Chronic Venous Disease and Lymphedema

2115CHAPTER 282

paresthesia, and the skin appears white and waxy. After rewarming,

there is cyanosis and erythema, wheal-and-flare formation, edema, and

superficial blisters. Deep frostbite involves muscle, nerves, and deeper

blood vessels. It may result in edema of the hand or foot, vesicles and

bullae, tissue necrosis, and gangrene (Fig. 281-3F).

Initial treatment is rewarming, performed in an environment where

reexposure to freezing conditions will not occur. Rewarming is accomplished by immersion of the affected part in a water bath at temperatures of 40°–44°C (104°–111°F). Massage, application of ice water, and

extreme heat are contraindicated. The injured area should be cleansed

with soap or antiseptic, and sterile dressings should be applied. Analgesics are often required during rewarming. Antibiotics are used if there

is evidence of infection. The efficacy of sympathetic blocking drugs

is not established. After recovery, the affected extremity may exhibit

increased sensitivity to cold.

■ FURTHER READING

Aboyans V, Criqui MH: The epidemiology of peripheral artery

disease, in Vascular Medicine: A Companion to Braunwald’s Heart

Disease, 3rd ed. MA Creager et al (eds). Philadelphia, Elsevier, 2020,

pp 212-230.

Bevan GH, White Solaru KT: Evidence-based medical management

of peripheral artery disease. Arterioscler Thromb Vasc Biol 40:541,

2020.

Conte MS et al: Global vascular guidelines on the management of

chronic limb-threatening ischemia. J Vasc Surg 69:3S-125S e40, 2019.

Gerhard-Herman MD et al: 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease:

A report of the American College of Cardiology/American Heart

Association Task Force on Clinical Practice Guidelines. Circulation

135:e726, 2017.

Gornik HL et al: First International Consensus on the diagnosis and

management of fibromuscular dysplasia. Vasc Med 24:164, 2019.

Hussain MA et al: Antithrombotic therapy for peripheral artery disease: Recent advances. J Am Coll Cardiol 21:2450, 2018.

Thukkani AK, Kinlay S: Endovascular intervention for peripheral

artery disease. Circ Res 116:1599, 2015.

Treat-Jacobson D et al: Optimal exercise programs for patients with

peripheral artery disease: A scientific statement from the American

Heart Association. Circulation 139:e10, 2019.

Wigley FM, Flavahan NA: Raynaud’s phenomenon. N Engl J Med

375:556, 2016.

■ CHRONIC VENOUS DISEASE

Chronic venous diseases range from telangiectasias and reticular

veins, to varicose veins, to chronic venous insufficiency with edema,

skin changes, and ulceration. This section of the chapter will focus

on identification and treatment of varicose veins and chronic venous

insufficiency, since these problems are encountered frequently by the

internist. The estimated prevalence of varicose veins in the United

States is ~15% in men and 30% in women. Chronic venous insufficiency with edema affects ~7.5% of men and 5% of women, and the

prevalence increases with age ranging from 2% among those <50 years

of age to 10% of those 70 years of age. Approximately 20% of patients

with chronic venous insufficiency develop venous ulcers.

282 Chronic Venous Disease

and Lymphedema

Mark A. Creager, Joseph Loscalzo

■ VENOUS ANATOMY

Veins in the extremities can be broadly classified as either superficial

or deep. The superficial veins are located between the skin and deep

fascia. In the legs, these include the great and small saphenous veins

and their tributaries. The great saphenous vein is the longest vein in the

body. It originates on the medial side of the foot and ascends anterior

to the medial malleolus and then along the medial side of the calf and

thigh, and drains into the common femoral vein. The small saphenous

vein originates on the dorsolateral aspect of the foot, ascends posterior

to the lateral malleolus and along the posterolateral aspect of the calf,

and drains into the popliteal vein. The deep veins of the leg accompany the major arteries. There are usually paired peroneal, anterior

tibial, and posterior tibial veins in the calf, which converge to form the

popliteal vein. Soleal tributary veins drain into the posterior tibial or

peroneal veins, and gastrocnemius tributary veins drain into the popliteal vein. The popliteal vein ascends in the thigh as the femoral vein.

The confluence of the femoral vein and deep femoral vein form the

common femoral vein, which ascends in the pelvis as the external iliac

and then common iliac vein, which converges with the contralateral

common iliac vein at the inferior vena cava. Perforating veins connect

the superficial and deep systems in the legs at multiple locations, normally allowing blood to flow from the superficial to deep veins. In the

arms, the superficial veins include the basilic, cephalic, and median

cubital veins and their tributaries. The basilic and cephalic veins course

along the medial and lateral aspects of the arm, respectively, and these

are connected via the median cubital vein in the antecubital fossa.

The deep veins of the arms accompany the major arteries and include

the radial, ulnar, brachial, axillary, and subclavian veins. The subclavian vein converges with the internal jugular vein to form the brachiocephalic vein, which joins the contralateral brachiocephalic vein to

form the superior vena cava. Bicuspid valves are present throughout

the venous system to direct the flow of venous blood centrally.

Pathophysiology of Chronic Venous Disease Varicose veins

are dilated, bulging, tortuous superficial veins, measuring at least

3 mm in diameter. The smaller and less tortuous reticular veins are

dilated intradermal veins, which appear blue-green, measure 1–3 mm

in diameter, and do not protrude from the skin surface. Telangiectasias,

or spider veins, are small, dilated veins, <1 mm in diameter, located

near the skin surface, and form blue, purple, or red linear, branching,

or spider-web patterns.

Varicose veins can be categorized as primary or secondary. Primary

varicose veins originate in the superficial system and result from

defective structure and function of the valves of the saphenous veins,

intrinsic weakness of the vein wall, and high intraluminal pressure.

Approximately one-half of these patients have a family history of

varicose veins. Other factors associated with primary varicose veins

include aging, pregnancy, hormonal therapy, obesity, and prolonged

standing. Secondary varicose veins result from venous hypertension,

associated with deep-venous insufficiency or deep-venous obstruction, and incompetent perforating veins that cause enlargement of

superficial veins. Arteriovenous fistulas also cause varicose veins in the

affected limb.

Chronic venous insufficiency is a consequence of incompetent veins

in which there is venous hypertension and extravasation of fluid and

blood elements into the tissue of the limb. It may occur in patients

with varicose veins but usually is caused by disease in the deep veins.

It also is categorized as primary or secondary. Primary deep-venous

insufficiency is a consequence of an intrinsic structural or functional

abnormality in the vein wall or venous valves leading to valvular reflux.

Secondary deep-venous insufficiency is caused by obstruction and/or

valvular incompetence from previous deep-vein thrombosis (Chap. 279).

Deep-venous insufficiency occurs following deep-vein thrombosis, as

the delicate valve leaflets become thickened and contracted and can

no longer prevent retrograde flow of blood and the vein itself becomes

rigid and thick walled. Although most veins recanalize after an episode

of thrombosis, the large proximal veins may remain occluded. Secondary incompetence develops in distal valves because high pressures

distend the vein and separate the leaflets. Other causes of secondary

2116 PART 6 Disorders of the Cardiovascular System

deep-venous insufficiency include May-Thurner syndrome, where the

left iliac vein is occluded or stenosed by extrinsic compression from

the overlapping right common iliac artery; extrinsic compression from

tumor or retroperitoneal fibrosis; arteriovenous fistulas resulting in

increased venous pressure; congenital deep-vein agenesis or hypoplasia; and venous malformations as may occur in Klippel-Trénaunay and

Parkes-Weber syndromes.

