SNS) and renin angiotensin-aldosterone system (RAAS), and cell membrane sodium or calcium transport. 19 Epigenetic links between environmental factors, such as diet, exercise, and smoking, with gene expression also are being defined. 20,21 Risk factors associated with primary hypertension include age, ethnicity, family history of hypertension and genetic factors, lower education and socioeconomic status, tobacco use, psychosocial stressors, sleep apnea, and dietary factors (including dietary fats, higher sodium intake, lower potassium intake, and excessive alcohol intake). 5 Glucose intolerance (diabetes mellitus) and obesity also are significant risk factors. Many of these factors also are risk factors for other cardiovascular disorders. In fact, hypertension, dyslipidemia, and glucose intolerance are often found together in a condition called metabolic syndrome. Orthostatic (postural) hypotension (OH): refers to a decrease in systolic blood pressure of at least 20 mmHg or a decrease in diastolic blood pressure of at least 10 mmHg within 3 minutes of moving to a standing position. 55 Primary OH is often called neurogenic and is usually the result of neurologic disorders that affect autonomic function. Compensatory changes during standing normally increase sympathetic activity mediated through stretch receptors (baroreceptors) in the carotid sinus and the aortic arch. This reflex response to shifts in volume caused by postural changes leads to a prompt increase in heart rate and constriction of the systemic arterioles, which maintains a stable blood pressure. These compensatory mechanisms are not effective in maintaining a stable blood pressure in individuals with orthostatic hypotension. Primary OH is often chronic. Older adults are susceptible to this type of OH because of slowing of postural reflexes as part of the aging process. It also occurs in neurologic diseases, such as Parkinson disease, multiple system atrophy, and inherited neurologic disorders. Multiple system atrophy is a severe form of chronic autonomic failure in which there are multiple central nervous system degenerative changes, and Parkinson disease. Orthostatic hypotension often is accompanied by dizziness, blurring or loss of vision, and syncope or fainting. To assess hypotensive episode frequency, severity, and correlation with symptoms, 24-hour blood pressure monitoring is recommended. Aneurysm: is a localized dilation or outpouching of a vessel wall or cardiac chamber. Laplace's law can provide an understanding of the hemodynamics of an aneurysm. True aneurysms involve all three layers of the arterial wall and are best described as a weakening of the vessel wall. Most are fusiform and circumferential. False aneurysm is an extravascular hematoma that communicates with the intravascular space. A common cause of this type of lesion is a leak between a vascular graft and a natural artery. Aneurysms most commonly occur in the thoracic or abdominal aorta. The aorta is particularly susceptible to aneurysm formation because of constant stress on the vessel wall and the absence of penetrating vasa vasorum in the media layer. Chronic inflammation of the wall of the aorta causes weakening of the intima and medial layers. Arteriosclerosis and hypertension are found in more than half of all individuals with aneurysms. Chronic hypertension results in mechanical and shear forces that contribute to remodeling and weakening of the vessel wall. Atherosclerosis is a common cause of aneurysms because plaque formation erodes the vessel wall. Infections, such as syphilis, collagen disorders (such as Marfan syndrome), and traumatic injury to the chest or abdomen, also can cause aortic aneurysms. Genetic susceptibilities have been identified including gene polymorphisms for the production of growth factors, myosin, and proteases. Aneurysms in the heart present with dysrhythmias, heart failure, and embolism of clots to the brain or other vital organs. Aortic aneurysms often are asymptomatic until they rupture, when they become painful. Symptoms of dysphagia (difficulty in swallowing) and dyspnea (breathlessness) are caused by the pressure of a thoracic aneurysm on surrounding organs. An abdominal aneurysm can impair flow to an extremity and cause symptoms of ischemia. Aneurysms that occur elsewhere in the body have variable symptoms and signs related to the size of the aneurysm and the potential for rupture and hemorrhage Thromboangiitis obliterans (Buerger disease): is an idiopathic autoimmune condition strongly associated with smoking that is characterized by the formation of thrombi filled with inflammatory and immune cells that disrupt flow in the peripheral arteries. 