2098 PART 6 Disorders of the Cardiovascular System

This rate can be decreased by more judicious selection of patients

who require a PICC, use of single-lumen rather than double- or

triple-lumen PICCs, and use of the smallest possible lumen size,

ideally 4 French rather than 5 or 6 French.

Isolated Calf DVT The GARFIELD-VTE Registry recruited 2145

patients with isolated calf DVT and 3846 patients with proximal

DVT with or without calf DVT. Isolated calf DVT patients were

more likely to have either undergone surgery or have experienced

leg trauma, and they were less likely to have active cancer or a prior

history of VTE. Almost all isolated calf DVT patients received

anticoagulation, and nearly half were anticoagulated for at least

1 year. In a smaller study of 871 patients with leg DVT, the 10-year

mortality was the same in patients with isolated calf DVT compared

to those with proximal leg DVT. Cancer-associated isolated calf

DVT had as high a recurrence rate as cancer-associated proximal

leg DVT.

SECONDARY PREVENTION

Anticoagulation or placement of an inferior vena cava (IVC) filter

constitutes secondary prevention of VTE. IVC filters are indicated in

patients with an absolute contraindication to anticoagulation and for

those who have suffered recurrent VTE while receiving therapeutic

doses of anticoagulation. Under most circumstances, IVC filters are

not indicated for primary prevention of VTE. The IVC filter should be

retrieved if the clinician judges that the patient no longer requires it.

For patients with swelling of the legs when acute DVT is diagnosed, below-knee graduated compression stockings may be prescribed, usually 30–40 mmHg or 20–30 mmHg, to lessen patient

DVT imaging test

Venous ultrasound

Diagnostic Nondiagnostic

Stop MR CT Phlebography

PE imaging test

Chest CT

Diagnostic Nondiagnostic, unavailable, or unsafe

Stop

Stop

Lung scan

Diagnostic Nondiagnostic

Venous ultrasound

Positive Negative

Treat for PE Transesophageal ECHO or MR or

invasive pulmonary angiography

FIGURE 279-11 Imaging tests to diagnose deep-venous thrombosis (DVT) and

pulmonary embolism (PE). ECHO, echocardiography; MR, magnetic resonance.

discomfort. They should be replaced every 3 months because they

lose their elasticity. However, prescription of vascular compression

stockings in asymptomatic newly diagnosed acute DVT patients

does not prevent the development of postthrombotic syndrome.

TREATMENT

Pulmonary Embolism

RISK STRATIFICATION

Hemodynamic instability, RV dysfunction on echocardiography,

RV enlargement on chest CT, and elevation of the troponin level

due to RV microinfarction portend a high risk of an adverse clinical

outcome despite anticoagulation. When RV function remains normal in a hemodynamically stable patient, a good clinical outcome is

highly likely with anticoagulation alone (Fig. 279-12).

ANTICOAGULATION

Effective anticoagulation is the foundation for successful treatment of DVT and PE. There are three major strategies: (1) the

classical but waning strategy of parenteral anticoagulation with

unfractionated heparin (UFH), low-molecular-weight heparin

(LMWH), or fondaparinux “bridged” to warfarin; (2) parenteral

therapy, switched after 5 days to a novel oral anticoagulant such as

dabigatran (a direct thrombin inhibitor) or edoxaban (an anti-Xa

agent); or (3) oral anticoagulation monotherapy with rivaroxaban

or apixaban (both are anti-Xa agents) with a 3-week or 1-week loading dose, respectively, followed by a maintenance dose. For patients

with VTE in the setting of suspected or proven heparin-induced

thrombocytopenia, one can choose between two parenteral direct

thrombin inhibitors: argatroban and bivalirudin (Table 279-4).

Unfractionated Heparin UFH binds to and accelerates 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. Use an initial bolus of 80 U/kg, followed by

an initial infusion rate of 18 U/kg per h in patients with normal liver

function. The short half-life of UFH is especially useful in patients

in whom hour-to-hour control of the intensity of anticoagulation

is desired. Heparin also has pleiotropic effects that may decrease

systemic and local inflammation.

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 essentially an ultra-low-molecular-weight heparin. It is administered as

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 279-12 Acute management of pulmonary thromboembolism. IVC, inferior

vena cava; PE, pulmonary embolism; RV, right ventricular.