Clinical Presentation Patients with venous varicosities are often

asymptomatic but still concerned about the cosmetic appearance of

their legs. Superficial venous thrombosis may be a recurring problem,

and rarely, a varicosity ruptures and bleeds. Symptoms in patients with

varicose veins or venous insufficiency, when they occur, include a dull

ache, throbbing or heaviness, or pressure sensation in the legs typically

after prolonged standing; these symptoms usually are relieved with

leg elevation. Additional symptoms may include cramping, burning,

pruritus, leg swelling, and skin ulceration.

The legs are examined in both the supine and standing positions.

Visual inspection and palpation of the legs in the standing position

confirm the presence of varicose veins. The location and extent of

the varicose veins should be noted. Edema, stasis dermatitis, and skin

ulceration near the ankle may be present if there is superficial venous

insufficiency and venous hypertension. Findings of deep-venous

insufficiency include increased leg circumference, venous varicosities,

edema, and skin changes. The edema, which is usually pitting, may

be confined to the ankles, extend above the ankles to the knees, or

involve the thighs in severe cases. Over time, the edema may become

less pitting and more indurated. Dermatologic findings associated

with venous stasis include hyperpigmentation, erythema, eczema,

lipodermatosclerosis, atrophie blanche, and a phlebectasia corona.

Lipodermatosclerosis is the combination of induration, hemosiderin

deposition, and inflammation, and typically occurs in the lower part of

the leg just above the ankle. Atrophie blanche is a white patch of scar

tissue, often with focal telangiectasias and a hyperpigmented border;

it usually develops near the medial malleolus. A phlebectasia corona

is a fan-shaped pattern of intradermal veins near the ankle or on the

foot. Skin ulceration may occur near the medial and lateral malleoli. A

venous ulcer is often shallow and characterized by an irregular border,

a base of granulation tissue, and the presence of exudate (Fig. 282-1).

FIGURE 282-1 Venous insufficiency with active venous ulcer near the medial

malleolus. (Courtesy of Dr. Steven Dean, with permission.)

Bedside maneuvers can be used to distinguish primary varicose

veins from secondary varicose veins caused by deep-venous insufficiency. With the contemporary use of venous ultrasound (see

below), however, these maneuvers are employed infrequently. The

Brodie-Trendelenburg test is used to determine whether varicose veins

are secondary to deep-venous insufficiency. As the patient is lying

supine, the leg is elevated and the veins allowed to empty. Then, a

tourniquet is placed on the proximal part of the thigh and the patient

is asked to stand. Filling of the varicose veins within 30 s indicates

that the varicose veins are caused by deep-venous insufficiency and

incompetent perforating veins. Primary varicose veins with superficial

venous insufficiency are the likely diagnosis if venous refilling occurs

promptly after tourniquet removal. The Perthes test assesses the

possibility of deep-venous obstruction. A tourniquet is placed on the

midthigh after the patient has stood, and the varicose veins are filled.

The patient is then instructed to walk for 5 min. A patent deep-venous

system and competent perforating veins enable the superficial veins

below the tourniquet to collapse. Deep-venous obstruction is likely to

be present if the superficial veins distend further with walking.

Differential Diagnosis The duration of leg edema helps to distinguish chronic venous insufficiency from acute deep-vein thrombosis.

Lymphedema, as discussed later in this chapter, is often confused with

chronic venous insufficiency, and both may occur together. Other disorders that cause leg swelling should be considered and excluded when

evaluating a patient with presumed venous insufficiency. Bilateral leg

swelling occurs in patients with congestive heart failure, hypoalbuminemia secondary to nephrotic syndrome or severe hepatic disease,

or myxedema caused by hypothyroidism or pretibial myxedema associated with Graves’ disease, and with drugs such as dihydropyridine

calcium channel blockers and thiazolidinediones. Unilateral causes of

leg swelling also include ruptured leg muscles, hematomas secondary

to trauma, and popliteal cysts. Cellulitis may cause erythema and swelling of the affected limb. Leg ulcers may be caused by severe peripheral

artery disease and critical limb ischemia; neuropathies, particularly

those associated with diabetes; and less commonly, skin cancer, vasculitis, or rarely as a complication of hydroxyurea. The location and

characteristics of venous ulcers help to differentiate these from other

causes.

Classification of Chronic Venous Disease The CEAP (clinical,

etiologic, anatomic, pathophysiologic) classification schema incorporates the range of symptoms and signs of chronic venous disease

to characterize its severity. It also broadly categorizes the etiology

as primary, secondary, or congenital; identifies the affected veins as

superficial, deep, or perforating; and characterizes the pathophysiology

as reflux, obstruction, both, or neither (Table 282-1).

Diagnostic Testing The principal diagnostic test to evaluate

patients with chronic venous disease is venous duplex ultrasonography. A venous duplex ultrasound examination uses a combination of

B-mode imaging and spectral Doppler to detect the presence of venous

obstruction and venous reflux in superficial and deep veins. Colorassisted Doppler ultrasound is useful to visualize venous flow patterns.

Obstruction may be diagnosed by the absence of flow, the presence

of an echogenic thrombus within the vein, or failure of the vein to

collapse when a compression maneuver is applied by the sonographer,

the last implicating the presence of an intraluminal thrombus. Venous

reflux is detected by prolonged reversal of venous flow direction during a Valsalva maneuver, particularly for the common femoral vein or

saphenofemoral junction, or after compression and release of a cuff

placed on the limb distal to the area being interrogated.

Some vascular laboratories use air or strange gauge plethysmography to assess the severity of venous reflux and complement findings

from the venous ultrasound examination. Venous volume and venous

refilling time are measured when the legs are placed in a dependent

position and after calf exercise to quantify the severity of venous reflux

and the efficiency of the calf muscle pump to affect venous return.

Chronic Venous Disease and Lymphedema

2117CHAPTER 282

Magnetic resonance, computed tomographic, and conventional

venography are rarely required to determine the cause and plan treatment for chronic venous insufficiency unless there is suspicion for

pathology that might warrant intervention. These modalities are used

to identify obstruction or stenosis of the inferior vena cava and iliofemoral veins, as may occur in patients with previous proximal deep-vein

thrombosis; occlusion of inferior vena cava filters; extrinsic compression from tumors; and May-Thurner syndrome.

TREATMENT

Chronic Venous Disease

SUPPORTIVE MEASURES

Varicose veins usually are treated with conservative measures.

Symptoms often decrease when the legs are elevated periodically, prolonged standing is avoided, and elastic support hose

are worn. External compression with elastic stockings, multilayer

elastic wraps, stretch bandages, or inelastic garments provides a

counterbalance to the hydrostatic pressure in the veins. Although

compression garments may improve symptoms, they do not prevent

progression of varicose veins. Graduated compression stockings

with pressures of 20–30 mmHg are suitable for most patients with

simple varicose veins, although higher pressures may be required

TABLE 282-1 CEAP (Clinical, Etiologic, Anatomic, Pathophysiologic)

Classification

Clinical Classification

C0

 No visible or palpable signs of venous disease

C1

 Telangiectasias or reticular veins

C2

 Varicose veins

C2r Recurrent varicose veins

C3

 Edema

C4

 Changes in skin and subcutaneous secondary to CVD

C4a Pigmentation or eczema

C4b Lipodermatosclerosis or atrophie blanche

C4c Corona phlebectatica

C5

 Healed venous ulcer

C6

 Active venous ulcer

C6r Recurrent active venous ulcer

Etiologic Classification

Ep

 Primary

Es

 Secondary

Esi Secondary – intravenous

Ese Secondary – extravenous

Ec

 Congenital

En

 No cause identified

Anatomic Classification

As

 Superficial

Ap

 Perforator

Ad

 Deep

An

 No venous anatomic location identified

Pathophysiologic Classification

Pr

 Reflux

Po

 Obstruction

Pr,o Reflux and obstruction

Pn

 No pathophysiology identified

Abbreviation: CVD, chronic venous disease.