65 Inflammatory cytokines and toxic oxygen radicals contribute to accompanying vasospasm. Over time, these thrombi become organized and fibrotic and result in permanent occlusion and obliteration of portions of small- and medium-sized arteries in the feet and sometimes in the hands. Typically affected are the digital, tibial, and plantar arteries of the feet and the digital, palmar, and ulnar arteries of the hands. The chief symptoms of thromboangiitis obliterans are pain and tenderness of the affected part. Clinical manifestations are caused by sluggish blood flow and include rubor (redness of the skin caused by dilated capillaries) and cyanosis (blueness of the skin caused by blood that remains in the capillaries after its oxygen has diffused into the interstitium). Chronic ischemia causes the skin to thin and become shiny and the nails to become thickened and malformed. In advanced disease, ischemia can cause gangrene, which may require amputation. Raynaud phenomenon and Raynaud disease: are characterized by attacks of vasospasm in the small arteries and arterioles of the fingers and, less commonly, the toes. Although the clinical manifestations of the phenomenon and the disease are the same, their causes differ. Raynaud disease (or primary Raynaud's) is a primary vasospastic disorder of unknown origin. It is estimated to affect nearly 5% of the general population and is associated with female gender, family history, smoking, manual occupation, migraine, and cardiovascular disease. 67 Blood vessels in affected individuals demonstrate endothelial dysfunction with an imbalance between endothelium derived vasodilators (e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1). Platelet activation may play a role and vasospastic attacks triggered by brief exposure to cold or by emotional stress. Raynaud phenomenon (or secondary Raynaud's) is secondary to systemic diseases, such as collagen vascular disease (e.g., scleroderma), chemotherapy, cocaine use, hypothyroidism, pulmonary hypertension, thoracic outlet syndrome, serum sickness, vasculitis, or malignancy. Vascular inflammation and vasospasm may reflect progression of the underlying disease. The clinical manifestations of the vasospastic attacks of either disorder are pallor, numbness, and the sensation of cold in the digits. Attacks tend to be bilateral, and manifestations usually begin at the tips of the digits and progress to the proximal phalanges. Sluggish blood flow resulting in ischemia may cause the skin to appear cyanotic. Rubor follows as vasospasm ends and the capillaries become engorged with oxygenated blood. Rubor often is accompanied by throbbing and paresthesias. Skin color returns to normal after the attack, but frequent, prolonged attacks may cause the skin of the fingertips to thicken and the nails to become brittle. In severe, chronic Raynaud phenomenon or disease, ischemia eventually can cause ulceration and gangrene. Atherosclerosis: is a form of arteriosclerosis in which thickening and hardening of the vessel are caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called a plaque. Atherosclerosis is not a single disease but rather a pathologic process that can affect vascular systems throughout the body, resulting in ischemic syndromes that can vary widely in their severity and clinical manifestations. It is the leading cause of coronary artery and cerebrovascular disease. Atherosclerosis is a chronic inflammatory condition that results from the interaction of numerous pathophysiologic processes culminating in damage to arterial walls. 70 Pathologically, the lesions progress from endothelial injury and dysfunction to fatty streak fibrotic plaque to complicated lesions. Atherosclerosis begins with injury to the endothelial cells that line artery walls. 71 There are many possible causes of endothelial injury such as aging, smoking, hypertension, and diabetes. Peripheral artery disease (PAD): refers to atherosclerotic disease of arteries that perfuses the limbs, especially the lower extremities. PAD affects 10% to 15% of those who are 60 years of age or older, and is associated with significant morbidity and mortality. 5 Prevalence increases with age, and PAD disproportionately affects blacks. The risk factors for PAD are the same as those for atherosclerotic disease, and it is especially prevalent in individuals who smoke and those with diabetes. PAD is a significant predictor of systemic atherosclerotic disease such that those with documented PAD have nearly double the risk of coronary artery disease than those without PAD. Lower-extremity ischemia, resulting from arterial obstruction in PAD, can be gradual or acute. In many individuals, gradually increasing obstruction to arterial blood flow to the legs caused by atherosclerosis in the iliofemoral vessels results in pain with ambulation called intermittent claudication; however, ischemia may not be painful and may go undetected for years. If a thrombus forms over the atherosclerotic lesion, perfusion can cease acutely with severe pain, loss of pulses, and skin color changes in the affected extremity. Coronary Artery Disease: The lowest prevalence among Asian Americans and the highest among native Hawaiians or other Pacific Islanders. NonHispanic whites and blacks have approximately the same CAD prevalence rates at 5.5% to 5.6%. 