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InternalMed_Harrison. While restoring renal blood flow and perfusion seems intuitively beneficial for high-grade occlusive lesions, revascularization procedures also pose hazards and expense. Patients with FMD are commonly younger females with otherwise normal vessels and a Perfusion Studies to Assess Differential Renal Blood Flow Shows the renal arteries and measures flow velocity as a means of assessing the severity of stenosis Shows the renal arteries and perirenal aorta Shows the renal arteries and perirenal aorta Shows location and severity of vascular lesion Inexpensive; widely available Not nephrotoxic, but concerns for gadolinium toxicity exclude use in GFR <30 mL/min/1.73 m2; provides excellent images


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InternalMed_Harrison. Shows location and severity of vascular lesion Inexpensive; widely available Not nephrotoxic, but concerns for gadolinium toxicity exclude use in GFR <30 mL/min/1.73 m2; provides excellent images Considered “gold standard” for diagnosis of large-vessel disease, usually performed simultaneous with planned intervention Heavily dependent on operator’s experience; less useful than invasive angiography for the diagnosis of fibromuscular dysplasia and abnormalities in accessory renal arteries Expensive; gadolinium excluded in renal failure, unable to visualize stented vessels Expensive, moderate volume of contrast required, potentially nephrotoxic Expensive, associated hazard of atheroemboli, contrast toxicity, procedure-related complications, e.g., dissection Abbreviation: GFR, glomerular filtration rate.


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InternalMed_Harrison. Abbreviation: GFR, glomerular filtration rate. long life expectancy. These patients often respond well to percutaneous renal artery angioplasty. If BP can be controlled to goal levels and kidney function remains stable in patients with ARAS, it may be argued that medical therapy with follow-up for disease progression is equally effective. Prospective trials up to now have failed to identify compelling benefits for interventional procedures regarding short-term results of BP and renal function, and long-term studies regarding cardiovascular outcomes, such as stroke, congestive heart failure, myocardial infarction, and end-stage renal failure, are not yet complete. Medical therapy should include blockade of the renin-angiotensin system, attainment of goal BPs, cessation of tobacco, statins, and aspirin. Renal revascularization is now often reserved for patients failing medical therapy or developing additional complications.


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InternalMed_Harrison. Techniques of renal revascularization are improving. With experienced operators, major complications occur in about 9% of cases, including renal artery dissection, capsular perforation, hemorrhage, and occasional atheroembolic disease. Although not common, atheroembolic disease can be catastrophic and accelerate both hypertension and kidney failure, precisely the events that revascularization is intended to prevent. Although renal blood flow usually can be restored by endovascular stenting, recovery of renal function is limited to about 25% of cases, with no change in 50% and some deterioration evident in others. Patients with rapid loss of kidney function, sometimes associated with antihypertensive drug therapy, or with vascular disease affecting the entire functioning kidney mass are more likely to recover function after restoring blood flow. When hypertension is refractory to effective therapy, revascularization offers real benefits. Table 299-2 summarizes currently accepted


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InternalMed_Harrison. are more likely to recover function after restoring blood flow. When hypertension is refractory to effective therapy, revascularization offers real benefits. Table 299-2 summarizes currently accepted guidelines for considering renal revascularization.


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InternalMed_Harrison. Emboli to the kidneys arise most frequently as a result of cholesterol crystals breaking free of atherosclerotic vascular plaque and lodging in downstream microvessels. Most clinical atheroembolic events follow angiographic procedures, often of the coronary vessels. It has been argued that nearly all vascular interventional procedures lead to plaque fracture and release of microemboli, but clinical manifestations develop only in a fraction of these. The incidence of clinical atheroemboli has been increasing with more vascular procedures and decline in GFR during treatment of systemic hypertension to achieve adequate blood pressure control with optimal medical • Rapid or recurrent decline in the GFR in association with a reduction in in the GFR during therapy with ACE inhibitors or ARBs congestive heart failure in a patient in whom the adequacy of


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InternalMed_Harrison. Factors Favoring Medical Therapy and Surveillance of Renal Artery Disease • Controlled blood pressure with stable renal function (e.g., stable renal (e.g., serial duplex ultrasound) risk for or previous experience with atheroembolic disease renal dysfunction (e.g., interstitial nephritis, diabetic nephropathy) Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; GFR, glomerular filtration rate.


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InternalMed_Harrison. Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; GFR, glomerular filtration rate. longer life spans. Atheroembolic renal disease is suspected in more 1629 than 3% of elderly subjects with end-stage renal disease (ESRD) and is likely underdiagnosed. It is more frequent in males with a history of diabetes, hypertension, and ischemic cardiac disease. Atheroemboli in the kidney are strongly associated with aortic aneurysmal disease and renal artery stenosis. Most clinical cases can be linked to precipitating events, such as angiography, vascular surgery, anticoagulation with heparin, thrombolytic therapy, or trauma. Clinical manifestations of this syndrome commonly develop between 1 and 14 days after an inciting event and may continue to develop for weeks thereafter.


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InternalMed_Harrison. Systemic embolic disease manifestations, such as fever, abdominal pain, and weight loss, are present in less than half of patients, although cutaneous manifestations including livedo reticularis and localized toe gangrene may be more common. Worsening hypertension and deteriorating kidney function are common, sometimes reaching a malignant phase. Progressive renal failure can occur and require dialytic support. These cases often develop after a stuttering onset over many weeks and have an ominous prognosis. Mortality rate after 1 year reaches 38%, and although some may eventually recover sufficiently to no longer require dialysis, many do not.


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InternalMed_Harrison. Beyond the clinical manifestations above, laboratory findings include rising creatinine, transient eosinophilia (60–80%), elevated sedimentation rate, and hypocomplementemia (15%). Establishing this diagnosis can be difficult and is often by exclusion. Definitive diagnosis depends on kidney biopsy demonstrating microvessel occlusion with cholesterol crystals that leave a “cleft” in the vessel. Biopsies obtained from patients undergoing surgical revascularization of the kidney indicate that silent cholesterol emboli are frequently present before any further manipulation is performed.


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InternalMed_Harrison. No effective therapy is available for atheroembolic disease once it has developed. Withdrawal of anticoagulation is recommended. Late recovery of kidney function after supportive measures sometimes occurs, and statin therapy may improve outcome. The role of embolic protection devices in the renal circulation is unclear, but a few prospective trials have failed to demonstrate major benefits. These devices are limited to distal protection during the endovascular procedure and offer no protection from embolic debris after removal.


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InternalMed_Harrison. Thrombotic occlusion of renal vessels or branch arteries can lead to declining renal function and hypertension. It is difficult to diagnose and is often overlooked, especially in elderly patients. Thrombosis can develop as a result of local vessel abnormalities, such as local dissection, trauma, or inflammatory vasculitis. Local microdissections sometimes lead to patchy, transient areas of infarctions labeled “segmental arteriolar mediolysis.” Although hypercoagulability conditions sometimes present as renal artery thrombosis, this is rare. It can also derive from distant embolic events, e.g., the left atrium in patients with atrial fibrillation or from fat emboli originating from traumatized tissue, most commonly large bone fractures. Cardiac sources include vegetations from subacute bacterial endocarditis. Systemic emboli to the kidneys may also arise from the venous circulation if right-to-left shunting occurs, e.g., through a patent foramen ovale.


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InternalMed_Harrison. Clinical manifestations vary depending on the rapidity of onset and extent of occlusion. Acute arterial thrombosis may produce flank pain, fever, leukocytosis, nausea, and vomiting. If kidney infarction results, enzymes such as lactate dehydrogenase (LDH) rise to extreme levels. If both kidneys are affected, renal function will decline precipitously with a drop in urine output. If a single kidney is involved, renal functional changes may be minor. Hypertension related to sudden release of renin from ischemic tissue can develop rapidly, as long as some viable tissue in the “peri-infarct” border zone remains. If the infarct zone demarcates precisely, the rise in BP and renin activity may resolve. Diagnosis of renal infarction may be established by vascular imaging with MRI, CT angiography, or arteriography (Fig. 299-2). Options for interventions of newly detected arterial occlusion include surgical reconstruction, anticoagulation, thrombolytic therapy,


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InternalMed_Harrison. Options for interventions of newly detected arterial occlusion include surgical reconstruction, anticoagulation, thrombolytic therapy, FIGURE 299-2 A. CT angiogram illustrating loss of circulation to the upper pole of the right kidney in a patient with fibromuscular disease and a renal artery aneurysm. Activation of the renin-angiotensin system produced rapidly developing hypertension. B. Angiogram illustrating high-grade renal artery stenosis affecting the left kidney. This lesion is often part of widespread atherosclerosis and sometimes is an extension of aortic plaque. This lesion develops in older individuals with preexisting atherosclerotic risk factors.


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InternalMed_Harrison. endovascular procedures, and supportive care, particularly antihyper-injury including microangiopathic hemolysis and renal dysfunction tensive drug therapy. Application of these methods depends on the can improve over time. Whereas series reported before the era of drug patient’s overall condition, the precipitating factors (e.g., local trauma therapy suggested that 1-year mortality rates exceeded 90%, current or systemic illness), the magnitude of renal tissue and function at risk, survival over 5 years exceeds 50%. and the likelihood of recurrent events in the future. For unilateral Malignant hypertension is less common in Western countries, disease, e.g., arterial dissection with thrombosis, supportive care with although it persists in parts of the world where medical care and antihyanticoagulation may suffice. Acute, bilateral occlusion is potentially pertensive drug therapy are less available. It most commonly develops catastrophic, producing anuric renal failure. Depending on


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InternalMed_Harrison. may suffice. Acute, bilateral occlusion is potentially pertensive drug therapy are less available. It most commonly develops catastrophic, producing anuric renal failure. Depending on the pre-in patients with treated hypertension who neglect to take medications cipitating event, surgical or thrombolytic therapies can sometimes or who may use vasospastic drugs, such as cocaine. Renal abnormalities restore kidney viability. typically include rising serum creatinine and occasionally hematuria and proteinuria. Biochemical findings may include evidence of hemo-MICROVASCULAR INJURY ASSOCIATED WITH HYPERTENSION lysis (anemia, schistocytes, and reticulocytosis) and changes associated with kidney failure. African-American males are more likely to develop rapidly progressive hypertension and kidney failure than are whites in“Malignant” Hypertension Although BP rises with age, it has long been the United States. Genetic polymorphisms (first identified as MYH9,recognized that some individuals


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InternalMed_Harrison. failure than are whites in“Malignant” Hypertension Although BP rises with age, it has long been the United States. Genetic polymorphisms (first identified as MYH9,recognized that some individuals develop rapidly progressive BP elevabut now thought to be APOL1) that are common in the Africantions with target organ injury including retinal hemorrhages, encepha-American population predispose to subtle focal sclerosing glomerularlopathy, and declining kidney function. Placebo arms during the disease, with severe hypertension developing at younger ages second-controlled trials of hypertension therapy identified progression to ary to renal disease in this instance.