Source: Data from F Lurie et al: J Vasc Surg 8:342, 2020.

for patients with varicose veins and manifestations of venous insufficiency such as edema and ulcers.

Patients with chronic venous insufficiency also should be advised

to avoid prolonged standing or sitting; frequent leg elevation is

helpful. Graded compression therapy consisting of stockings or

multilayered compression bandages is the standard of care for

advanced chronic venous insufficiency characterized by edema,

skin changes, or venous ulcers defined as CEAP clinical class C3–

C6. Graduated compression stockings of 30–40 mmHg are more

effective than lesser grades for healing venous ulcers. The length

of stocking depends on the distribution of edema. Calf-length

stockings are tolerated better by most patients, particularly elderly

patients; for patients with varicose veins or edema extending to the

thigh, thigh-length stockings or panty hose should be considered.

Exercise training, including leg muscle strengthening, may improve

calf muscle pump function and antegrade venous flow, and reduce

the severity of chronic venous insufficiency. Overweight and obese

patients should be advised to lose weight via caloric restriction and

exercise.

In addition to a compression bandage or stocking, patients

with venous ulcers also may be treated with low-adherent absorbent dressings that take up exudates while maintaining a moist

environment. Other types of dressings include hydrocolloid (an

adhesive dressing composed of polymers such as carboxymethylcellulose that absorbs exudates by forming a gel), hydrogel

(a nonabsorbent dressing comprising >80% water or glycerin

that moisturizes wounds), foam (an absorbent dressing made

with polymers such as polyurethane), and alginate (an absorbent,

biodegradable dressing that is derived from seaweed), but there

is little evidence that these are more effective than low-adherent

absorbent dressings. The choice of specific dressing depends on

the amount of drainage, presence of infection, and integrity of the

skin surrounding the ulcer. Ulcers should be debrided of necrotic

tissue. Antibiotics are not indicated unless the ulcer is infected.

The multilayered compression bandage or graduated compression

garment is then put over the dressing.

MEDICAL THERAPIES

There are no drugs approved by the U.S. Food and Drug Administration for the treatment of chronic venous insufficiency. Diuretics may reduce edema, but at the risk of volume depletion and

compromise in renal function. Topical steroids may be used for a

short period of time to treat inflammation associated with stasis

dermatitis. Several herbal supplements, such as horse chestnut

seed extract (aescin); flavonoids, including diosmin, hesperidin, or

the two combined as micronized purified flavonoid fraction; and

French maritime pine bark extract, are touted to have venoconstrictive and anti-inflammatory properties. Although meta-analyses

have suggested that aescin reduces edema, pruritus, and pain and

that micronized purified flavonoid fraction in conjunction with

compression therapy facilitates venous ulcer healing, there is insufficient evidence to recommend the general use of these substances

in patients with chronic venous insufficiency.

INTERVENTIONAL AND SURGICAL THERAPIES

Ablative procedures, including endovenous thermal and nonthermal ablation, sclerotherapy, and surgery, are used to treat varicose

veins in selected patients who have persistent symptoms, great

saphenous vein incompetency, and complications of venous insufficiency including dermatitis, edema, and ulcers. Ablative therapy

may also be indicated for cosmetic reasons.

Endovenous thermal ablation procedures of the saphenous veins

include endovenous laser therapy and radiofrequency ablation.

To ablate the great saphenous vein, a catheter is placed percutaneously and advanced from the level of the knee to just below the

saphenofemoral junction via ultrasound guidance. Thermal energy

is then delivered as the catheter is pulled back. The heat injures the

endothelium and media and promotes thrombosis and fibrosis,

2118 PART 6 Disorders of the Cardiovascular System

resulting in venous occlusion. Average 1- and 5-year occlusion rates

exceed 90% following endovenous laser therapy and are slightly less

after radiofrequency ablation. Deep-vein thrombosis of the common femoral vein adjacent to the saphenofemoral junction is an

uncommon but potential complication of endovenous thermal ablation. Other adverse effects of thermal ablation procedures include

pain, paresthesias, bruising, hematoma, and hyperpigmentation.

Nonthermal ablation procedures of the saphenous veins include

endovenous delivery of a cyanoacrylate tissue adhesive, which

causes fibrosis, and mechanochemical ablation, which involves

insertion of a rotating wire to injure the endothelium and infusion

of a liquid sclerosant. One-year occlusion rates approximate or

exceed 90%, respectively. Adverse effects of nonthermal ablation

procedures include superficial thrombophlebitis, deep vein thrombosis, ecchymoses, hematomas, and hyperpigmentation.

Sclerotherapy involves the injection of a chemical into a vein to

cause fibrosis and obstruction. Sclerosing agents approved by the

U.S. Food and Drug Administration include sodium tetradecyl sulfate, polidocanol, sodium morrhuate, and glycerin. The sclerosing

agent is administered as a liquid or mixed with air or CO2

/O2

 to

create a foam. It is first injected into the great saphenous vein or

its affected tributaries, often with ultrasound guidance. Thereafter,

smaller more distal veins and incompetent perforating veins are

injected. Following completion of the procedure, elastic bandages

are applied, or 30–40 mmHg compression stockings are worn for

1–2 weeks. Average 1- and 5-year occlusion rates are 81 and 74%,

respectively, following sclerotherapy. Complications are uncommon

and include deep-vein thrombosis, hematomas, damage to adjacent

saphenous or sural nerves, and infection. Anaphylaxis is a very rare

but severe complication.

Surgical therapy usually involves ligation and stripping of the

great and small saphenous veins. The procedure is performed under

general anesthesia. Incisions are made at the groin and the upper

calf. The great saphenous vein is ligated below the saphenofemoral

junction, and a wire is inserted into the great saphenous vein and

advanced distally. The proximal part of the great saphenous vein is

secured to the wire and retrieved, i.e., stripped, via the calf incision.

Stripping of the great saphenous vein below the knee and stripping

of the small saphenous vein usually are not performed because of

the respective risks of saphenous and sural nerve injury. Complications of great saphenous vein ligation and stripping include deepvein thrombosis, bleeding, hematoma, infection, and nerve injury.

Recurrent varicose veins occur in up to 50% patients by 5 years, due

to technical failures, deep-venous insufficiency, and incompetent

perforating veins.

Stab phlebectomy is another surgical treatment for varicose

veins. A small incision is made alongside the varicose vein, and it

is avulsed by means of a forceps or hook. This procedure may be

performed in conjunction with saphenous vein ligation and stripping or thermal ablation. Subfascial endoscopic perforator surgery

(SEPS) uses endoscopy to identify and occlude incompetent perforating veins. It also may be performed along with other ablative

procedures.