5 CAD and associated myocardial infarction is the number one cause of death in both men and women, resulting in a death every 1 minute and 20 seconds in the United States. Risk factors for CAD are the same as those for atherosclerosis and can be categorized as conventional (major) and nontraditional (novel) and modifiable versus nonmodifiable. It is estimated that 65% of whites and 90% of blacks with CAD events have one or more of these risk factors, and avoidable death rates are nearly twice as high among blacks as compared with whites. Conventional or major risk factors for CAD that are nonmodifiable include (1) advanced age, (2) male gender or women after menopause, and (3) family history. Aging and menopause are associated with increased exposure to risk factors and poor endothelial healing. Family history may contribute to CAD through genetics and shared environmental exposure. Many gene polymorphisms have been associated with CAD and its risk factors. Major modifiable conventional risks include (1) dyslipidemia, (2) hypertension, (3) cigarette smoking, (4) diabetes and insulin resistance, (5) obesity and sedentary lifestyle, and (6) an atherogenic diet. If individuals receive appropriate preventive care, modification of these factors can significantly reduce the risk for CAD. Nontraditional, or novel, risk factors for CAD include (1) increased serum markers for inflammation, ischemia, and thrombosis; (2) adipokines; (3) chronic kidney disease; (4) air pollution and ionizing radiation; (5) medications; (6) coronary artery calcification and carotid wall thickness; and (7) the microbiome. Transient Myocardial Ischemia: CAD can diminish the myocardial blood supply causing ischemia. The coronary arteries normally supply blood flow sufficient to meet the demands of the myocardium because it labors under varying workloads. Oxygen extraction from these vessels occurs with maximal efficiency. If efficient exchange does not meet myocardial oxygen needs, healthy coronary arteries are able to dilate to increase the flow of oxygenated blood to the myocardium. Narrowing of a major coronary artery by more than 50% impairs blood flow sufficiently to hamper cellular metabolism under conditions of increased myocardial demand. Myocardial ischemia develops if the supply of coronary blood cannot meet the demand of the myocardium for oxygen and nutrients. Imbalances between myocardial demand and coronary blood supply can result from a number of conditions. Common causes of increased myocardial demand for blood include tachycardia, exercise, hypertension (hypertrophy), and valvular disease. Stable Angina: Angina pectoris is chest pain caused by myocardial ischemia. Stable angina is caused by gradual luminal narrowing and hardening of the arterial walls, so that affected vessels cannot dilate in response to increased myocardial demand associated with physical exertion or emotional stress. With rest, blood flow is restored and no necrosis of myocardial cells results. Angina pectoris is typically experienced as transient substernal chest discomfort, ranging from a sensation of heaviness or pressure to moderately severe pain. Individuals often describe the sensation by clenching a fist over the left sternal border. The discomfort may be mistaken for indigestion. The pain is caused by the buildup of lactic acid or abnormal stretching of the ischemic myocardium that irritates myocardial nerve fibers. These afferent sympathetic fibers enter the spinal cord from levels C3 to T4, accounting for the variety of locations and radiation patterns of anginal pain. Pain may radiate to the neck, lower jaw, left arm, and left shoulder or occasionally to the back or down the right arm. Pallor, diaphoresis, and dyspnea may be associated with the pain. The pain is usually relieved by rest and nitrates. Myocardial ischemia in women may not present with typical angina. Common symptoms in women include atypical chest pain, palpitations, sense of unease, and severe fatigue. In addition, it is estimated that half of women with stable angina do not have obstructive coronary artery disease, but rather have microvascular angina that results from vasoconstriction of small coronary arterioles deep in the myocardium. Prinzmetal Angina: Prinzmetal angina (also called variant angina) is chest pain attributable to transient ischemia of the myocardium that occurs unpredictably and almost exclusively at rest. This form of angina often occurs at night during rapid eye movement sleep and may have a cyclic pattern of occurrence. Pain is caused by vasospasm of one or more major coronary arteries with or without associated atherosclerosis. The angina may result from decreased vagal activity, hyperactivity of the sympathetic nervous system, and decreased nitric oxide activity. Other causes include altered calcium channel function in arterial smooth muscle and endothelial dysfunction with release of inflammatory mediators, such as serotonin, histamine, endothelin, or thromboxane. 