Deep-Venous Thrombosis and Pulmonary Thromboembolism

2099CHAPTER 279

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.

Warfarin This vitamin K antagonist prevents carboxylationdependent activation of coagulation factors II, VII, IX, and X (Chapter 65). The full effect of warfarin requires daily therapy for at least 5

days. Overlapping UFH, LMWH, fondaparinux, or parenteral direct

thrombin inhibitors with warfarin for at least 5 days will nullify the

early procoagulant effect of warfarin. The dose of warfarin is usually

targeted to achieve a target international normalized ratio (INR) of

2.5, with a range of 2.0–3.0. Hundreds of drug-drug and drug-food

interactions affect warfarin metabolism. Warfarin can cause major

hemorrhage, including intracranial hemorrhage, even when the

INR remains within the desired therapeutic range. Warfarin can

also cause “off-target” side effects such as alopecia or arterial vascular calcification. Centralized anticoagulation clinics have improved

the efficacy and safety of warfarin dosing. Some patients can selfmonitor their INR with a home point-of-care fingerstick machine,

and a few can be taught to self-dose their warfarin.

Novel Oral Anticoagulants Novel oral anticoagulants (NOACs)

are administered in a fixed dose, establish effective anticoagulation

within hours of ingestion, require no laboratory coagulation monitoring and no restriction on eating green leafy vegetables, and have

few drug-drug interactions.

Management of Bleeding from Anticoagulants For life-threatening or

intracranial hemorrhage due to heparin or LMWH, administer protamine sulfate. The dabigatran antibody idarucizumab is an effective,

rapidly acting antidote for dabigatran. Andexanet reverses the bleeding complications from the anti-Xa anticoagulants. Major bleeding

from warfarin is best managed with prothrombin complex concentrate. With less serious bleeding, fresh-frozen plasma or intravenous

vitamin K can be used. Oral vitamin K is effective for managing

minor bleeding or an excessively high INR in the absence of bleeding.

TABLE 279-4 Anticoagulation of VTE

Non-Warfarin Anticoagulation

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

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 (with suspected or proven

heparin-induced thrombocytopenia)

Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily with the

dinner meal thereafter

Apixaban 10 mg twice daily for 1 week, followed by 5 mg twice daily thereafter

Dabigatran: 5 days of unfractionated heparin, LMWH, or fondaparinux followed

by dabigatran 150 mg twice daily

Edoxaban: 5 days of unfractionated heparin, LMWH, or fondaparinux followed

by edoxaban 60 mg once daily with normal renal function, weight >60 kg, in the

absence of potent P-glycoprotein inhibitors

Warfarin Anticoagulation

Requires 5–10 days of administration to achieve effectiveness as monotherapy

Use full-dose unfractionated heparin, LMWH, or fondaparinux as “bridging

agents” when initiating warfarin. 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.

Usual start dose is 5 mg

Titrate to INR, target 2.0–3.0

Abbreviations: aPTT, activated partial thromboplastin time; INR, international

normalized ratio; LMWH, low-molecular-weight heparin.

TABLE 279-5 Take-Home Points from the European Society of

Cardiology 2019 Pulmonary Embolism Guidelines

1. Terminology such as “provoked” versus “unprovoked” PE/DVT is no longer

supported by the Guidelines, as it is potentially misleading and not helpful for

decision-making regarding the duration of anticoagulation.

2. Extended oral anticoagulation of indefinite duration should be considered for

patients with a first episode of PE and:

a. No identifiable risk factor

b. A persistent risk factor

c. A minor transient or reversible risk factor

Abbreviations: PE, pulmonary embolism; VTE, venous thromboembolism.

Cancer and Venous Thromboembolism For patients with cancer

and VTE, prescribe LMWH as monotherapy or a NOAC in the

absence of a gastrointestinal cancer, and continue extended-duration

anticoagulation until the patient is declared cancer-free.

Duration of Anticoagulation Based on contemporary observational and randomized trials, data-driven guidelines have changed

fundamentally our conceptual approach to determining the optimal

duration of anticoagulation. We should no longer try to classify a

VTE as “provoked” or “unprovoked.” The reason is that many types

of provoked VTE lead to as great a risk of recurrence after anticoagulation is discontinued as unprovoked VTE. The European Society

of Cardiology (ESC) Pulmonary Embolism Guidelines, rewritten in

2019, are instructive in this regard (Tables 279-5 and 279-6).