Endovascular interventions, surgical bypass, and reconstruction of the valves of the deep veins are performed when feasible

to treat patients with advanced chronic venous insufficiency who

have not responded to other therapies. Catheter-based interventions, usually involving placement of endovenous stents, may be

considered to treat some patients with chronic occlusions of the

iliac veins. Technical success rates exceed 85% in most series, and

long-term patency is achieved in ~75% of these patients. Iliocaval

bypass, femoroiliac venous bypass, and femorofemoral crossover

venous bypass are procedures used occasionally to treat iliofemoral

vein occlusion; saphenopopliteal vein bypass can be used to treat

chronic femoropopliteal vein obstruction. Long-term patency rates

for venous bypass procedures generally exceed 60% and are associated with improvement in symptoms. Surgical reconstruction of

the valves of the deep veins and valve transfer procedures are used

to treat valvular incompetence. Valvuloplasty involves tightening

the valve by commissural apposition. With valve transfer procedures, a segment of vein with a competent valve, such as a brachial

or axillary vein, or adjacent saphenous or deep femoral vein, is

inserted as an interposition graft in the incompetent vein. Both

valvuloplasty and vein transfer operations result in ulcer healing in

the majority of patients, although success rates are somewhat better

with valvuloplasty.

Lymphedema Lymphedema is a chronic condition caused by

impaired transport of lymph and characterized by swelling of one or

more limbs and occasionally the trunk and genitalia. Fluid accumulates in interstitial tissues when there is an imbalance between lymph

production and lymph absorption, a process governed in large part by

Starling forces. Deficiency, reflux, or obstruction of lymph vessels perturbs the ability of the lymphatic system to reabsorb proteins that had

been filtered by blood vessels, and the tissue osmotic load promotes

interstitial accumulation of water. Persistent lymphedema leads to

inflammatory and immune responses characterized by infiltration of

mononuclear cells, fibroblasts, and adipocytes, leading to adipose and

collagen deposition in the skin and subcutaneous tissues.

Lymphatic Anatomy Lymphatic capillaries are blind-ended tubes

formed by a single layer of endothelial cells. The absent or widely fenestrated basement membrane of lymphatic capillaries allows access to

interstitial proteins and particles. Lymphatic capillaries merge to form

microlymphatic precollector vessels, which contain few smooth muscle

cells. The precollector vessels drain into collecting lymphatic vessels,

which comprise endothelial cells, a basement membrane, smooth muscle, and bileaflet valves. The collecting lymphatic vessels in turn merge

to form larger lymphatic conduits. Analogous to venous anatomy, there

are superficial and deep lymphatic vessels in the legs, which communicate at the popliteal and inguinal lymph nodes. Pelvic lymphatic vessels

drain into the thoracic duct, which ascends from the abdomen to the

thorax and connects with the left brachiocephalic vein. Lymph is propelled centrally by the phasic contractile activity of lymphatic smooth

muscle and facilitated by the contractions of contiguous skeletal muscle. The presence of lymphatic valves ensures unidirectional flow.

Etiology Lymphedema may be categorized as primary or secondary (Table 282-2). The prevalence of primary lymphedema is ~1.15

per 100,000 persons <20 years of age. Females are affected more frequently than males. Primary lymphedema may be caused by agenesis,

hypoplasia, hyperplasia, or obstruction of the lymphatic vessels. There

are three clinical subtypes: congenital lymphedema, which appears

shortly after birth; lymphedema praecox, which has its onset at the

time of puberty; and lymphedema tarda, which usually begins after

age 35. Familial forms of congenital lymphedema (Milroy’s disease)

and lymphedema praecox (Meige’s disease) may be inherited in an

autosomal dominant manner with variable penetrance; autosomal

or sex-linked recessive forms are less common. At least 19 genes are

associated with inherited forms of lymphedema. Mutations in genes

expressing vascular endothelial growth factor receptor 3 (VEGFR3),

which is a determinant of lymphangiogenesis, cause Milroy’s disease;

and a mutation of the gene encoding VEGF-C, a ligand for VEGFR3,

may cause a Milroy’s disease-like phenotype. A mutation of the

LSC1 gene is associated with the cholestasis-lymphedema syndrome.

Mutations in the FOXC2 gene, which encodes a transcription factor

that interacts with a signaling pathway involved in the development

of lymphatic vessels, cause the lymphedema-distichiasis syndrome,

in which lymphedema praecox occurs in patients who also have

a double row of eyelashes. A mutation of SOX18, a transcription factor upstream of lymphatic endothelial cell differentiation,

has been described in patients with lymphedema, alopecia, and

telangiectasias (hypotrichosis, lymphedema, telangiectasia syndrome).

Mutations of the CCBE1 gene, which enhances the lymphangiogenic effects of VEGF-C, cause Hennekam’s lymphangiectasialymphedema syndrome, and KIF11 gene mutations are associated

with microcephaly-lymphedema syndrome. Mutations of the GATA2

gene, which is involved in the development of lymphatic valves, cause

Chronic Venous Disease and Lymphedema

2119CHAPTER 282

lymphedema and a predisposition to acute myeloid leukemia. Patients

with a chromosomal aneuploidy, such as Turner’s syndrome, Klinefelter’s

syndrome, or trisomy 18, 13, or 21, may develop lymphedema. Syndromic

vascular anomalies associated with lymphedema also include KlippelTrénaunay syndrome and Parkes-Weber syndrome. Other disorders

associated with lymphedema include Noonan’s syndrome, yellow nail

syndrome, intestinal lymphangiectasia syndrome, lymphangiomyomatosis, and neurofibromatosis type 1.

Secondary lymphedema is an acquired condition that results from

damage to or obstruction of previously normal lymphatic channels.

Recurrent episodes of bacterial lymphangitis, usually caused by streptococci, are a very common cause of lymphedema. The most common

etiology of secondary lymphedema worldwide is lymphatic filariasis,

affecting >120 million children and adults and causing lymphedema

and elephantiasis in 14 million of these affected individuals (Chap. 233).

Recurrent bacterial lymphangitis by Streptococcus may result in chronic

TABLE 282-2 Causes of Lymphedema

Primary

Sporadic (no identified cause)

Genetic disorders

Milroy’s disease (VEGFR3, VEGF-C)

Meige’s disease (gene mutation not established)

Lymphedema-distichiasis syndrome (FOXC2)

Cholestasis-lymphedema (LSC1)

Hennekam’s lymphangiectasia-lymphedema syndrome (LCCBE1)

Emberger’s syndrome-lymphedema and predisposition to AML (GATA2)

Microcephaly-lymphedema syndrome (KIF11)

Hypotrichosis-lymphedema-telangiectasia (SOX18)

Chromosomal aneuploidies

Turner’s syndrome

Klinefelter’s syndrome

Trisomy 13, 18, or 21

Other disorders associated with primary lymphedema

Noonan’s syndrome

Klippel-Trénaunay syndrome

Parkes-Weber syndrome

Yellow nail syndrome

Intestinal lymphangiectasia syndrome

Lymphangiomyomatosis

Neurofibromatosis type 1

Secondary

Infection

Bacterial lymphangitis (Streptococcus pyogenes, Staphylococcus aureus)

Lymphogranuloma venereum (Chlamydia trachomatis)

Filariasis (Wucheria bancrofti, Brugia malayi, B. timori)

Tuberculosis

Neoplastic infiltration of lymph nodes

Lymphoma

Prostate

Others

Surgery or irradiation of axillary or inguinal lymph nodes for treatment of cancer

Iatrogenic

 Lymphatic division (during peripheral bypass surgery, varicose vein surgery, or

harvesting of saphenous veins)

Miscellaneous

Contact dermatitis

Podoconiosis

Rheumatoid arthritis

Pregnancy

Factitious

lymphedema. Other infectious causes include lymphogranuloma

venereum and tuberculosis. A common acquired cause of lymphedema

in tropical countries is podoconiosis, which results from barefoot

exposure and absorption of silicate particles in soil derived from

volcanic rock. In developed countries, the most common secondary

cause of lymphedema is surgical excision or irradiation of axillary and

inguinal lymph nodes for treatment of cancers, such as breast, cervical,

endometrial, and prostate cancer, sarcomas, and malignant melanoma.