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InternalMed_Harrison. severe levels in 20% of subjects over 5 years. If untreated, patients with target organ injury including papilledema and declining kidney “Hypertensive Nephrosclerosis” Based on experience with malignant function suffered mortality rates in excess of 50% over 6–12 months, hypertension and epidemiologic evidence linking BP with long-term hence the designation “malignant.” Postmortem studies of such risks of kidney failure, it has long been assumed that lesser degrees of patients identified vascular lesions, designated “fibrinoid necrosis,” hypertension induce less severe, but prevalent, changes in kidney veswith breakdown of the vessel wall, deposition of eosinophilic mate-sels and loss of kidney function. As a result, a large portion of patients rial including fibrin, and a perivascular cellular infiltrate. A separate reaching ESRD without a specific etiologic diagnosis are assigned the lesion was identified in the larger interlobular arteries in many patients designation


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InternalMed_Harrison. cellular infiltrate. A separate reaching ESRD without a specific etiologic diagnosis are assigned the lesion was identified in the larger interlobular arteries in many patients designation “hypertensive nephrosclerosis.” Pathologic examination with hyperplastic proliferation of the vascular wall cellular elements, commonly identifies afferent arteriolar thickening with deposition of deposition of collagen, and separation of layers, designated the homogeneous eosinophilic material (hyaline arteriolosclerosis) associ“onionskin” lesion. For many of these patients, fibrinoid necrosis led ated with narrowing of vascular lumina. Clinical manifestations include to obliteration of glomeruli and loss of tubular structures. Progressive retinal vessel changes associated with hypertension (arteriolar narkidney failure ensued and, without dialysis support, led to early rowing, crossing changes), left ventricular hypertrophy, and elevated mortality in untreated malignant-phase hypertension. These


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InternalMed_Harrison. narkidney failure ensued and, without dialysis support, led to early rowing, crossing changes), left ventricular hypertrophy, and elevated mortality in untreated malignant-phase hypertension. These vascular BP. The role of these vascular changes in kidney function is unclear. changes could develop with pressure-related injury from a variety Postmortem and biopsy samples from normotensive kidney donors of hypertensive pathways, including but not limited to activation of demonstrate similar vessel changes associated with aging, dyslipidemia, the renin-angiotensin system and severe vasospasm associated with and glucose intolerance. Although BP reduction does slow progression catecholamine release. Occasionally, endothelial injury is sufficient to of proteinuric kidney diseases and is warranted to reduce the excessive induce microangiopathic hemolysis, as discussed below. cardiovascular risks associated with CKD, antihypertensive therapy


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InternalMed_Harrison. Antihypertensive therapy is the mainstay of therapy for malignant does not alter the course of kidney dysfunction identified specifically as hypertension. With effective BP reduction, manifestations of vascular hypertensive nephrosclerosis. Deep venous Thrombosis and Pulmonary Thromboembolism Samuel Z. Goldhaber EPIDEMIOLOGY Venous thromboembolism (VTE) encompasses deep venous throm-300 FIGURE 300-1 Skin ulceration in the lateral malleolus from post-thrombotic syndrome of the leg.


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InternalMed_Harrison. FIGURE 300-1 Skin ulceration in the lateral malleolus from post-thrombotic syndrome of the leg. bosis (DVT) and pulmonary embolism (PE) and causes cardiovascular death and disability. In the United States, the Surgeon General estimates there are 100,000 to 180,000 deaths annually from PE and has declared that PE is the most common preventable cause of death among hospitalized patients. Survivors may succumb to the disabilities of chronic thromboembolic pulmonary hypertension or postthrombotic syndrome. Chronic thromboembolic pulmonary hypertension causes breathlessness, especially with exertion. Postthrombotic syndrome (also known as chronic venous insufficiency) damages the venous valves of the leg and causes ankle or calf swelling and leg aching, especially after prolonged standing. In its most severe form, postthrombotic syndrome causes skin ulceration (Fig. 300-1).


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InternalMed_Harrison. PATHOPHYSIOLOGY Inflammation and Platelet Activation Virchow’s triad of inflammation, hypercoagulability, and endothelial injury leads to recruitment of activated platelets, which release microparticles. These microparticles contain proinflammatory mediators that bind neutrophils, stimulating them to release their nuclear material and form web-like extracellular networks called neutrophil extracellular traps. These prothrombotic networks contain histones that stimulate platelet aggregation and promote platelet-dependent thrombin generation. Venous thrombi form and flourish in an environment of stasis, low oxygen tension, and upregulation of proinflammatory genes. Prothrombotic States The two most common autosomal dominant genetic mutations are factor V Leiden, which causes resistance to the FIGURE 300-2 Deep venous thrombosis at autopsy.


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InternalMed_Harrison. FIGURE 300-2 Deep venous thrombosis at autopsy. endogenous anticoagulant, activated protein C (which inactivates clotting factors V and VIII), and the prothrombin gene mutation, which increases the plasma prothrombin concentration (Chaps. 78 and 142). Antithrombin, protein C, and protein S are naturally occurring coagulation inhibitors. Deficiencies of these inhibitors are associated with VTE but are rare. Antiphospholipid antibody syndrome is the most common acquired cause of thrombophilia and is associated with venous or arterial thrombosis. Other common predisposing factors include cancer, obesity, cigarette smoking, systemic arterial hypertension, chronic obstructive pulmonary disease, chronic kidney disease, blood transfusion, long-haul air travel, air pollution, oral contraceptives, pregnancy, postmenopausal hormone replacement, surgery, and trauma.


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InternalMed_Harrison. Embolization When deep venous thrombi (Fig. 300-2) detach from their site of formation, they embolize to the vena cava, right atrium, and right ventricle, and lodge in the pulmonary arterial circulation, thereby causing acute PE. Paradoxically, these thrombi occasionally embolize to the arterial circulation through a patent foramen ovale or atrial septal defect. Many patients with PE have no evidence of DVT because the clot has already embolized to the lungs. Physiology The most common gas exchange abnormalities are arterial hypoxemia and an increased alveolar-arterial O2 tension gradient, which represents the inefficiency of O2 transfer across the lungs. Anatomic dead space increases because breathed gas does not enter gas exchange units of the lung. Physiologic dead space increases because ventilation to gas exchange units exceeds venous blood flow through the pulmonary capillaries. Other pathophysiologic abnormalities include: 1.


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InternalMed_Harrison. Other pathophysiologic abnormalities include: 1. Increased pulmonary vascular resistance due to vascular obstruction or platelet secretion of vasoconstricting neurohumoral agents such as serotonin. Release of vasoactive mediators can produce ventilation-perfusion mismatching at sites remote from the embolus, thereby accounting for discordance between a small PE and a large alveolar-arterial O2 gradient. 2. Impaired gas exchange due to increased alveolar dead space from vascular obstruction, hypoxemia from alveolar hypoventilation relative to perfusion in the nonobstructed lung, right-to-left shunting, or impaired carbon monoxide transfer due to loss of gas exchange surface. 3. Alveolar hyperventilation due to reflex stimulation of irritant receptors. 4. Increased airway resistance due to constriction of airways distal to the bronchi. 5. Decreased pulmonary compliance due to lung edema, lung hemorrhage, or loss of surfactant.


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InternalMed_Harrison. 5. Decreased pulmonary compliance due to lung edema, lung hemorrhage, or loss of surfactant. Pulmonary Hypertension, Right Ventricular (RV) Dysfunction, and RV Microinfarction Pulmonary artery obstruction causes a rise in pulmonary 1632 artery pressure and in pulmonary vascular resistance. When RV wall tension rises, RV dilation and dysfunction ensue, with release of the cardiac biomarker, brain natriuretic peptide. The interventricular septum bulges into and compresses an intrinsically normal left ventricle (LV). Diastolic LV dysfunction reduces LV distensibility and impairs LV filling. Increased RV wall tension also compresses the right coronary artery, limits myocardial oxygen supply, and precipitates right coronary artery ischemia and RV microinfarction, with release of cardiac biomarkers such as troponin. Underfilling of the LV may lead to a fall in LV cardiac output and systemic arterial pressure, with consequent circulatory collapse and death.


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InternalMed_Harrison. CLASSIFICATION OF PULMONARY EMBOLISM AND DEEP VENOUS THROMBOSIS Pulmonary Embolism Massive PE accounts for 5–10% of cases, and is characterized by extensive thrombosis affecting at least half of the pulmonary vasculature. Dyspnea, syncope, hypotension, and cyanosis are hallmarks of massive PE. Patients with massive PE may present in cardiogenic shock and can die from multisystem organ failure. Submassive PE accounts for 20–25% of patients, and is characterized by RV dysfunction despite normal systemic arterial pressure. The combination of right heart failure and release of cardiac biomarkers indicates an increased likelihood of clinical deterioration. Low-risk PE constitutes about 70–75% of cases. These patients have an excellent prognosis.


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InternalMed_Harrison. Deep Venous Thrombosis Lower extremity DVT usually begins in the calf and propagates proximally to the popliteal vein, femoral vein, and iliac veins. Leg DVT is about 10 times more common than upper extremity DVT, which is often precipitated by placement of pacemakers, internal cardiac defibrillators, or indwelling central venous catheters. The likelihood of upper extremity DVT increases as the catheter diameter and number of lumens increase. Superficial venous thrombosis usually presents with erythema, tenderness, and a “palpable cord.” Patients are at risk for extension of the thrombosis to the deep venous system.


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InternalMed_Harrison. Clinical Evaluation PE is known as “the Great Masquerader.” Diagnosis is difficult because symptoms and signs are nonspecific. The most common symptom is unexplained breathlessness. When occult PE occurs concomitantly with overt congestive heart failure or pneumo nia, clinical improvement often fails to occur despite standard medical treatment of the concomitant illness. This scenario presents a clinical clue to the possible coexistence of PE. With DVT, the most common symptom is a cramp or “charley horse” in the lower calf that persists and intensifies over several days. Point score criteria help estimate the clinical likelihood of DVT and PE (Table 300-1). Patients with a low-to-moderate likelihood of DVT or PE should undergo initial diagnostic evaluation with d-dimer testing alone (see “Blood Tests”) without obligatory imaging tests (Fig. 300-3).