117 The level of hs-CRP may be elevated in individuals with this form of angina. Prinzmetal angina is usually a benign condition, but can occasionally cause serious dysrhythmias especially if treatment is withdrawn; therefore, calcium channel blockers or long acting nitrates, or both, should be continued even if clinical remission is achieved. If the spasm persists long enough, infarction or serious dysrhythmias may occur. Silent Ischemia and Mental Stress (Induced Ischemia): Myocardial ischemia does not always cause angina and may be associated only with nonspecific symptoms such as fatigue, dyspnea, or feeling of unease. Some individuals only have silent ischemia, whereas episodes of silent myocardial ischemia may occur in individuals who also experience angina. Global or regional abnormalities in left ventricular sympathetic afferent innervation have been implicated in diabetes mellitus, following surgical denervation during coronary artery bypass grafting (CABG) or cardiac transplantation, or following ischemic local nerve injury by MI. There also is evidence that individuals with silent ischemia produce less lactate than those with angina. Silent ischemia also may occur in some individuals during mental stress and anger. Mental stress results in the release of catecholamines and an increase in heart rate, blood pressure, and vascular resistance, as well as electrical instability. In addition, it has been linked to increased hs-CRP level, decreased activity of vasodilators such as nitric oxide, and a hypercoagulable state that may contribute to acute ischemic events. Acute Coronary Syndromes: When there is sudden coronary obstruction caused by thrombus formation over a ruptured or ulcerated atherosclerotic plaque, acute coronary syndromes result. The acute coronary syndromes (ACS) include unstable angina and myocardial infarction. Unstable angina is the result of reversible myocardial ischemia and is a harbinger of impending infarction. Myocardial infarction (MI) results when prolonged ischemia causes irreversible damage to the heart muscle. MI can be further subdivided into non–ST-elevation MI (nonSTEMI) and ST-elevation MI (STEMI) (see the Pathophysiology section). Sudden cardiac death can occur as a result of any of the acute coronary syndromes. Unstable angina: is a form of acute coronary syndrome that results in reversible myocardial ischemia. It is important to recognize this syndrome because it signals that the atherosclerotic plaque has ruptured, and infarction may soon follow. Unstable angina occurs when fissuring or superficial erosion of the plaque leads to transient episodes of thrombotic vessel occlusion and vasoconstriction at the site of plaque damage. This thrombus is labile and occludes the vessel for no more than 10 to 20 minutes, with return of perfusion before significant myocardial necrosis occurs. Unstable angina presents as new-onset angina, angina that is occurring at rest, or angina that is increasing in severity or frequency. Individuals may experience increased dyspnea, diaphoresis, and anxiety as the angina worsens. Myocardial Infarction: When coronary blood flow is interrupted for an extended period, myocyte necrosis occurs. This results in MI. Pathologically there are two major types of MI: subendocardial infarction and transmural infarction. Clinically, however, MI is categorized as STEMI or nonSTEMI. Plaque progression, disruption, and subsequent clot formation are the same for myocardial infarction as they are for unstable angina. In this case, however, the thrombus is less labile and occludes the vessel for a prolonged period, such that myocardial ischemia progresses to myocyte necrosis and death. The duration of ischemia determines the size and character of the infarction. If the thrombus breaks up before complete distal tissue necrosis has occurred, the infarction will involve only the myocardium directly beneath the endocardium (subendocardial MI). This infarction usually presents with ST depression and T-wave inversion and is termed non-STEMI. It is especially important to recognize this form of acute coronary syndrome because recurrent clot formation on the disrupted atherosclerotic plaque is likely to occur unless some intervention is undertaken as soon as possible. If the thrombus lodges permanently in the vessel, the infarction will extend through the myocardium all the way from endocardium to epicardium (transmural MI), resulting in severe cardiac dysfunction. Transmural infarction usually causes marked elevations in the ST segments on ECG, called STEMI. Functional changes can include (1) decreased cardiac contractility with abnormal wall motion, (2) altered left ventricular compliance, (3) decreased stroke volume, (4) decreased ejection fraction, (5) increased left ventricular end-diastolic pressure and volume, and (6) sinoatrial node malfunction. Life-threatening dysrhythmias and heart failure often follow myocardial infarction. The first symptom of acute MI is usually sudden, severe, chest pain. It may be described as