INFERIOR VENA CAVA FILTERS

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 via collateral veins that develop. Paradoxically, by providing a nidus for clot

formation, filters increase the DVT rate, even though they usually

prevent PE. Consider placing retrievable rather than permanent

filters. The retrievable filters can be removed many months after

insertion, unless thrombus forms and is trapped within the filter.

MANAGEMENT OF MASSIVE PE

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. Norepinephrine and dobutamine are firstline vasopressor and inotropic agents, respectively, for treatment

of PE-related shock. Norepinephrine increases RV inotropy and

systemic arterial pressure. It also restores the coronary perfusion

TABLE 279-6 Risk of Recurrent Venous Thromboembolism after

Discontinuing Anticoagulation (European Society of Cardiology 2019

Pulmonary Embolism Guidelines

RISK OF RECURRENCE EXAMPLES

Low risk (<3% per year) Major surgery or trauma

Intermediate risk (3–8% per

year)

Minor surgery

Hospitalized with acute medical illness

Pregnancy/estrogens

Long-haul flight

Inflammatory bowel disease

Autoimmune disease

No identifiable risk factor (formerly called

“unprovoked”)

High risk (>8% per year) Active cancer

Antiphospholipid syndrome

2100 PART 6 Disorders of the Cardiovascular System

gradient. Dobutamine increases RV inotropy and lowers filling

pressures. It may worsen systemic arterial hypotension unless used

in combination with a vasopressor. Maintain a low threshold for

initiating these pressors. If heroic measures are warranted, consider

veno-arterial extracorporeal membrane oxygenation (ECMO). This

strategy should only be employed when ECMO is being used as a

“bridge” to definitive treatment with thrombolysis or embolectomy.

FIBRINOLYSIS

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 U.S. Food and Drug Administration (FDA)–approved systemically administered fibrinolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) prescribed 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. A popular off-label dosing regimen is 50 mg of TPA administered over 2 h. This

lower dose may be associated with fewer bleeding complications.

Contraindications to fibrinolysis include intracranial disease,

recent surgery, and trauma. The overall major bleeding rate is

~10%, including a 2–3% risk of intracranial hemorrhage. Careful

screening of patients for contraindications to fibrinolytic therapy

(Chap. 275) is the best way to minimize bleeding risk.

For patients with submassive PE who have preserved systolic

blood pressure but moderate or severe RV dysfunction, use of

fibrinolysis remains controversial. A 2019 American Heart Association Scientific Statement suggests considering advanced therapy

with thrombolysis or embolectomy in patients with lack of improvement, clinical deterioration, severe physical distress with anticoagulation alone, clot in transit, severe or persistent RV strain, signs

of low cardiac output, low bleeding risk, and good life expectancy.

PHARMACOMECHANICAL CATHETER-DIRECTED THERAPY

Pharmacomechanical catheter-directed therapy usually combines

physical fragmentation or pulverization of thrombus with catheterdirected 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. With pharmacomechanical

catheter-directed therapy, the dose of alteplase can be markedly

reduced, usually to a range of 20–25 mg, instead of the peripheral intravenous systemic dose of 100 mg. In 2014, the FDA

approved ultrasound-facilitated catheter-directed thrombolysis

for acute massive and submassive PE. Using a total tPA dose of

24 mg administered over 12 h, this approach decreased RV dilation,

reduced pulmonary hypertension, decreased anatomic thrombus

burden, and minimized intracranial hemorrhage. Lower doses and

shorter durations of TPA are currently being studied.

PULMONARY EMBOLECTOMY

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.

PULMONARY THROMBOENDARTERECTOMY

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 and, if necessary,

at 6 months, with repeat echocardiograms 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, when successful, can markedly reduce, and sometimes even

cure, pulmonary hypertension (Chap. 283). The operation requires

median sternotomy, cardiopulmonary bypass, deep hypothermia,

and periods of hypothermic circulatory arrest. The mortality rate at

experienced centers is ~5%. Inoperable patients should be managed

with pulmonary vasodilator therapy and balloon angioplasty of

pulmonary arterial webs.

EMOTIONAL SUPPORT

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 fear they will not

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 Women’s Hospital,

a physician-nurse–facilitated PE support group was initiated to

address these concerns and has met monthly for >30 years. The

nonprofit organization North American Thrombosis Forum (www

.NATFonline.org) has initiated monthly online support groups that

garner worldwide participation.