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InternalMed_Harrison. PE should undergo initial diagnostic evaluation with d-dimer testing alone (see “Blood Tests”) without obligatory imaging tests (Fig. 300-3). However, patients with a high clinical likelihood of VTE should skip d-dimer testing and undergo imaging as the next step in the diagnostic algorithm. Clinical Pearls Not all leg pain is due to DVT, and not all dyspnea is due to PE (Table 300-2). Sudden, severe calf discomfort suggests a ruptured Baker’s cyst. Fever and chills usually herald cellulitis rather than DVT. Physical findings, if present, may consist only of mild palpation discomfort in the lower calf. However, massive DVT often presents with marked thigh swelling, tenderness, and erythema. If the leg is diffusely edematous, DVT is unlikely. More probable is an acute exacerbation of venous insufficiency due to postthrombotic syndrome. Upper extremity venous thrombosis may present with asymmetry in the supraclavicular fossa or in the circumference of the upper arms.


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InternalMed_Harrison. Pulmonary infarction usually indicates a small PE. This condition is exquisitely painful because the thrombus lodges peripherally, near the innervation of pleural nerves. Nonthrombotic PE etiologies include fat embolism after pelvic or long bone fracture, tumor embolism, bone marrow, and air embolism. Cement embolism and bony fragment embolism Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate Likelihood if Score Is 1 to 2; High Likelihood if Score Is 3 or Greater can occur after total hip or knee replacement. Intravenous drug users may inject themselves with a wide array of substances that can embolize such as hair, talc, and cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin.


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InternalMed_Harrison. Nonimaging Diagnostic Modalities • Blood tEsts The quantitative plasma d-dimer enzyme-linked immunosorbent assay (ELISA) rises in the presence of DVT or PE because of the breakdown of fibrin by plasmin. Elevation of d-dimer indicates endogenous although often clinically ineffective thrombolysis. The sensitivity of the d-dimer is >80% for DVT (including isolated calf DVT) and >95% for PE. The d-dimer is less sensitive for DVT than for PE because the DVT thrombus size is smaller. A normal d-dimer is a useful “rule out” test. However, the d-dimer assay is not specific. Levels increase in patients with myocardial infarction, pneumonia, sepsis, cancer, and the postoperative state and those in the second or third trimester of pregnancy. Therefore, d-dimer rarely has a useful role among hospitalized patients, because levels are frequently elevated due to systemic illness.


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InternalMed_Harrison. FIGURE 300-3 How to decide whether diagnostic imaging is needed. For assessment of clinical likelihood, see Table 300-1. Pneumonia, asthma, chronic obstructive pulmonary disease Pleurisy: “viral syndrome,” costochondritis, musculoskeletal discomfort Rib fracture, pneumothorax ElEvatEd cardiac BiomarkErs Serum troponin and plasma heart-type fatty acid–binding protein levels increase because of RV microinfarction. Myocardial stretch causes release of brain natriuretic peptide or NT-pro-brain natriuretic peptide. ElEctrocardiogram The most frequently cited abnormality, in addition to sinus tachycardia, is the S1Q3T3 sign: an S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III (Chap. 268). This finding is relatively specific but insensitive. RV strain and ischemia cause the most common abnormality, T-wave inversion in leads V1 to V4.


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InternalMed_Harrison. Noninvasive Imaging Modalities • vEnous ultrasonography Ultrasonography of the deep venous system relies on loss of vein compressibility as the primary criterion for DVT. When a normal vein is imaged in cross-section, it readily collapses with gentle manual pressure from the ultrasound transducer. This creates the illusion of a “wink.” With acute DVT, the vein loses its compressibility because of passive distention by acute thrombus. The diagnosis of acute DVT is even more secure when thrombus is directly visualized. It appears homogeneous and has low echogenicity (Fig. 300-4). The vein itself often appears mildly dilated, and collateral channels may be absent.


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InternalMed_Harrison. Venous flow dynamics can be examined with Doppler imaging. Normally, manual calf compression causes augmentation of the Doppler flow pattern. Loss of normal respiratory variation is caused by an obstructing DVT or by any obstructive process within the pelvis. For patients with a technically poor or nondiagnostic venous ultrasound, one should consider alternative imaging modalities for DVT, such as computed tomography (CT) and magnetic resonance imaging. FIGURE 300-4 Venous ultrasound, with and without compression of the leg veins. CFA, common femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left.


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InternalMed_Harrison. FIGURE 300-4 Venous ultrasound, with and without compression of the leg veins. CFA, common femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left. FIGURE 300-5 Large bilateral proximal PE on a coronal chest CT image in a 54-year-old man with lung cancer and brain metastases. He had developed sudden onset of chest heaviness and shortness of breath while at home. There are filling defects in the main and segmental pulmonary arteries bilaterally (white arrows). Only the left upper lobe segmental artery is free of thrombus. chEst roEntgEnography A normal or nearly normal chest x-ray often occurs in PE. Well-established abnormalities include focal oligemia (Westermark’s sign), a peripheral wedged-shaped density above the diaphragm (Hampton’s hump), and an enlarged right descending pulmonary artery (Palla’s sign).


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InternalMed_Harrison. chEst ct CT of the chest with intravenous contrast is the principal imaging test for the diagnosis of PE (Fig. 300-5). Multidetector-row spiral CT acquires all chest images with ≤1 mm of resolution during a short breath hold. Sixth-order branches can be visualized with resolution superior to that of conventional invasive contrast pulmonary angiography. The CT scan also provides an excellent four-chamber view of the heart. RV enlargement on chest CT indicates an increased likelihood of death within the next 30 days compared with PE patients who have normal RV size. When imaging is continued below the chest to the knee, pelvic and proximal leg DVT also can be diagnosed by CT scanning. In patients without PE, the lung parenchymal images may establish alternative diagnoses not apparent on chest x-ray that explain the presenting symptoms and signs such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, and aortic pathology. Sometimes asymptomatic early-stage lung cancer is


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InternalMed_Harrison. on chest x-ray that explain the presenting symptoms and signs such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, and aortic pathology. Sometimes asymptomatic early-stage lung cancer is diagnosed incidentally.


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InternalMed_Harrison. lung scanning Lung scanning has become a second-line diagnostic test for PE, used mostly for patients who cannot tolerate intravenous contrast. Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected intravenously and are trapped in the pulmonary capillary bed. The perfusion scan defect indicates absent or decreased blood flow, possibly due to PE. Ventilation scans, obtained with a radiolabeled inhaled gas such as xenon or krypton, improve the specificity of the perfusion scan. Abnormal ventilation scans indicate abnormal nonventilated lung, thereby providing possible explanations for perfusion defects other than acute PE, such as asthma and chronic obstructive pulmonary disease. A high-probability scan for PE is defined as two or more segmental perfusion defects in the presence of normal ventilation.


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InternalMed_Harrison. The diagnosis of PE is very unlikely in patients with normal and nearly normal scans and is about 90% certain in patients with high-probability scans. Unfortunately, most 1634 patients have nondiagnostic scans, and fewer than one-half of patients with angiographically confirmed PE have a high probability scan. As many as 40% of patients with high clinical suspicion for PE but “lowprobability” scans do, in fact, have PE at angiography. magnEtic rEsonancE (mr) (contrast-EnhancEd) imaging When ultrasound is equivocal, MR venography with gadolinium contrast is an excellent imaging modality to diagnose DVT. MR pulmonary angiography may detect large proximal PE but is not reliable for smaller segmental and subsegmental PE.


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InternalMed_Harrison. Echocardiography Echocardiography is not a reliable diagnostic imaging tool for acute PE because most patients with PE have normal echocardiograms. However, echocardiography is a very useful diagnostic tool for detecting conditions that may mimic PE, such as acute myocardial infarction, pericardial tamponade, and aortic dissection. Transthoracic echocardiography rarely images thrombus directly. The best-known indirect sign of PE on transthoracic echocardiography is McConnell’s sign: hypokinesis of the RV free wall with normal or hyperkinetic motion of the RV apex. One should consider trans-esophageal echocardiography when CT scanning facilities are not available or when a patient has renal failure or severe contrast allergy that precludes administration of contrast despite premedication with high-dose steroids. This imaging modality can identify saddle, right main, or left main PE.


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InternalMed_Harrison. Invasive Diagnostic Modalities • pulmonary angiography Chest CT with contrast (see above) has virtually replaced invasive pulmonary angiography as a diagnostic test. Invasive catheter-based diagnostic testing is reserved for patients with technically unsatisfactory chest CTs and for those in whom an interventional procedure such as catheter-directed thrombolysis is planned. A definitive diagnosis of PE depends on visualization of an intraluminal filling defect in more than one projection. Secondary signs of PE include abrupt occlusion (“cutoff”) of vessels, segmental oligemia or avascularity, a prolonged arterial phase with slow filling, and tortuous, tapering peripheral vessels. contrast phlEBography Venous ultrasonography has virtually replaced contrast phlebography as the diagnostic test for suspected DVT. Integrated Diagnostic Approach An integrated diagnostic approach (Fig. 300-3) streamlines the workup of suspected DVT and PE (Fig. 300-6).


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InternalMed_Harrison. Integrated Diagnostic Approach An integrated diagnostic approach (Fig. 300-3) streamlines the workup of suspected DVT and PE (Fig. 300-6). Primary therapy consists of clot dissolution with pharmacomechanical therapy that usually includes low-dose catheter-directed thrombolysis. This approach is reserved for patients with extensive femoral, iliofemoral, or upper extremity DVT. The open vein hypothesis postulates that patients who receive primary therapy will sustain less long-term damage to venous valves, with consequent lower rates of postthrombotic syndrome. A National Heart, Lung, and Blood Institute–sponsored randomized controlled trial called ATTRACT (NCT00790335) is testing this hypothesis.