Lymphedema of the arm occurs in 13% of breast cancer patients after

axillary node dissection and in 22% after both surgery and radiotherapy. Lymphedema of the leg affects ~15% of patients with cancer after

inguinal lymph node dissection. Tumors, such as prostate cancer and

lymphoma, also can infiltrate and obstruct lymphatic vessels. Less

common causes include contact dermatitis, rheumatoid arthritis, pregnancy, and self-induced or factitious lymphedema after application of

tourniquets.

Clinical Presentation Lymphedema is generally a painless condition,

but patients may experience a chronic dull, heavy sensation in the

leg, and most often, they are concerned about the appearance of the

leg. Lymphedema of the lower extremity initially involves the foot

and gradually progresses up the leg so that the entire limb becomes

edematous (Fig. 282-2). In the early stages, the edema is soft and pits

easily with pressure. Over time, subcutaneous adipose tissue accumulates, the limb enlarges further and loses its normal contour, and the

toes appear square. Thickening of the skin is detected by Stemmer’s

sign, which is the inability to tent the skin at the base of the toes. Peau

d’orange is a term used to describe dimpling of the skin, resembling

that of an orange peel, caused by lymphedema. In the chronic

stages, the edema no longer pits and the limb acquires a woody

texture as the tissues become indurated and fibrotic. The International

Society of Lymphology describes four clinical stages of lymphedema

(Table 282-3).

Differential Diagnosis Lymphedema should be distinguished

from other disorders that cause unilateral leg swelling, such as

deep-vein thrombosis and chronic venous insufficiency. In the latter

condition, the edema is softer, and there is often evidence of a stasis

A B

FIGURE 282-2 A. Lymphedema characterized by swelling of the leg, nonpitting

edema, and squaring of the toes. (Courtesy of Dr. Marie Gerhard-Herman, with

permission.) B. Advanced chronic stage of lymphedema illustrating the woody

appearance of the leg with acanthosis and verrucous overgrowths. (Courtesy of

Dr. Jeffrey Olin, with permission.)

2120 PART 6 Disorders of the Cardiovascular System

dermatitis, hyperpigmentation, and superficial venous varicosities,

as described earlier. Other causes of leg swelling that resemble

lymphedema are myxedema and lipedema. Lipedema usually occurs in

women and is caused by accumulation of adipose tissue in the leg from

the thigh to the ankle with sparing of the feet.

Diagnostic Testing The evaluation of patients with lymphedema

should include diagnostic studies to clarify the cause. Abdominal

and pelvic ultrasound and computed tomography (CT) can be used

to detect obstructing lesions such as neoplasms. Magnetic resonance

imaging (MRI) of the affected limb may reveal a honeycomb pattern characteristic of lymphedema in the epifascial compartment

and identify enlarged lymphatic channels and lymph nodes. MRI

also is useful to distinguish lymphedema from lipedema. Lymphoscintigraphy and lymphangiography are rarely indicated, but either

can be used to confirm the diagnosis or differentiate primary from

secondary lymphedema. Lymphoscintigraphy involves the injection

of radioactively labeled technetium-containing colloid into the distal

subcutaneous tissue of the affected extremity, which is imaged with a

scintigraphic camera to visualize lymphatic vessels and lymph nodes.

Findings indicative of primary lymphedema include absent or delayed

filling of the lymphatic vessels or dermal back flow caused by lymphatic

reflux. Findings of secondary lymphedema include dilated lymphatic

vessels distal to an area of obstruction. In lymphangiography, iodinated

radiocontrast material is injected into a distal lymphatic vessel that

has been isolated and cannulated. In primary lymphedema, lymphatic

channels are absent, hypoplastic, or ectatic. In secondary lymphedema,

lymphatic channels often appear dilated beneath the level of obstruction. The complexities of lymphatic cannulation and the risk of

lymphangitis associated with the contrast agent limit the utility of

lymphangiography. Optical imaging with a near-infrared fluorescence

dye may enable quantitative imaging of lymph flow.

TREATMENT

Lymphedema

Patients with lymphedema of the lower extremities must be

instructed to take meticulous care of their feet and legs to prevent

cellulitis and lymphangitis. Skin hygiene is important, and emollients can be used to prevent drying. Prophylactic antibiotics are

often helpful, and fungal infection should be treated aggressively.

Patients should be encouraged to participate in physical activity;

frequent leg elevation can reduce the amount of edema. Psychosocial support is indicated to assist patients cope with anxiety or

TABLE 282-3 Stages of Lymphedema

Stage 0 (or Ia)

A latent or subclinical condition where swelling is not evident despite impaired

lymph transport. It may exist for months or years before overt edema occurs.

Stage I

Early accumulation of fluid relatively high in protein content that subsides with

limb elevation. Pitting may occur. An increase in proliferating cells may also be

seen.

Stage II

Limb elevation alone rarely reduces tissue swelling, and pitting is manifest. Late

in stage II, the limb may or may not pit as excess fat and fibrosis supervene.

Stage III

Lymphostatic elephantiasis where pitting can be absent and trophic skin

changes such as acanthosis, further deposition of fat and fibrosis, and warty

overgrowths have developed.

Source: Adapted from The 2013 Consensus Document of the International Society of

Lymphology: Lymphology 46:1, 2013.

depression related to body image, self-esteem, functional disability,

and fear of limb loss.

Physical therapy, including massage to facilitate lymphatic drainage, may be helpful. The type of massage used in decongestive physiotherapy for lymphedema involves mild compression of the skin of

the affected extremity to dilate the lymphatic channels and enhance

lymphatic motility. Multilayered, compressive bandages are applied

after each massage session to reduce recurrent edema. After optimal

reduction in limb volume by decongestive physiotherapy, patients

can be fitted with graduated compression hose. Occasionally, intermittent pneumatic compression devices can be applied at home to

facilitate reduction of the edema. Diuretics are contraindicated

and may cause depletion of intravascular volume and metabolic

abnormalities.

Liposuction in conjunction with decongestive physiotherapy

may be considered to treat lymphedema, particularly postmastectomy lymphedema. Other surgical interventions are rarely used and

often not successful in ameliorating lymphedema. Microsurgical

lymphaticovenous anastomotic procedures have been performed to

rechannel lymph flow from obstructed lymphatic vessels into the

venous system. Limb reduction procedures to resect subcutaneous

tissue and excessive skin are performed occasionally in severe cases

of lymphedema to improve mobility.