■ PREVENTION OF VTE

Prevention of DVT and PE (Table 279-7) 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

TABLE 279-7 Prevention of Venous Thromboembolism Among

Hospitalized Patients

CONDITION PROPHYLAXIS STRATEGY

High-risk nonorthopedic surgery Unfractionated heparin 5000 units SC

bid or tid

Enoxaparin 40 mg daily

Dalteparin 2500 or 5000 units daily

Medical oncology Enoxaparin or dalteparin

Rivaroxaban or apixaban

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)

Enoxaparin 40 mg daily

Dalteparin 2500 or 5000 units daily

Fondaparinux 2.5 mg daily

Rivaroxaban 10 mg daily, beginning

6–10 h postoperatively

Aspirin 81–325 mg daily

Dabigatran 110 mg first day, then 2

20 mg daily

Apixaban 2.5 mg bid, beginning 12–24 h

postoperatively

Medically ill patients, especially if

immobilized, with a history of prior

VTE, with an indwelling central venous

catheter, or with cancer (but without

active gastroduodenal ulcer, major

bleeding within 3 months, or platelet

count <50,000)

Unfractionated heparin 5000 units bid

or tid

Enoxaparin 40 mg daily

Dalteparin 2500 or 5000 units daily

Fondaparinux 2.5 mg daily

Medically ill patients about to be

discharged from hospital

Rivaroxaban

Anticoagulation contraindicated Intermittent pneumatic compression

devices (but whether graduated

compression stockings are effective in

medical patients remains uncertain)

Abbreviations: INR, international normalized ratio; VTE, venous thromboembolism.

Diseases of the Aorta

2101CHAPTER 280

increase the use of preventive measures and, at Brigham and Women’s

Hospital, have reduced the symptomatic VTE rate by >40%. Audits of

hospitals to ensure that prophylaxis protocols are followed correctly

will also increase utilization of preventive measures.

Duration of in-hospital prophylaxis is short because the length

of stay for hospitalization due to medical illnesses such as pneumonia is short. The FDA has approved extended-duration VTE

prophylaxis continuing after hospital discharge with the anti-Xa

agent rivaroxaban.

■ FURTHER READING

Barco S et al: Trends in mortality related to pulmonary embolism

in the European Region, 2000-15: Analysis of vital registration data

from the WHO Mortality Database. Lancet Respir Med 8:277, 2019.

Bikdeli B et al: COVID-19 and thrombotic or thromboembolic

disease: Implications for prevention, antithrombotic therapy, and

follow-up. J Am Coll Cardiol 75:2590, 2020.

Blondon M et al: Age-adjusted D-dimer cutoff for the diagnosis of

pulmonary embolism: A cost-effectiveness analysis. J Thromb Haemost

18:865, 2020.

Dudzinkski DM et al: Interventional treatment of pulmonary embolism. Circ Cardiovasc Interv 10:e004345, 2017.

Giri J et al: Interventional therapies for acute pulmonary embolism:

Current status and principles for the development of novel evidence.

Circulation 140:e774, 2019.

Kahn SR et al: Functional and exercise limitations after a first episode

of pulmonary embolism: Results of the ELOPE prospective cohort

study. Chest 151:1058, 2017.

Kline JA et al: Over-testing for suspected pulmonary embolism in

American emergency departments. The continuing epidemic. Circ

Cardiovasc Qual Outcomes 13:e005753, 2020.

Konstantinides SV et al: 2019 ESC Guidelines for the diagnosis and

management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J

41:543, 2020.

Piazza G et al: A prospective, single-arm, multicenter trial of ultrasoundfacilitated, catheter-directed, low-dose fibrinolysis for acute massive

and submassive pulmonary embolism. The SEATTLE II study. J Am

Coll Cardiol Cardiovasc Interv 8:1382, 2015.

Weitz JI et al: Rivaroxaban or aspirin for extended treatment of venous

thromboembolism. N Engl J Med 376:1211, 2017.

Woolf SH, Schoomaker H: Life expectancy and mortality rates in

the United States, 1959-2017. JAMA 322:1996, 2019.

The aorta is the conduit through which blood ejected from the left

ventricle is delivered to the systemic arterial bed. In adults, its diameter is ~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.