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InternalMed_Harrison. Anticoagulation or placement of an inferior vena caval filter constitutes secondary prevention of VTE. To lessen the severity of post-thrombotic syndrome of the legs, below-knee graduated compression stockings may be prescribed, 30–40 mmHg, for 2 years after the DVT episode. They should be replaced every 3 months because they lose their elasticity. Hemodynamic instability, RV dysfunction on echocardiography, RV enlargement on chest CT, or elevation of the troponin level Diagnostic Nondiagnostic, unavailable, or unsafe FIGURE 300-6 Imaging tests to diagnose DVT and PE. ECHO, echocardiography. due to RV microinfarction portend a high risk of an adverse clinical outcome. When RV function remains normal in a hemodynamically stable patient, a good clinical outcome is highly likely with anticoagulation alone (Fig. 300-7). Effective anticoagulation is the foundation for successful treatment of DVT and PE. There are three options: (1) the conventional strategy


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InternalMed_Harrison. Effective anticoagulation is the foundation for successful treatment of DVT and PE. There are three options: (1) the conventional strategy Risk stratify Normotension plus normal RV Normotension plus RV hypokinesis Hypotension Anticoagulation plus thrombolysis IVC filter Embolectomy: catheter/surgical Anticoagulation alone Secondary prevention Individualize therapy Primary therapy FIGURE 300-7 Acute management of pulmonary thromboembo-lism. RV, right ventricular; IVC, inferior vena cava. Unfractionated heparin, bolus and continuous infusion, to achieve aPTT 2–3 times the upper limit of the laboratory normal, or Enoxaparin 1 mg/kg twice daily with normal renal function, or Dalteparin 200 U/kg once daily or 100 U/kg twice daily, with normal renal function, or


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InternalMed_Harrison. Enoxaparin 1 mg/kg twice daily with normal renal function, or Dalteparin 200 U/kg once daily or 100 U/kg twice daily, with normal renal function, or Tinzaparin 175 U/kg once daily with normal renal function, or Fondaparinux weight-based once daily; adjust for impaired renal function Direct thrombin inhibitors: argatroban or bivalirudin Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily with the dinner meal thereafter Apixaban (not yet licensed)


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InternalMed_Harrison. Requires 5–10 days of administration to achieve effectiveness as monotherapy (Unfractionated heparin, low-molecular-weight heparin, and fondaparinux are the usual immediately effective “bridging agents” used when initiating warfarin) Usual start dose is 5 mg Titrate to INR, target 2.0–3.0 Continue parenteral anticoagulation for a minimum of 5 days and until two sequential INR values, at least 1 day apart, achieve the target INR range of parenteral therapy “bridged” to warfarin, (2) parenteral therapy “bridged” to a novel oral anticoagulant such as dabigatran (a direct thrombin inhibitor) or edoxaban (an anti-Xa agent), or (3) oral anticoagulation with rivaroxaban or apixaban (both are anti-Xa agents) with a loading dose followed by a maintenance dose as monotherapy without parenteral anticoagulation.


InternalMed_Harrison

InternalMed_Harrison. The three heparin-based parenteral anticoagulants are (1) unfractionated heparin (UFH), (2) low-molecular-weight heparin (LMWH), and (3) fondaparinux. For patients with suspected or proven heparin-induced thrombocytopenia, there are two parenteral direct thrombin inhibitors: argatroban and bivalirudin (Table 300-3). Unfractionated Heparin UFH anticoagulates by binding to and accelerating the activity of antithrombin, thus preventing additional thrombus formation. UFH is dosed to achieve a target activated partial thromboplastin time (aPTT) of 60–80 s. The most popular nomogram uses an initial bolus of 80 U/kg, followed by an initial infusion rate of 18 U/kg per h. The major advantage of UFH is its short half-life, which is especially useful in patients in whom hour-to-hour control of the intensity of anticoagulation is desired.


InternalMed_Harrison

InternalMed_Harrison. The major advantage of UFH is its short half-life, which is especially useful in patients in whom hour-to-hour control of the intensity of anticoagulation is desired. Low-Molecular-Weight Heparins These fragments of UFH exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than does UFH. No monitoring or dose adjustment is needed unless the patient is markedly obese or has chronic kidney disease. Fondaparinux Fondaparinux, an anti-Xa pentasaccharide, is administered as a weight-based once-daily subcutaneous injection in a prefilled syringe. No laboratory monitoring is required. Fondaparinux is synthesized in a laboratory and, unlike LMWH or UFH, is not derived from animal products. It does not cause heparin-induced thrombocytopenia. The dose must be adjusted downward for patients with renal dysfunction.


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InternalMed_Harrison. Warfarin This vitamin K antagonist prevents carboxylation activation of coagulation factors II, VII, IX, and X. The full effect of warfarin requires at least 5 days, even if the prothrombin time, used for monitoring, becomes elevated more rapidly. If warfarin 1635 is initiated as monotherapy during an acute thrombotic illness, a paradoxical exacerbation of hypercoagulability increases the likelihood of thrombosis. Overlapping UFH, LMWH, fondaparinux, or parenteral direct thrombin inhibitors with warfarin for at least 5 days will nullify the early procoagulant effect of warfarin. warfarin dosing In an average-size adult, warfarin is often initiated in a dose of 5 mg. The prothrombin time is standardized by calculating the international normalized ratio (INR), which assesses the anticoagulant effect of warfarin (Chap. 78). The target INR is usually 2.5, with a range of 2.0–3.0.


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InternalMed_Harrison. The warfarin dose is usually titrated empirically to achieve the target INR. Proper dosing is difficult because hundreds of drug-drug and drug-food interactions affect warfarin metabolism. Increasing age and systemic illness reduce the required warfarin dose. Pharmacogenomics may provide more precise initial dosing of warfarin. CYP2C9 variant alleles impair the hydroxylation of S-warfarin, thereby lowering the dose requirement. Variants in the gene encoding the vitamin K epoxide reductase complex 1 (VKORC1) can predict whether patients require low, moderate, or high warfarin doses. Centralized anticoagulation clinics have improved the efficacy and safety of warfarin dosing. Patients can self-monitor their INR with a home point-of-care fingerstick machine and can occasionally be taught to self-dose their warfarin.


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InternalMed_Harrison. Novel Oral Anticoagulants Novel oral anticoagulants are administered in a fixed dose, establish effective anticoagulation within hours of ingestion, require no laboratory coagulation monitoring, and have few of the drug-drug or drug-food interactions that make warfarin so difficult to dose. Rivaroxaban, a factor Xa inhibitor, is approved for treatment of acute DVT and acute PE as monotherapy, without a parenteral “bridging” anticoagulant. Apixaban is likely to receive similar approval for oral monotherapy. Dabigatran, a direct thrombin inhibitor, and edoxaban, a factor Xa inhibitor, are likely to be approved for treatment of VTE after an initial course of parenteral anticoagulation.


InternalMed_Harrison

InternalMed_Harrison. Complications of Anticoagulants The most serious adverse effect of anticoagulation is hemorrhage. For life-threatening or intracranial hemorrhage due to heparin or LMWH, protamine sulfate can be administered. Heparin-induced thrombocytopenia is less common with LMWH than with UFH. There is no specific reversal agent for bleeding caused by fondaparinux, direct thrombin inhibitors, or factor Xa inhibitors. Major bleeding from warfarin is best managed with prothrombin complex concentrate. With serious but non–life-threatening bleeding, fresh-frozen plasma or intravenous vitamin K can be used. Recombinant human coagulation factor VIIa (rFVIIa) is an off-label option to manage catastrophic bleeding from warfarin, but prothrombin complex concentrate is a better choice. Oral vitamin K is effective for managing minor bleeding or an excessively high INR in the absence of bleeding.


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InternalMed_Harrison. Duration of Anticoagulation For DVT isolated to an upper extremity or calf that has been provoked by surgery, trauma, estrogen, or an indwelling central venous catheter or pacemaker, 3 months of anticoagulation usually suffice. For an initial episode of provoked proximal leg DVT or PE, 3 to 6 months of anticoagulation are considered sufficient. For patients with cancer and VTE, prescribe LMWH as monotherapy without warfarin and continue anticoagulation indefinitely unless the patient is rendered cancer-free.


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InternalMed_Harrison. Among patients with idiopathic, unprovoked VTE, the recurrence rate is high after cessation of anticoagulation. VTE that occurs during long-haul air travel is considered unprovoked. Unprovoked VTE may be caused by an exacerbation of an underlying inflammatory state and can be conceptualized as a chronic illness, with latent periods between flares of recurrent episodes. American College of Chest Physicians (ACCP) guidelines recommend considering 1636 anticoagulation for an indefinite duration with a target INR between 2 and 3 for patients with idiopathic VTE. An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 1.5 and 2. Counterintuitively, the presence of genetic mutations such as heterozygous factor V Leiden and prothrombin gene mutation does not appear to increase the risk of recurrent VTE. However, patients with antiphospholipid antibody syndrome may warrant


InternalMed_Harrison

InternalMed_Harrison. such as heterozygous factor V Leiden and prothrombin gene mutation does not appear to increase the risk of recurrent VTE. However, patients with antiphospholipid antibody syndrome may warrant indefinite-duration anticoagulation, even if the initial VTE was provoked by trauma or surgery.


InternalMed_Harrison

InternalMed_Harrison. The two principal indications for insertion of an IVC filter are (1) active bleeding that precludes anticoagulation and (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of recurrent PE in patients with right heart failure who are not candidates for fibrinolysis and prophylaxis of extremely high-risk patients are “softer” indications for filter placement. The filter itself may fail by permitting the passage of small-to medium-size clots. Large thrombi may embolize to the pulmonary arteries via collateral veins that develop. A more common complication is caval thrombosis with marked bilateral leg swelling.


InternalMed_Harrison

InternalMed_Harrison. Paradoxically, by providing a nidus for clot formation, filters increase the DVT rate, even though they usually prevent PE (over the short term). Retrievable filters can now be placed for patients with an anticipated temporary bleeding disorder or for patients at temporary high risk of PE, such as individuals undergoing bariatric surgery who have a prior history of perioperative PE. The filters can be retrieved up to several months after insertion unless thrombus forms and is trapped within the filter. The retrievable filter becomes permanent if it remains in place or if, for technical reasons such as rapid endothelialization, it cannot be removed.


InternalMed_Harrison

InternalMed_Harrison. For patients with massive PE and hypotension, replete volume with 500 mL of normal saline. Additional fluid should be infused with extreme caution because excessive fluid administration exacerbates RV wall stress, causes more profound RV ischemia, and worsens LV compliance and filling by causing further interventricular septal shift toward the LV. Dopamine and dobutamine are first-line inotropic agents for treatment of PE-related shock. Maintain a low threshold for initiating these pressors. Often, a “trial-and-error” approach works best; other agents that may be effective include norepinephrine, vasopressin, or phenylephrine.


InternalMed_Harrison

InternalMed_Harrison. Successful fibrinolytic therapy rapidly reverses right heart failure and may result in a lower rate of death and recurrent PE by (1) dissolving much of the anatomically obstructing pulmonary arterial thrombus, (2) preventing the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hypertension, and (3) lysing much of the source of the thrombus in the pelvic or deep leg veins, thereby decreasing the likelihood of recurrent PE. The preferred fibrinolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) administered as a continuous peripheral intravenous infusion over 2 h. The sooner thrombolysis is administered, the more effective it is. However, this approach can be used for at least 14 days after the PE has occurred.