Therapeutic lymphangiogenesis has been studied in rodent models of lymphedema. Overexpression of VEGF-C generates new

lymphatic vessels and improves lymphedema in a murine model of

primary lymphedema, and administration of recombinant VEGF-C

or VEGF-D stimulated lymphatic growth in preclinical models of

postsurgical lymphedema. There may be additional benefit when

administered in conjunction with lymph node transfer. Clinical trials in patients with lymphedema are required to determine efficacy

of gene transfer and cell-based therapies for lymphedema.

■ FURTHER READING

Aspelund A et al: Lymphatic system in cardiovascular medicine. Circ

Res 118:515, 2016.

Brouillard P et al: Genetics of lymphatic anomalies. J Clin Invest

124:898, 2014.

Executive Committee: The diagnosis and treatment of peripheral

lymphedema: 2016 consensus document of the International Society

of Lymphology. Lymphology 49:170, 2016.

Jayaraj A, Gloviczki P: Chronic venous insufficiency, in Vascular

Medicine, MA Creager, JA Beckman, J Loscalzo (eds). Philadelphia,

Elsevier, 2020, pp 709-727.

Kahn SR et al: The postthrombotic syndrome: Evidence-based prevention, diagnosis, and treatment strategies: A scientific statement from

the American Heart Association. Circulation 130:1636, 2014.

Masuda E et al: The 2020 appropriate use criteria for chronic lower

extremity venous disease of the American Venous Forum, the Society

for Vascular Surgery, the American Vein and Lymphatic Society, and

the Society of Interventional Radiology. J Vasc Surg Venous Lymphat

Disord 8:505.e4, 2020.

Rabinovich A, Kahn SR: The postthrombotic syndrome: Current

evidence and future challenges. J Thromb Haemost 15:230, 2017.

Rockson SG: Diseases of the lymphatic circulation, in Vascular

Medicine, MA Creager, JA Beckman, J Loscalzo (eds). Philadelphia,

Elsevier, 2020, pp 771-784.

Schleimer K et al: Update on diagnosis and treatment strategies in

patients with post-thrombotic syndrome due to chronic venous

obstruction and role of endovenous recanalization. J Vasc Surg

Venous Lymphat Disord 7:592, 2019.

Sharma A, Wasan S: Varicose veins, in Vascular Medicine, MA

Creager, JA Beckman, J Loscalzo (eds). Philadelphia, Elsevier, 2020,

pp 693-708.

Pulmonary Hypertension

2121CHAPTER 283

Pulmonary hypertension (PH) is a heterogenous disease involving

pathogenic remodeling of the pulmonary vasculature, which increases

pulmonary artery pressure and vascular resistance. The most common

causes of PH are left heart or primary lung disease; PH is also observed

in some patients as a late complication of luminal pulmonary embolism. Pulmonary arterial hypertension (PAH) is an uncommon, but

distinct, PH subtype characterized by the interplay between molecular

and genetic events that cause an obliterative arteriopathy and symptoms of dyspnea, chest pain, and syncope. If left untreated, PH carries a

high mortality rate, largely owing to decompensated right heart failure.

There have been significant advances in the field with regard to

understanding disease pathogenesis, diagnosis, and classification.

For example, the mean pulmonary artery pressure (mPAP) used to

diagnose PH has been lowered from ≥25 mmHg to >20 mmHg. This

adjustment emphasizes earlier detection of PH, as a substantial delay in

diagnosis of up to 2 years is common and has important implications

for both quality of life and life span. Clinicians should be able to recognize the signs and symptoms of PH and complete a systematic evaluation in at-risk patients. In this way, prompt diagnosis, appropriate

treatment, and optimized patient outcome are achievable.

■ PATHOBIOLOGY

Apoptosis resistance, cell proliferation, dysregulated metabolism, and

increased oxidant stress involving pulmonary vascular cells and adventitial fibroblasts underlie the pathogenesis of PAH. These events lead to

283 Pulmonary Hypertension

Bradley A. Maron, Joseph Loscalzo

hypertrophic, fibrotic, and plexogenic remodeling of distal (small) pulmonary arterioles, which decreases vascular compliance and promotes

in situ thrombosis (Fig. 283-1). A minority of patients appear to have

a vasoconstriction-dominant phenotype, which, if present, requires a

unique treatment strategy discussed in greater detail below.

Abnormalities in multiple molecular pathways and genes that regulate pulmonary vascular endothelial and smooth muscle cells have

been identified (Table 283-1). These abnormalities include decreased

expression of the voltage-regulated potassium channel, mutations in

the bone morphogenetic protein receptor-2, increased tissue factor

expression, overactivation of the serotonin transporter, hypoxiainduced activation of hypoxia-inducible factor-1α, and activation of

nuclear factor of activated T cells. Recently, overlap in the pathobiology

of PAH with solid tumor cancers has been recognized, leading to the

identification of pyruvate dehydrogenase kinase and neural precursor

cell expressed developmentally downregulated 9 (NEDD9) as important in PAH. Thrombin deposition in the pulmonary vasculature that

develops as an independent abnormality or as a result of endothelial

dysfunction may amplify the obliterative arteriopathy.

■ PATHOPHYSIOLOGY

In PAH, pathologic changes to pulmonary arterial compliance result

in a progressive increase in total pulmonary vascular resistance (PVR).

The resting PVR increases through the temporal progression of PAH,

corresponding to a rise in mPAP. To preserve cardiac output (CO) in the

face of elevated right ventricular afterload, right ventricular work must

increase. A sustained (or progressive) increase in right ventricular work

causes a shift in the efficiency of right ventricular systolic function by

which maintaining pulmonary circulatory pressure depletes myocardial

energy. These changes occur at the expense of energy normally reserved

to maintain optimal blood perfusion through the alveolar-capillary

Br

A B C

D E F

FIGURE 283-1 Panels on the left show examples of plexogenic pulmonary arteriopathy. Representative images of a normal lung (A) and examples of pulmonary vascular

remodeling in pulmonary arterial hypertension (B–F), including idiopathic pulmonary arterial hypertension (B–E) and pulmonary venoocclusive disease (F), are shown. A.

Normal pulmonary artery (arrow) adjacent to a terminal bronchiole (Br). B. Marked media and intima thickening of small vessels (arrow), partly surrounded by lymphoid

cells form a cluster reminiscent of a primary follicle (arrowhead). C. Idiopathic pulmonary hypertension lung with a markedly muscularized medium-sized pulmonary artery

(arrow), which distally branches into a plexiform lesion (lower arrowhead) and an adjacent plexiform lesion (upper arrowhead). D. Complex vascular lesion (circle) with a

combination of telangiectatic-like dilations of the pulmonary artery (arrowheads) and a plexiform lesion (arrow). E. Medium-sized pulmonary artery with complete lumen

obliteration with a loose collagen, poorly cellular matrix (arrows). F. Interlobular septal, medium-sized vein (arrowhead) obliterated by loose connective tissue (arrows),

likely the result of an organized thrombus, characteristic of venoocclusive disease. (These representative images were provided courtesy of Dr. Rubin Tuder. The samples

were obtained through the evaluation of lungs collected by the Pulmonary Hypertension Breakthrough Initiative, with similar pulmonary vascular pathology spectrum as

reported in reference E Stacher et al: Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186:261, 2012.) Adapted with permission of

the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved. Reproduced with permission from BA Maron et al: Pulmonary Arterial

Hypertension: Diagnosis, Treatment, and Novel Advances. Am J Respir Crit Care Med 203:1472, 2021.