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

280 Diseases of the Aorta

Mark A. Creager, Joseph Loscalzo

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 product of pressure and radius), will be increased.

CONGENITAL ANOMALIES OF THE AORTA

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.

Coarctation of the aorta (Chap. 269) typically occurs near the

insertion of the ligamentum arteriosum, adjacent to the left subclavian

artery. It may be associated with a bicuspid aortic valve, aortic arch

hypoplasia, other congenital heart defects, and intracranial aneurysms. A pulse delay or pressure differential between the upper and

lower extremities should raise suspicion of aortic coarctation. Imaging

modalities, including echocardiography, CT, and MR angiography are

used to confirm the diagnosis. If untreated, hypertension develops in

the arteries proximal to the coarctation. Treatment of hemodynamically significant aortic coarctation includes endovascular stent implantation if feasible or surgical repair.

AORTIC ANEURYSM

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.

■ ETIOLOGY

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 280-1). 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 aging, cigarette smoking, hypercholesterolemia, hypertension, and male sex.

The most common pathologic condition associated with degenerative aortic aneurysms is atherosclerosis. Many patients with aortic

aneurysms have coexisting risk factors for atherosclerosis, as well as

atherosclerosis in other blood vessels.

The pathologic condition of aortic aneurysms associated with genetic

or developmental diseases is medial degeneration, a histopathologic

2102 PART 6 Disorders of the Cardiovascular System

fibromuscular dysplasia, although the nature of the aortic pathology is

not established.

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, TGFBR2, TGFBR3, as well as

TGFB2 and TGFB3, may cause thoracic aortic aneurysms. 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

anomalies; and osteoarthritis. Thoracic aortic aneurysm is associated

with autosomal dominant polycystic kidney disease, which is caused

by mutations in PKD1. Mutations of the genes encoding the smooth

muscle–specific alpha-actin (ACTA2), smooth muscle cell–specific myosin heavy chain 11 (MHC11), myosin light chain kinase (MYLK), and type

I cGMP-dependent protein kinase (PRKG1) and mutations of TGFBR2

and SMAD3 have been reported in some patients with nonsyndromic

familial thoracic aortic aneurysms. Mutations in type III procollagen

(COL3A1) have been implicated in Ehlers-Danlos type IV syndrome.

The infectious causes of aortic aneurysms include syphilis, tuberculosis, and other bacterial infections. Syphilis (Chap. 182) 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. 178) 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.

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 are associated with dilation of

the ascending aorta. Aortic aneurysms occur in patients with Behçet’s

syndrome (Chap. 364), 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.

■ THORACIC AORTIC ANEURYSMS

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

TABLE 280-1 Diseases of the Aorta: Etiology and Associated Factors

Aortic aneurysm

Degenerative

 Aging

 Cigarette smoking

 Hypercholesterolemia

 Hypertension

 Atherosclerosis

Genetic or developmental

 Marfan’s syndrome

 Loeys-Dietz syndrome

 Ehlers-Danlos syndrome type IV

 Aneurysm-osteoarthritis syndrome

 Bicuspid aortic valve

 Turner’s syndrome

 Familial

 Fibromuscular dysplasia

Chronic aortic dissection

Aortitis (see below)

Infective (see below)

Trauma

Acute aortic syndromes (aortic dissection, acute intramural hematoma,

penetrating atherosclerotic ulcer)

Degenerative disorders (see above)

Genetic/developmental disorders (see above)

Hypertension

Aortitis (see below)

Pregnancy

Trauma

Aortic occlusion

Atherosclerosis

Thromboembolism

Aortitis

Vasculitis

 Takayasu’s arteritis

 Giant cell arteritis

Rheumatic

 Rheumatoid aortitis

 HLA-B27–associated spondyloarthropathies

 Behçet’s syndrome

 Cogan’s syndrome

 IgG4-related systemic disease

 Idiopathic aortitis

Infective

 Syphilis

 Tuberculosis

 Mycotic (Salmonella, staphylococcal, streptococcal, fungal)

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. Found in patients with Marfan’s syndrome,

Loeys-Dietz syndrome, Ehlers-Danlos syndrome type IV (Chap.

413), hypertension, bicuspid aortic valves, Turner’s syndrome, and

familial thoracic aortic aneurysm syndromes, it sometimes appears as

an isolated condition in patients without any other apparent disease.

Thoracic and abdominal aortic aneurysms also occur in patients with