InternalMed_Harrison

InternalMed_Harrison. Contraindications to fibrinolysis include intracranial disease, recent surgery, and trauma. The overall major bleeding rate is about 10%, including a 1–3% risk of intracranial hemorrhage. Careful screening of patients for contraindications to fibrinolytic therapy (Chap. 295) is the best way to minimize bleeding risk. The only Food and Drug Administration–approved indication for PE fibrinolysis is massive PE. For patients with submassive PE, who have preserved systolic blood pressure but moderate or severe RV dysfunction, use of fibrinolysis remains controversial. Results of a 1006-patient European multicentered randomized trial of submassive PE, using the thrombolytic agent tenecteplase, were published in 2014. Death or hemodynamic collapse within 7 days of randomization was reduced by 56% in the tenecteplase group. However, hemorrhagic stroke occurred in 2% of tenecteplase patients versus 0.2% in patients who only received heparin.


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InternalMed_Harrison. Many patients have relative contraindications to full-dose thrombolysis. Pharmacomechanical catheter-directed therapy usually combines physical fragmentation or pulverization of thrombus with catheter-directed low-dose thrombolysis. Mechanical techniques include catheter maceration and intentional embolization of clot more distally, suction thrombectomy, rheolytic hydrolysis, and low-energy ultrasound-facilitated thrombolysis. The dose of alteplase can be markedly reduced, usually to a range of 20 to 25 mg instead of the peripheral intravenous systemic dose of 100 mg. The risk of major hemorrhage with systemically administered fibrinolysis has prompted a renaissance of interest in surgical embolectomy, an operation that had almost become extinct. More rapid referral before the onset of irreversible multisystem organ failure and improved surgical technique have resulted in a high survival rate.


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InternalMed_Harrison. Chronic thromboembolic pulmonary hypertension develops in 2–4% of acute PE patients. Therefore, PE patients who have initial pulmonary hypertension (usually diagnosed with Doppler echocardiography) should be followed up at about 6 weeks with a repeat echocardiogram to determine whether pulmonary arterial pressure has normalized. Patients impaired by dyspnea due to chronic thromboembolic pulmonary hypertension should be considered for pulmonary thromboendarterectomy, which, if successful, can markedly reduce, and sometimes even cure, pulmonary hypertension (Chap. 304). The operation requires median sternotomy, cardiopulmonary bypass, deep hypothermia, and periods of hypothermic circulatory arrest. The mortality rate at experienced centers is approximately 5%. Inoperable patients should be managed with pulmonary vasodilator therapy.


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InternalMed_Harrison. Patients with VTE may feel overwhelmed when they learn that they are suffering from PE or DVT. Some have never previously encountered serious cardiovascular illness. They wonder whether they will be able to adapt to the new limitations imposed by anticoagulation. They worry about the health of their families and the genetic implications of their illness. Those who are advised to discontinue anticoagulation may feel especially vulnerable about the potential for suffering recurrent VTE. At Brigham and Woman’s Hospital, a physician-nurse–facilitated PE support group was initiated to address these concerns and has met monthly for more than 20 years.


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InternalMed_Harrison. Prevention of DVT and PE (Table 300-4) is of paramount importance because VTE is difficult to detect and poses a profound medical and economic burden. Low-dose UFH or LMWH is the most common form of in-hospital prophylaxis. Computerized reminder systems can increase the use of preventive measures and, at Brigham and Women’s Hospital, have reduced the symptomatic VTE rate by more than 40%. Audits of hospitals to ensure that prophylaxis protocols are being used will also increase utilization of preventive measures. Duration of prophylaxis is an important consideration. Extended-duration prophylaxis has not been shown to be both effective and safe in medically ill patients after hospital discharge in separate large trials that have tested enoxaparin, apixaban, and rivaroxaban. There is an ongoing trial of a novel oral anticoagulant, betrixaban, for extended-duration VTE prophylaxis in medically ill patients.


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InternalMed_Harrison. Dalteparin 2500 or 5000 units daily Cancer surgery, including gynecologic cancer surgery Enoxaparin 40 mg daily, consider 1 month of prophylaxis Major orthopedic surgery Warfarin (target INR 2.0–3.0) Fondaparinux 2.5 mg daily Dabigatran 220 mg daily (not in the United States) Apixaban 2.5 mg bid (not in the United States) Intermittent pneumatic compression (with or without pharmacologic prophylaxis) Medically ill patients, especially if immobilized, with a history of Unfractionated heparin 5000 units bid or tid prior VTE, with an indwelling central venous catheter, or with cancer Enoxaparin 40 mg daily (but without active gastroduodenal ulcer, major bleeding within Dalteparin 2500 or 5000 units daily 3 months, or platelet count <50,000) Fondaparinux 2.5 mg daily Anticoagulation contraindicated Intermittent pneumatic compression devices (but whether graduated compression stockings are effective in medical patients is controversial) Diseases of the Aorta


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InternalMed_Harrison. Anticoagulation contraindicated Intermittent pneumatic compression devices (but whether graduated compression stockings are effective in medical patients is controversial) Diseases of the Aorta Patients who have undergone total hip or knee replacement or cancer surgery will benefit from extended pharmacologic VTE prophylaxis after hospital discharge. For hip replacement or extensive cancer surgery, the duration of prophylaxis is usually at least 1 month. Diseases of the Aorta Mark A. Creager, Joseph Loscalzo The aorta is the conduit through which blood ejected from the left ven-tricle is delivered to the systemic arterial bed. In adults, its diameter is approximately 3 cm at the origin and in the ascending portion, 2.5 cm in the descending portion in the thorax, and 1.8–2 cm in the abdomen. 301


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InternalMed_Harrison. The aortic wall consists of a thin intima composed of endothelium, subendothelial connective tissue, and an internal elastic lamina; a thick tunica media composed of smooth muscle cells and extracellular matrix; and an adventitia composed primarily of connective tissue enclosing the vasa vasorum and nervi vascularis. In addition to the conduit function of the aorta, its viscoelastic and compliant properties serve a buffering function. The aorta is distended during systole to allow a portion of the stroke volume and elastic energy to be stored, and it recoils during diastole so that blood continues to flow to the periphery. Owing to its continuous exposure to high pulsatile pressure and shear stress, the aorta is particularly prone to injury and disease resulting from mechanical trauma. The aorta is also more prone to rupture than is any other vessel, especially with the development of aneurysmal dilation, since its wall tension, as governed by Laplace’s law (i.e., proportional to the


InternalMed_Harrison

InternalMed_Harrison. aorta is also more prone to rupture than is any other vessel, especially with the development of aneurysmal dilation, since its wall tension, as governed by Laplace’s law (i.e., proportional to the product of pressure and radius), will be increased.


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InternalMed_Harrison. Congenital anomalies of the aorta usually involve the aortic arch and its branches. Symptoms such as dysphagia, stridor, and cough may occur if an anomaly causes a ring around or otherwise compresses the esophagus or trachea. Anomalies associated with symptoms include double aortic arch, origin of the right subclavian artery distal to the left subclavian artery, and right-sided aortic arch with an aberrant left subclavian artery. A Kommerell’s diverticulum is an anatomic remnant of a right aortic arch. Most congenital anomalies of the aorta do not cause symptoms and are detected during catheter-based procedures. The diagnosis of suspected congenital anomalies of the aorta typically is confirmed by computed tomographic (CT) or magnetic resonance (MR) angiography. Surgery is used to treat symptomatic anomalies.


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InternalMed_Harrison. An aneurysm is defined as a pathologic dilation of a segment of a blood vessel. A true aneurysm involves all three layers of the vessel wall and is distinguished from a pseudoaneurysm, in which the intimal and medial layers are disrupted and the dilated segment of the aorta is lined by adventitia only and, at times, by perivascular clot. Aneurysms also may be classified according to their gross appearance. A fusiform aneurysm affects the entire circumference of a segment of the vessel, resulting in a diffusely dilated artery. In contrast, a saccular aneurysm involves only a portion of the circumference, resulting in an outpouching of the vessel wall. Aortic aneurysms also are classified according to location, i.e., abdominal versus thoracic. Aneurysms of the descending thoracic aorta are usually contiguous with infradiaphragmatic aneurysms and are referred to as thoracoabdominal aortic aneurysms.


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InternalMed_Harrison. Aortic aneurysms result from conditions that cause degradation or abnormal production of the structural components of the aortic wall: elastin and collagen. The causes of aortic aneurysms may be broadly categorized as degenerative disorders, genetic or developmental diseases, vasculitis, infections, and trauma (Table 301-1). Inflammation, oxidative stress, proteolysis, and biomechanical wall stress contribute to the degenerative processes that characterize most aneurysms of the abdominal and descending thoracic aorta. These are mediated by B cell and T cell lymphocytes, macrophages, inflammatory cytokines, and matrix metalloproteinases that degrade elastin and collagen and alter the tensile strength and ability of the aorta to accommodate pulsatile stretch. The associated histopathology demonstrates destruction of elastin and collagen, decreased vascular smooth muscle, in-growth of new blood vessels, and inflammation. Factors associated with degenerative aortic aneurysms include


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InternalMed_Harrison. demonstrates destruction of elastin and collagen, decreased vascular smooth muscle, in-growth of new blood vessels, and inflammation. Factors associated with degenerative aortic aneurysms include aging, cigarette smoking, hypercholesterolemia, hypertension, and male sex.


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InternalMed_Harrison. DiSEASES oF THE AoRTA: ETiologY AnD ASSoCiATED FACToRS Acute aortic syndromes (aortic dissection, acute intramural hematoma, Mycotic (Salmonella, staphylococcal, streptococcal, fungal) The most common pathologic condition associated with degenerative aortic aneurysms is atherosclerosis. Many patients with aortic aneurysms have coexisting risk factors for atherosclerosis (Chap. 291e), as well as atherosclerosis in other blood vessels.


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InternalMed_Harrison. Medial degeneration, previously designated cystic medial necrosis, is the histopathologic term used to describe the degeneration of collagen and elastic fibers in the tunica media of the aorta as well as the loss of medial cells that are replaced by multiple clefts of mucoid material, such as proteoglycans. Medial degeneration characteristically affects the proximal aorta, results in circumferential weakness and dilation, and leads to the development of fusiform aneurysms involving the ascending aorta and the sinuses of Valsalva. This condition is particularly prevalent in patients with Marfan’s syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome type IV (Chap. 427), hypertension, congenital bicuspid aortic valves, and familial thoracic aortic aneurysm syndromes; sometimes it appears as an isolated condition in patients without any other apparent disease.