2122 PART 6 Disorders of the Cardiovascular System

interface for blood oxygenation, a process termed right ventricular–

pulmonary arterial uncoupling. In end-stage PAH, the CO declines,

leading to a decrease in mPAP (Fig. 283-2), and extrapulmonary

vascular manifestations are frequent; these include overactivation of

neurohumoral signaling, renal failure, and volitional muscle atrophy,

which is likely due to deconditioning (Fig. 283-3).

■ DIAGNOSIS

The diagnosis of PH can be missed without a reasonable index of

suspicion. Indeed, findings from clinical registries suggest that PH is

often overlooked, even among patients with numerous risk factors.

This shortcoming may be because PH symptoms are nonspecific, insidious, and overlap considerably with many common conditions, such as

asthma or left heart failure. Additionally, there is a misconception that

in patients with comorbid cardiopulmonary conditions (e.g., interstitial lung disease, mitral valve disease), PH is merely an extension of the

underlying disease rather than a specific clinical entity.

Most patients will present with dyspnea and/or fatigue, whereas

edema, chest pain, presyncope, and syncope are less common and

associated with more advanced disease. In early phases of PAH, the

physical examination is often unrevealing. As the disease progresses,

there may be evidence of right ventricular failure with elevated jugular

venous pressure, lower extremity edema, and ascites. Additionally, the

cardiovascular examination may reveal an accentuated P2

 component

of the second heart sound, a right-sided S3

 or S4

, and a holosystolic

tricuspid regurgitant murmur. It is also important to seek signs of the

diseases that are commonly concurrent with PH: clubbing may be seen

in some chronic lung diseases, sclerodactyly and telangiectasia may

signify scleroderma (or the limited cutaneous form, CREST [calcinosis,

Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and

telangiectasia]), and crackles on examination of the lungs and systemic

hypertension may be clues to left-sided systolic or diastolic heart failure.

Overview of the Diagnostic Clinical Evaluation Once clinical

suspicion is raised, a systematic approach to diagnosis and assessment is essential. In advanced disease, electrocardiography may show

right ventricular hypertrophy or strain, and enlargement of pulmonary arteries and obliteration of the retrosternal space is often

observed on chest roentgenography (Fig. 283-4). In turn, echocardiography with agitated saline (bubble) study is the most important initial

screening test. Elevated estimated pulmonary artery systolic pressure

(>35 mmHg) or a hypertrophied or dilated right ventricle support the

diagnosis of PH. Important additional information can be gleaned about

specific etiologies of PH, such as valvular disease, left ventricular systolic

and diastolic function, left atrial enlargement, and intracardiac shunt.

A high-quality echocardiogram that is absolutely normal may obviate the need for further PH evaluation. However, this is distinct from

an echocardiogram in which tricuspid regurgitation is not detected. In

this scenario, the information required to estimate pulmonary artery

pressure is lacking, and PH is observed in one-third of such patients.

Patients with evidence of PH on echocardiography or in whom unexplained dyspnea or hypoxemia is evident despite an unremarkable

echocardiogram often require further assessment.

Additional tests focusing on functional capacity are useful for quantifying disease burden, such as a 6-minute walk distance (6-MWD) assessment, which also aids in assessing prognosis. Cardiopulmonary exercise

testing (CPET) differentiates between cardiac and pulmonary causes of

dyspnea and includes measuring peak volume of oxygen consumption,

which is an integrated parameter of cardiopulmonary fitness and also

useful in prognosticating PH. In patients with a normal CPET, further

invasive testing is often unnecessary. One exception to this approach is in

patients with reassuring CPET results but in whom a significant decrease

in exercise tolerance from baseline is nonetheless reported, often observed

in elite athletes or highly conditioned individuals with early-stage PH.

Invasive hemodynamic monitoring with right heart catheterization

(RHC) is the gold standard for PH diagnosis and severity assessment.

Interpretation of RHC data, however, is often optimized by information from diagnostic tests that support and frame the clinical context

of pulmonary vascular disease.

TABLE 283-1 Molecular and Genetic Determinants of the Pathogenesis

of Pulmonary Arterial Hypertension

Alterations in regulators of proliferation

• Growth factors

• PDGF

• FGF

• VEGF

• EGF

• TGF-β

• BMP

• Transcription factors

• MMPs

• Cytokines

• Chemokines

• Mitochondria

Alterations in mediators of fibrosis

• TGF-β1

• NEDD9

• Programmed death-ligand 1

• ADAMTS8

• Galectin-3

Alterations in inflammatory mediators

• Altered T-cell subsets

• Monocytes and macrophages

• IL-1β

• IL-6

• MCP-1

• RANTES

• Fractalkine

Alterations in vascular tone

• Endothelin

• Nitric oxide

• Serotonin

• Prostaglandin

• K+

 channels

• Ca2+ channels

Hypoxia-induced remodeling

• HIF-1α

• ROS

• Mitochondria

Alterations in TGF-β signaling pathways

• BMPR2

• ALK1

• Endoglin (ENG)

• SMAD9

• TGF-β1

Selected genetic risk factors

• BMPR2

• EIF2AK4

• SOX17

• AQP1

• SMAD9

• ENG

• KCNK3

• CAV1

Abbreviations: ADAMT, a disintegrin and metalloproteinase with thrombospondin

motifs; ALK1, activin receptor-like kinase 1; AQP, aquaporin; BMP, bone

morphogenic protein; CAV, caveolin; EGF, epidermal-derived growth factor; EIF2AK4,

eukaryotic translation initiation factor 2 alpha kinase 4; FGF, fetal-derived growth

factor; HIF-1α, hypoxia-inducible factor-1; IL, interleukin; KCNK, Potassium two

pore domain channel subfamily K member 3; MCP-1, monocyte chemoattractant

protein-1; MMP, mucous membrane pemphigoid; NEDD9, neural precursor cell

expressed, developmentally downregulated 9; PDGF, platelet-derived growth

factor; ROS, reactive oxygen species; SOX, SRY-box transcription factor 17; TGF-β,

transforming growth factor β; VEGF, vascular endothelial-derived growth factor.

Pulmonary Hypertension

2123CHAPTER 283

Chronic kidney

disease

Pulmonary

vasculopathy

Right ventricular:

Cardiomyocyte

dysfunction

Hypertrophy

Fibrosis

Dilation

↓RV-PA coupling

Volitional

muscle atrophy

Alveolar-capillary

thickening

↑Angiotensin II

↑Aldosterone

↑Bioactive

estrogens

FIGURE 283-3 Systemic manifestations of pulmonary arterial hypertension (PAH).

In PAH, the vasculopathy is severe and increases pulmonary vascular resistance.

This promotes right ventricular–pulmonary arterial uncoupling, which describes

inefficient work and energy expenditure by the right ventricle. Systemic

manifestations, which are likely secondary to changes in cardiopulmonary

hemodynamics, include overactivation of neurohumoral signaling, chronic kidney

disease, increased bioactive sex hormones, and volitional muscle atrophy. RV-PA,

right ventricular–pulmonary arterial.