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InternalMed_Harrison. Familial clusterings of aortic aneurysms occur in 20% of patients, suggesting a hereditary basis for the disease. Mutations of the gene that encodes fibrillin-1 are present in patients with Marfan’s syndrome. Fibrillin-1 is an important component of extracellular microfibrils, which support the architecture of elastic fibers and other connective tissue. Deficiency of fibrillin-1 in the extracellular matrix leads to excessive signaling by transforming growth factor β (TGF-β). Loeys-Dietz syndrome is caused by mutations in the genes that encode TGF-β receptors 1 (TGFBR1) and 2 (TGFBR2). Increased signaling by TGF-β and mutations of TGFBR1 and TGFBR2 may cause thoracic aortic aneurysms. Mutations of type III procollagen have been implicated in Ehlers-Danlos type IV syndrome. Mutations of SMAD3, which encodes a downstream signaling protein involved with TGF binding to its receptors, have been described in a syndrome of thoracic aortic aneurysm; craniofacial, skeletal, and cutaneous


InternalMed_Harrison

InternalMed_Harrison. of SMAD3, which encodes a downstream signaling protein involved with TGF binding to its receptors, have been described in a syndrome of thoracic aortic aneurysm; craniofacial, skeletal, and cutaneous anomalies; and osteoarthritis. Mutations of the genes encoding the smooth muscle–specific alpha-actin (ACTA2), smooth muscle cell–specific myosin heavy chain 11 (MHC11), and myosin light chain kinase (MYLK) and mutations of TGFBR2 and SMAD3 have been reported in some patients with nonsyndromic familial thoracic aortic aneurysms.


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InternalMed_Harrison. The infectious causes of aortic aneurysms include syphilis, tuberculosis, and other bacterial infections. Syphilis (Chap. 206) is a relatively uncommon cause of aortic aneurysm. Syphilitic periaortitis and mesoaortitis damage elastic fibers, resulting in thickening and weakening of the aortic wall. Approximately 90% of syphilitic aneurysms are located in the ascending aorta or aortic arch. Tuberculous aneurysms (Chap.


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InternalMed_Harrison. 202) typically affect the thoracic aorta and result from direct extension of infection from hilar lymph nodes or contiguous abscesses as well as from bacterial seeding. Loss of aortic wall elasticity results from granulomatous destruction of the medial layer. A mycotic aneurysm is a rare condition that develops as a result of staphylococcal, streptococcal, Salmonella, or other bacterial or fungal infections of the aorta, usually at an atherosclerotic plaque. These aneurysms are usually saccular. Blood cultures are often positive and reveal the nature of the infective agent.


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InternalMed_Harrison. Vasculitides associated with aortic aneurysm include Takayasu’s arteritis and giant cell arteritis, which may cause aneurysms of the aortic arch and descending thoracic aorta. Spondyloarthropathies such as ankylosing spondylitis, rheumatoid arthritis, psoriatic arthritis, relapsing polychondritis, and reactive arthritis (formerly known as Reiter’s syndrome) are associated with dilation of the ascending aorta. Aortic aneurysms occur in patients with Behçet’s syndrome (Chap. 387), Cogan’s syndrome, and IgG4-related systemic disease. Aortic aneurysms also result from idiopathic aortitis. Traumatic aneurysms may occur after penetrating or nonpenetrating chest trauma and most commonly affect the descending thoracic aorta just beyond the site of insertion of the ligamentum arteriosum. Chronic aortic dissections are associated with weakening of the aortic wall that may lead to the development of aneurysmal dilatation.


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InternalMed_Harrison. The clinical manifestations and natural history of thoracic aortic aneurysms depend on their location. Medial degeneration is the most common pathology associated with ascending aortic aneurysms, whereas atherosclerosis is the condition most frequently associated with aneurysms of the descending thoracic aorta. The average growth rate of thoracic aneurysms is 0.1–0.2 cm per year. Thoracic aortic aneurysms associated with Marfan’s syndrome or aortic dissection may expand at a greater rate. The risk of rupture is related to the size of the aneurysm and the presence of symptoms, ranging approximately from 2–3% per year for thoracic aortic aneurysms <4.0 cm in diameter to 7% per year for those >6 cm in diameter. Most thoracic aortic aneurysms are asymptomatic; however, compression or erosion of adjacent tissue by aneurysms may cause symptoms such as chest pain, shortness of breath, cough, hoarseness, and dysphagia. Aneurysmal dilation of the ascending aorta may cause congestive heart


InternalMed_Harrison

InternalMed_Harrison. of adjacent tissue by aneurysms may cause symptoms such as chest pain, shortness of breath, cough, hoarseness, and dysphagia. Aneurysmal dilation of the ascending aorta may cause congestive heart failure as a consequence of aortic regurgitation, and compression of the superior vena cava may produce congestion of the head, neck, and upper extremities.


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InternalMed_Harrison. A chest x-ray may be the first test that suggests the diagnosis of a thoracic aortic aneurysm (Fig. 301-1). Findings include widening of the mediastinal shadow and displacement or compression of the trachea or left main stem bronchus. Echocardiography, particularly transesophageal echocardiography, can be used to assess the proximal ascending aorta and descending thoracic aorta. Contrast-enhanced CT, magnetic resonance imaging (MRI), and conventional invasive aortography are sensitive and specific tests for assessment of aneurysms of the thoracic aorta and involvement of branch vessels (Fig. 301-2). In asymptomatic patients whose aneurysms are too small to justify surgery, noninvasive testing with either contrast-enhanced CT or MRI should be performed at least every 6–12 months to monitor expansion. FIGURE 301-1 A chest x-ray of a patient with a thoracic aortic aneurysm.


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InternalMed_Harrison. FIGURE 301-2 A magnetic resonance angiogram demonstrating a fusiform aneurysm of the ascending thoracic aorta. (Courtesy of Dr. Michael Steigner, Brigham and Women’s Hospital, Boston, MA, with permission.) β-Adrenergic blockers currently are recommended for patients with thoracic aortic aneurysms, particularly those with Marfan’s syndrome, who have evidence of aortic root dilatation to reduce the rate of further expansion. Additional medical therapy should be given as necessary to control hypertension. Recent studies indicate that angiotensin receptor antagonists and angiotensin-converting enzyme inhibitors reduce the rate of aortic dilation in patients with Marfan’s syndrome by blocking TGF-β signaling; clinical outcome trials of this treatment approach are in progress. Operative repair with placement of a prosthetic graft is indicated in patients with symptomatic ascending thoracic aortic aneurysms and for most asymptomatic aneurysms when the ascending aortic diameter is >5.5 cm. In


InternalMed_Harrison

InternalMed_Harrison. placement of a prosthetic graft is indicated in patients with symptomatic ascending thoracic aortic aneurysms and for most asymptomatic aneurysms when the ascending aortic diameter is >5.5 cm. In patients with Marfan’s syndrome or bicuspid aortic valve, ascending thoracic aortic aneurysms of 4–5 cm should be considered for surgery. Operative repair is indicated for patients with descending thoracic aortic aneurysms when the diameter is >6 cm, and endovascular repair should be considered if feasible when the diameter is >5.5 cm. Repair is also recommended when the diameter of an aneurysm has increased >1 cm per year.


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InternalMed_Harrison. Abdominal aortic aneurysms occur more frequently in males than in females, and the incidence increases with age. Abdominal aortic aneurysms ≥4.0 cm may affect 1–2% of men older than 50 years. At least 90% of all abdominal aortic aneurysms >4.0 cm are related to atherosclerotic disease, and most of these aneurysms are below the level of the renal arteries. Prognosis is related to both the size of the aneurysm and the severity of coexisting coronary artery and cerebrovascular disease. The risk of rupture increases with the size of the aneurysm: the 5-year risk for aneurysms <5 cm is 1–2%, whereas it is 20–40% for aneurysms >5 cm in diameter. The formation of mural thrombi within aneurysms may predispose to peripheral embolization.


InternalMed_Harrison

InternalMed_Harrison. An abdominal aortic aneurysm commonly produces no symptoms. It usually is detected on routine examination as a palpable, pulsatile, expansile, and nontender mass, or it is an incidental finding observed on an abdominal imaging study performed for other reasons. As abdominal aortic aneurysms expand, however, they may become painful. Some patients complain of strong pulsations in the abdomen; others experience pain in the chest, lower back, or scrotum. Aneurysmal pain is usually a harbinger of rupture and represents a medical emergency. More often, acute rupture occurs without any prior warning, and this complication is always life-threatening. Rarely, there is leakage of the aneurysm with severe pain and tenderness. Acute pain and hypotension occur with rupture of the aneurysm, which requires an emergency operation.


InternalMed_Harrison

InternalMed_Harrison. Abdominal radiography may demonstrate the calcified outline of the aneurysm; however, about 25% of aneurysms are not calcified and cannot be visualized by x-ray imaging. An abdominal ultrasound can delineate the transverse and longitudinal dimensions of an abdominal aortic aneurysm and may detect mural thrombus. Abdominal ultrasound is useful for serial documentation of aneurysm size and can be used to screen patients at risk for developing an aortic aneurysm. In one large study, ultrasound screening of men age 65–74 years was associated with a risk reduction in aneurysm-related death of 42%. For this reason, screening by ultrasonography is recommended for men age 65–75 years who have ever smoked. In addition, siblings or offspring of persons with abdominal aortic aneurysms, as well as individuals with thoracic aortic or peripheral arterial aneurysms, should be considered for screening for abdominal aortic aneurysms. CT with contrast and MRI are accurate noninvasive tests to determine


InternalMed_Harrison

InternalMed_Harrison. with thoracic aortic or peripheral arterial aneurysms, should be considered for screening for abdominal aortic aneurysms. CT with contrast and MRI are accurate noninvasive tests to determine the location and size of abdominal aortic aneurysms and to plan endovascular or open surgical repair (Fig. 301-3). Contrast aortography may be used for the evaluation of patients with aneurysms, but the procedure carries a small risk of complications such as bleeding, allergic reactions, and atheroembolism. Since the presence of mural thrombi may reduce the luminal size, aortography may underestimate the diameter of an aneurysm.


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InternalMed_Harrison. Diseases of the Aorta FIGURE 301-3 A computed tomographic angiogram depicting a fusiform abdominal aortic aneurysm before (left) and after (right) treatment with a bifurcated stent graft. (Courtesy of Drs. Elizabeth George and Frank Rybicki, Brigham and Women’s Hospital, Boston, MA, with permission.)


InternalMed_Harrison

InternalMed_Harrison. Operative repair of the aneurysm with insertion of a prosthetic graft or endovascular placement of an aortic stent graft (Fig. 301-3) is indicated for abdominal aortic aneurysms of any size that are expanding rapidly or are associated with symptoms. For asymptomatic aneurysms, abdominal aortic aneurysm repair is indicated if the diameter is >5.5 cm. In randomized trials of patients with abdominal aortic aneurysms <5.5 cm, there was no difference in the long-term (5to 8-year) mortality rate between those followed with ultrasound surveillance and those undergoing elective surgical repair. Thus, serial noninvasive follow-up of smaller aneurysms (<5 cm) is an alternative to immediate repair. The decision to perform an open surgical operation or endovascular repair is based in part on the vascular anatomy and comorbid conditions. Endovascular repair of abdominal aortic aneurysms has a lower short-term morbidity rate but a comparable long-term mortality rate with open surgical


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InternalMed_Harrison. on the vascular anatomy and comorbid conditions. Endovascular repair of abdominal aortic aneurysms has a lower short-term morbidity rate but a comparable long-term mortality rate with open surgical reconstruction. Long-term surveillance with CT or MR aortography is indicated after endovascular repair to detect leaks and possible aneurysm expansion.


InternalMed_Harrison

InternalMed_Harrison. In surgical candidates, careful preoperative cardiac and general medical evaluations (followed by appropriate therapy for complicating conditions) are essential. Preexisting coronary artery disease, congestive heart failure, pulmonary disease, diabetes mellitus, and advanced age add to the risk of surgery. β-Adrenergic blockers decrease perioperative cardiovascular morbidity and mortality. With careful preoperative cardiac evaluation and postoperative care, the operative mortality rate approximates 1–2%. After acute rupture, the mortality rate of emergent operation is 45–50%. Endovascular repair with stent placement is an alternative approach to treat ruptured aneurysms and may be associated with a lower mortality rate.


InternalMed_Harrison

InternalMed_Harrison. The four major acute aortic syndromes are aortic rupture (discussed earlier), aortic dissection, intramural hematoma, and penetrating atherosclerotic ulcer. Aortic dissection is caused by a circumferential or, less frequently, transverse tear of the intima. It often occurs along the right lateral wall of the ascending aorta where the hydraulic shear stress is high. Another common site is the descending thoracic aorta just below the ligamentum arteriosum. The initiating event is either a primary intimal tear with secondary dissection into the media or a medial hemorrhage that dissects into and disrupts the intima. The pulsatile aortic flow then dissects along the elastic lamellar plates of the aorta and creates a false lumen. The dissection usually propagates distally down the descending aorta and into its major branches, but it may propagate proximally. Distal propagation may be limited by atherosclerotic plaque. In some cases, a secondary distal intimal disruption occurs, resulting


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InternalMed_Harrison. aorta and into its major branches, but it may propagate proximally. Distal propagation may be limited by atherosclerotic plaque. In some cases, a secondary distal intimal disruption occurs, resulting in the reentry of blood from the false to the true lumen.


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InternalMed_Harrison. There are at least two important pathologic and radiologic variants of aortic dissection: intramural hematoma without an intimal flap and penetrating atherosclerotic ulcer. Acute intramural hematoma is thought to result from rupture of the vasa vasorum with hemorrhage into the wall of the aorta. Most of these hematomas occur in the descending thoracic aorta. Acute intramural hematomas may progress to dissection and rupture. Penetrating atherosclerotic ulcers are caused by erosion of a plaque into the aortic media, are usually localized, and are not associated with extensive propagation. They are found primarily in the middle and distal portions of the descending thoracic aorta and are associated with extensive atherosclerotic disease. The ulcer can erode beyond the internal elastic lamina, leading to medial hematoma, and may progress to false aneurysm formation or rupture.


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InternalMed_Harrison. Several classification schemes have been developed for thoracic aortic dissections. DeBakey and colleagues initially classified aortic dissections as type I, in which an intimal tear occurs in the ascending aorta but involves the descending aorta as well; type II, in which the dissection is limited to the ascending aorta; and type III, in which the intimal tear is located in the descending aorta with distal propagation of the dissection (Fig. 301-4). Another classification (Stanford) is that of type A, in which the dissection involves the ascending aorta (proximal dissection), and type B, in which it is limited to the arch and/or descending aorta (distal dissection). From a management standpoint, classification of aortic dissections and intramural hematomas into type A or B is more practical and useful, since DeBakey types I and II are managed in a similar manner.


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InternalMed_Harrison. The factors that predispose to aortic dissection include those associated with medial degeneration and others that increase aortic wall stress (Table 301-1). Systemic hypertension is a coexisting condition in


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InternalMed_Harrison. FIGURE 301-4 Classification of aortic dissections. Stanford classification: Type A dissections (top) involve the ascending aorta independent of site of tear and distal extension; type B dissections (bottom) involve transverse and/or descending aorta without involvement of the ascending aorta. DeBakey classification: Type I dissection involves ascending to descending aorta (top left); type II dissection is limited to ascending or transverse aorta, without descending aorta (top center + top right); type III dissection involves descending aorta only (bottom left). (From DC Miller, in RM Doroghazi, EE Slater [eds]: Aortic Dissection. New York, McGraw-Hill, 1983, with permission.) 70% of patients. Aortic dissection is the major cause of morbidity and mortality in patients with Marfan’s syndrome (Chap. 427) or Loeys-Dietz syndrome, and similarly may affect patients with Ehlers-Danlos syndrome. The incidence also is increased in patients with inflammatory aortitis (i.e., Takayasu’s


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InternalMed_Harrison. syndrome (Chap. 427) or Loeys-Dietz syndrome, and similarly may affect patients with Ehlers-Danlos syndrome. The incidence also is increased in patients with inflammatory aortitis (i.e., Takayasu’s arteritis, giant cell arteritis), congenital aortic valve anomalies (e.g., bicuspid valve), coarctation of the aorta, and a history of aortic trauma. In addition, the risk of dissection is increased in otherwise normal women during the third trimester of pregnancy. Aortic dissection also may occur as a consequence of weight lifting, cocaine use, or deceleration injury.


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InternalMed_Harrison. The peak incidence of aortic dissection is in the sixth and seventh decades. Men are more affected than women by a ratio of 2:1. The presentations of aortic dissection and its variants are the consequences of intimal tear, dissecting hematoma, occlusion of involved arteries, and compression of adjacent tissues. Acute aortic dissection presents with the sudden onset of pain (Chap. 19), which often is described as very severe and tearing and is associated with diaphoresis. The pain may be localized to the front or back of the chest, often the interscapular region, and typically migrates with propagation of the dissection. Other symptoms include syncope, dyspnea, and weakness. Physical findings may include hypertension or hypotension, loss of pulses, aortic regurgitation, pulmonary edema, and neurologic findings due to carotid artery obstruction (hemiplegia, hemianesthesia) or spinal cord ischemia (paraplegia). Bowel ischemia, hematuria, and myocardial ischemia have all been observed.


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InternalMed_Harrison. and neurologic findings due to carotid artery obstruction (hemiplegia, hemianesthesia) or spinal cord ischemia (paraplegia). Bowel ischemia, hematuria, and myocardial ischemia have all been observed. These clinical manifestations reflect complications resulting from the dissection occluding the major arteries. Furthermore, clinical manifestations may result from the compression of adjacent structures (e.g., superior cervical ganglia, superior vena cava, bronchus, esophagus) by the expanding dissection, causing aneurysmal dilation, and include Horner’s syndrome, superior vena cava syndrome, hoarseness, dysphagia, and airway compromise. 1641 Hemopericardium and cardiac tamponade may complicate a type A lesion with retrograde dissection. Acute aortic regurgitation is an important and common (>50%) complication of proximal dissection. It is the outcome of either a circumferential tear that widens the aortic root or a disruption of the annulus by a dissecting hematoma that tears a


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InternalMed_Harrison. common (>50%) complication of proximal dissection. It is the outcome of either a circumferential tear that widens the aortic root or a disruption of the annulus by a dissecting hematoma that tears a leaflet(s) or displaces it, inferior to the line of closure. Signs of aortic regurgitation include bounding pulses, a wide pulse pressure, a diastolic murmur often radiating along the right sternal border, and evidence of congestive heart failure. The clinical manifestations depend on the severity of the regurgitation.


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InternalMed_Harrison. In dissections involving the ascending aorta, the chest x-ray often reveals a widened superior mediastinum. A pleural effusion (usually left-sided) also may be present. This effusion is typically serosanguineous and not indicative of rupture unless accompanied by hypotension and falling hematocrit. In dissections of the descending thoracic aorta, a widened mediastinum may be observed on chest x-ray. In addition, the descending aorta may appear to be wider than the ascending portion. An electrocardiogram that shows no evidence of myocardial ischemia is helpful in distinguishing aortic dissection from myocardial infarction. Rarely, the dissection involves the right or, less commonly, left coronary ostium and causes acute myocardial infarction.


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InternalMed_Harrison. The diagnosis of aortic dissection can be established by noninvasive techniques such as echocardiography, CT, and MRI. Aortography is used less commonly because of the accuracy of these noninvasive techniques. Transthoracic echocardiography can be performed simply and rapidly and has an overall sensitivity of 60–85% for aortic dissection. For diagnosing proximal ascending aortic dissections, its sensitivity exceeds 80%; it is less useful for detecting dissection of the arch and descending thoracic aorta. Transesophageal echocardiography requires greater skill and patient cooperation but is very accurate in identifying dissections of the ascending and descending thoracic aorta but not the arch, achieving 98% sensitivity and approximately 90% specificity. Echocardiography also provides important information regarding the presence and severity of aortic regurgitation and pericardial effusion. CT and MRI are both highly accurate in identifying the intimal flap and the extent of the


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InternalMed_Harrison. important information regarding the presence and severity of aortic regurgitation and pericardial effusion. CT and MRI are both highly accurate in identifying the intimal flap and the extent of the dissection and involvement of major arteries; each has a sensitivity and specificity >90%. They are useful in recognizing intramural hemorrhage and penetrating ulcers. The relative utility of transesophageal echocardiography, CT, and MRI depends on the availability and expertise in individual institutions as well as on the hemodynamic stability of the patient, with CT and MRI obviously less suitable for unstable patients.


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InternalMed_Harrison. Medical therapy should be initiated as soon as the diagnosis is considered. The patient should be admitted to an intensive care unit for hemodynamic monitoring. Unless hypotension is present, therapy should be aimed at reducing cardiac contractility and systemic arterial pressure, and thus shear stress. For acute dissection, unless contraindicated, β-adrenergic blockers should be administered parenterally, using intravenous propranolol, metoprolol, or the short-acting esmolol to achieve a heart rate of approximately 60 beats/ min. This should be accompanied by sodium nitroprusside infusion to lower systolic blood pressure to ≤120 mmHg. Labetalol (Chap. 298), a drug with both βand α-adrenergic blocking properties, also may be used as a parenteral agent in acute therapy for dissection.


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InternalMed_Harrison. The calcium channel antagonists verapamil and diltiazem may be used intravenously if nitroprusside or β-adrenergic blockers cannot be employed. The addition of a parenteral angiotensin-converting enzyme (ACE) inhibitor such as enalaprilat to a β-adrenergic blocker also may be considered. Isolated use of a direct vasodilator such as hydralazine is contraindicated because these agents can increase hydraulic shear and may propagate the dissection. Emergent or urgent surgical correction is the preferred treatment for acute ascending aortic dissections and intramural hematomas (type A) and for complicated type B dissections, including


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InternalMed_Harrison. CHAPTER 301 Diseases of the Aorta 1642 those characterized by propagation, compromise of major aortic branches, impending rupture, or continued pain. Surgery involves excision of the intimal flap, obliteration of the false lumen, and placement of an interposition graft. A composite valve-graft conduit is used if the aortic valve is disrupted. The overall in-hospital mortality rate after surgical treatment of patients with aortic dissection is reported to be 15–25%. The major causes of perioperative mortality and morbidity include myocardial infarction, paraplegia, renal failure, tamponade, hemorrhage, and sepsis. Endoluminal stent grafts may be considered in selected patients. Other transcatheter techniques, such as fenestration of the intimal flaps and stenting of narrowed branch vessels to increase flow to compromised organs, are used in selected patients. For uncomplicated and stable distal dissections and intramural hematomas (type B), medical therapy is the preferred treatment.


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InternalMed_Harrison. to increase flow to compromised organs, are used in selected patients. For uncomplicated and stable distal dissections and intramural hematomas (type B), medical therapy is the preferred treatment. The in-hospital mortality rate of medically treated patients with type B dissection is 10–20%. Long-term therapy for patients with aortic dissection and intramural hematomas (with or without surgery) consists of control of hypertension and reduction of cardiac contractility with the use of beta blockers plus other antihypertensive agents, such as ACE inhibitors or calcium antagonists. Patients with chronic type B dissection and intramural hematomas should be followed on an outpatient basis every 6–12 months with contrast-enhanced CT or MRI to detect propagation or expansion. Patients with Marfan’s syndrome are at high risk for postdissection complications. The long-term prognosis for patients with treated dissections is generally good with careful follow-up; the 10-year survival rate is


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InternalMed_Harrison. syndrome are at high risk for postdissection complications. The long-term prognosis for patients with treated dissections is generally good with careful follow-up; the 10-year survival rate is approximately 60%.


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InternalMed_Harrison. Atherosclerosis may affect the thoracic and abdominal aorta. Occlusive aortic disease caused by atherosclerosis usually is confined to the distal abdominal aorta below the renal arteries. Frequently the disease extends to the iliac arteries (Chap. 302). Claudication characteristically involves the buttocks, thighs, and calves and may be associated with impotence in males (Leriche’s syndrome). The severity of the symptoms depends on the adequacy of collaterals. With sufficient collateral blood flow, a complete occlusion of the abdominal aorta may occur without the development of ischemic symptoms. The physical findings include the absence of femoral and other distal pulses bilaterally and the detection of an audible bruit over the abdomen (usually at or below the umbilicus) and the common femoral arteries. Atrophic skin, loss of hair, and coolness of the lower extremities usually are observed. In advanced ischemia, rubor on dependency and pallor on elevation can be seen.


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InternalMed_Harrison. The diagnosis usually is established by physical examination and noninvasive testing, including leg pressure measurements, Doppler velocity analysis, pulse volume recordings, and duplex ultrasonography. The anatomy may be defined by MRI, CT, or conventional aortography, typically performed when one is considering revascularization. Catheter-based endovascular or operative treatment is indicated in patients with lifestyle-limiting or debilitating symptoms of claudication and patients with critical limb ischemia. Acute occlusion in the distal abdominal aorta constitutes a medical emergency because it threatens the viability of the lower extremities; it usually results from an occlusive (saddle) embolus that almost always originates from the heart. Rarely, acute occlusion may occur as the result of in situ thrombosis in a preexisting severely narrowed segment of the aorta.


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InternalMed_Harrison. The clinical picture is one of acute ischemia of the lower extremities. Severe rest pain, coolness, and pallor of the lower extremities and the absence of distal pulses bilaterally are the usual manifestations. Diagnosis should be established rapidly by MRI, CT, or aortography. Emergency thrombectomy or revascularization is indicated. Aortitis, a term referring to inflammatory disease of the aorta, may be caused by large vessel vasculitides such as Takayasu’s arteritis and giant cell arteritis, rheumatic and HLA-B27–associated spondyloarthropathies, Behçet’s syndrome, antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides, Cogan’s syndrome, IgG4-related systemic disease, and infections such as syphilis, tuberculosis, and Salmonella, or may be associated with retroperitoneal fibrosis. Aortitis may result in aneurysmal dilation and aortic regurgitation, occlusion of the aorta and its branch vessels, or acute aortic syndromes.


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InternalMed_Harrison. This inflammatory disease often affects the ascending aorta and aortic arch, causing obstruction of the aorta and its major arteries. Takayasu’s arteritis is also termed pulseless disease because of the frequent occlusion of the large arteries originating from the aorta. It also may involve the descending thoracic and abdominal aorta and occlude large branches such as the renal arteries. Aortic aneurysms also may occur. The pathology is a panarteritis characterized by mononuclear cells and occasionally giant cells, with marked intimal hyperplasia, medial and adventitial thickening, and, in the chronic form, fibrotic occlusion. The disease is most prevalent in young females of Asian descent but does occur in women of other geographic and ethnic origins and also in young men. During the acute stage, fever, malaise, weight loss, and other systemic symptoms may be evident. Elevations of the erythrocyte sedimentation rate and C-reactive protein are common. The chronic stages of the


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InternalMed_Harrison. the acute stage, fever, malaise, weight loss, and other systemic symptoms may be evident. Elevations of the erythrocyte sedimentation rate and C-reactive protein are common. The chronic stages of the disease, which is intermittently active, present with symptoms related to large artery occlusion, such as upper extremity claudication, cerebral ischemia, and syncope. The process is progressive, and there is no definitive therapy. Glucocorticoids and immunosuppressive agents are effective in some patients during the acute phase. Surgical bypass or endovascular intervention of a critically stenotic artery may be necessary.


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InternalMed_Harrison. (See also Chap. 385) This vasculitis occurs in older individuals and affects women more often than men. Primarily large and medium-size arteries are affected. The pathology is that of focal granulomatous lesions involving the entire arterial wall; it may be associated with polymyalgia rheumatica. Obstruction of medium-size arteries (e.g., temporal and ophthalmic arteries) and major branches of the aorta and the development of aortitis and aortic regurgitation are important complications of the disease. High-dose glucocorticoid therapy may be effective when given early.


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InternalMed_Harrison. Rheumatoid arthritis (Chap. 380), ankylosing spondylitis (Chap. 384), psoriatic arthritis (Chap. 384), reactive arthritis (formerly known as Reiter’s syndrome) (Chap. 384), relapsing polychondritis, and inflammatory bowel disorders may all be associated with aortitis involving the ascending aorta. The inflammatory lesions usually involve the ascending aorta and may extend to the sinuses of Valsalva, the mitral valve leaflets, and adjacent myocardium. The clinical manifestations are aneurysm, aortic regurgitation, and involvement of the cardiac conduction system.


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InternalMed_Harrison. Idiopathic abdominal aortitis is characterized by adventitial and periaortic inflammation with thickening of the aortic wall. It is associated with abdominal aortic aneurysms and idiopathic retroperitoneal fibrosis. Affected individuals may present with vague constitutional symptoms, fever, and abdominal pain. Retroperitoneal fibrosis can cause ureteral obstruction and hydronephrosis. Glucocorticoids and immunosuppressive agents may reduce the inflammation. Infective aortitis may result from direct invasion of the aortic wall by bacterial pathogens such as Staphylococcus, Streptococcus, and Salmonella or by fungi. These bacteria cause aortitis by infecting the aorta at sites of atherosclerotic plaque. Bacterial proteases lead to degradation of collagen, and the ensuing destruction of the aortic wall leads to the formation of a saccular aneurysm referred to as a mycotic


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InternalMed_Harrison. Arterial Diseases of the Extremities Mark A. Creager, Joseph Loscalzo PERIPHERAL ARTERY DISEASE Peripheral artery disease (PAD) is defined as a clinical disorder in 302 Arterial Diseases of the Extremities aneurysm. Mycotic aneurysms have a predilection for the suprarenal abdominal aorta. The pathologic characteristics of the aortic wall include acute and chronic inflammation, abscesses, hemorrhage, and necrosis. Mycotic aneurysms typically affect the elderly and occur in men three times more frequently than in women. Patients may present with fever, sepsis, and chest, back, or abdominal pain; there may have been a preceding diarrheal illness. Blood cultures are positive in the majority of patients. Both CT and MRI are useful to diagnose mycotic aneurysms. Treatment includes antibiotic therapy and surgical removal of the affected part of the aorta and revascularization of the lower extremities with grafts placed in uninfected tissue.


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InternalMed_Harrison. Syphilitic aortitis is a late manifestation of luetic infection (Chap. 206) that usually affects the proximal ascending aorta, particularly the aortic root, resulting in aortic dilation and aneurysm formation. Syphilitic aortitis occasionally may involve the aortic arch or the descending aorta. The aneurysms may be saccular or fusiform and are usually asymptomatic, but compression of and erosion into adjacent structures may result in symptoms; rupture also may occur.


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InternalMed_Harrison. The initial lesion is an obliterative endarteritis of the vasa vasorum, especially in the adventitia. This is an inflammatory response to the invasion of the adventitia by the spirochetes. Destruction of the aortic media occurs as the spirochetes spread into this layer, usually via the lymphatics accompanying the vasa vasorum. Destruction of collagen and elastic tissues leads to dilation of the aorta, scar formation, and calcification. These changes account for the characteristic radiographic appearance of linear calcification of the ascending aorta.


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InternalMed_Harrison. The disease typically presents as an incidental chest radiographic finding 15–30 years after initial infection. Symptoms may result from aortic regurgitation, narrowing of coronary ostia due to syphilitic aortitis, compression of adjacent structures (e.g., esophagus), or rupture. Diagnosis is established by a positive serologic test, i.e., rapid plasmin reagin (RPR) or fluorescent treponemal antibody. Treatment includes penicillin and surgical excision and repair.