Intervention

focus

Dual pharmacotherapy

prescription exercise

treat systemic targets

Maximal medical therapy

surgical referral

Clinical

“stage” A B C

CO

PAP

PVR

RAP

Genetic

screen

Developmental

screen

Exercise

testing

Hemodynamic

Histologic

Structural

Adv.

fibroblast

Pericyte

EC

SMC

Elastin

Proliferation of fibroblasts

and SMCs, swelling of ECs,

and fragmented Elastin

Endothelial channel

formation

Inflamatory

cell

Smooth muscle-like

cells encroach on

lumen inflammation

Time

RISK STRATIFICATION EARLY AND AGGRESSIVE

INTERVENTION

FULL INTERVENTION

FIGURE 283-2 An integrated overview of pulmonary arterial hypertension (PAH). In PAH, initial changes in the histopathophenotype of distal pulmonary arterioles precedes

significant changes in hemodynamics or the development of symptoms in most patients (clinical stage A). As vascular remodeling progresses, there is an increase in

pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), and right atrial pressure (RAP). In clinical stage B, symptoms are evident and, when diagnosed,

prompt early, aggressive treatment. Effacement of pulmonary arterioles results in severely increased PVR that promotes right heart failure, defined by a decrease in

cardiac output (CO) and PAP. Patients in clinical stage C have severe symptoms and require full therapeutic intervention. Identifying clinical stage A patients remains

challenging, although genetic risk factors or symptoms with exercise may be informative. EC, endothelial cell; SMC, smooth muscle cell. (Reprinted with permission of the

American Thoracic Society. Copyright © 2022 American Thoracic Society. All rights reserved. BA Maron, SH Abman, 2017: Translational advances in the field of pulmonary

hypertension: Focusing on Developmental Origins and Disease Inception for the Prevention of Pulmonary Hypertension. Am J Respir Crit Care Med 195:292, 2017.)

Stepwise Approach to Diagnosing PH One common PH

diagnostic strategy is outlined below; however, the approach should

be individualized in practice according to a particular patient’s clinical

and risk factor profile. For example, patients with a strong history of

inhaled tobacco use may benefit from prioritizing diagnostic tests

assessing pulmonary function and the lung parenchyma, whereas a

myocardial ischemia evaluation should be considered early in the evaluation of patients with left-sided cardiomyopathy.

PULMONARY FUNCTION AND LUNG IMAGING Pulmonary function

testing results may suggest restrictive or obstructive lung diseases as

the cause of dyspnea or PH. In PAH, an isolated reduction in diffusing

capacity of the lungs for carbon monoxide (DlCO) is a classic finding.

High-resolution computed tomography (CT) provides useful information, particularly enlargement of the main pulmonary artery, right

ventricle, and atria, as well as peripheral pruning of small vessels; however, high-resolution CT may also reveal signs of venous congestion,

including centrilobular ground glass infiltrate and thickened septa.

In the absence of left heart disease, these findings suggest pulmonary

venous disease, a rare cause of PAH that can be quite challenging to

diagnose. CT is also critical for distinguishing co-morbid interstitial

lung disease, emphysema, or overlap syndromes that include fibrosis

and obstructive pulmonary disease.

2124 PART 6 Disorders of the Cardiovascular System

SLEEP STUDIES Nocturnal desaturation is a common finding in PH,

even in the absence of sleep-disordered breathing. Thus, all patients

should undergo nocturnal oximetry screening, regardless of whether

classic symptoms of obstructive sleep apnea or obesity-hypoventilation

syndrome are present.

ASSESSMENT OF PULMONARY ARTERIAL THROMBOSIS Patients with

prior luminal pulmonary embolism are at increased risk for chronic

thromboembolic pulmonary hypertension (CTEPH), which is a specific

PH subtype characterized by vascular fibrosis and arterial microthrombus. Although CTEPH is curable in many patients by surgical endarterectomy, it is also widely underdiagnosed. Ventilation-perfusion (V.

/Q

.

 )

scanning is the primary test used to screen and diagnose CTEPH, which

should be considered in any patient with PH of unclear etiology. The role

of CT angiography in the diagnosis and management of CTEPH continues to evolve. At present, CT angiography is commonly used to stage

anatomic thromboembolic burden, which may be ultimately necessary

to determine operative candidacy. The definitive diagnostic procedure

remains pulmonary angiography since contrast enhancement in this

study provides detailed information on webbing, stricture, and vascular

tapering patterns pathognomonic for CTEPH.

SEROLOGY Laboratory data that are important for screening include

a human immunodeficiency virus (HIV) test when clinically indicated.

In addition, all patients should have antinuclear antibodies, rheumatoid factor, and anti-Scl-70 antibodies assessed to screen for the most

common rheumatologic diseases associated with PH. Liver function

and hepatitis serology tests are important to screen for underlying

liver disease. Methamphetamine use is recognized increasingly as a

cause of PAH, and screening should be considered in patients from

endemic regions or in whom the cause of PAH is not otherwise established. Finally, brain natriuretic peptide (BNP) and the N-terminus

of its pro-peptide (NT-proBNP) correlate with right ventricular (dys)

function, hemodynamic severity, and functional status in PAH. Medical

therapy also lowers NT-proBNP levels in PAH, and therefore this test

may be used as a biomarker for assessing treatment response in clinical

practice.

INVASIVE CARDIOPULMONARY HEMODYNAMICS The RHC remains

the gold standard test to both establish the diagnosis of PH and guide

selection of appropriate medical therapy. The hemodynamic criteria

for diagnosing PH requires, first, an mPAP >20 mmHg. Precapillary

and postcapillary PH are then distinguished by virtue of a pulmonary artery wedge pressure (PAWP) (or left ventricular end-diastolic

pressure [LVEDP]) ≤15 mmHg or >15 mmHg, respectively. Isolated

precapillary PH also requires a PVR ≥3.0 Wood units (WU), whereas

isolated postcapillary PH is defined by PVR <3.0 WU. Increasingly,

combined pre- and postcapillary PH is recognized, defined by elevated

mPAP >20 mmHg, PVR ≥3.0 WU, and PAWP >15 mmHg (Fig. 283-5).

These hemodynamic profiles inform PH clinical categorization. For

example, isolated precapillary PH is most often due to primary lung disease, PAH, or CTEPH. Isolated postcapillary PH occurs in patients with

mitral valvular disease, left ventricular systolic dysfunction, or heart failure with preserved ejection faction. The same etiologies for isolated postcapillary PH also underlie combined pre- and postcapillary PH. When

present, this indicates that chronic vascular congestion due to left atrial

hypertension has resulted in substantial pulmonary vascular remodeling.

Vasoreactivity testing should be reserved mainly for patients with

idiopathic or hereditary PAH. Vasodilators with a short duration of

action, such as inhaled nitric oxide (NO•

) or inhaled epoprostenol, are

preferred for testing. A decrease in mPAP by ≥10 mmHg to an absolute level ≤40 mmHg without a decrease in CO is defined as a positive

pulmonary vasodilator response, and such responders are considered

for long-term treatment with calcium channel blockers. Less than 5%

of patients are deemed vasoreactive, although prognosis among these

patients is particularly favorable.

■ PULMONARY HYPERTENSION CLASSIFICATION

In 1998, a PH clinical classification schema was formulated, of which

PAH (formerly primary pulmonary hypertension) is a subgroup,

according to similarities in pathophysiologic mechanisms and clinical

presentation. The categorization of PH at that time and currently exists

for the purpose of facilitating novel treatments to be tested among

different presentations (Fig. 283-6). Efforts are underway to define

RV

A

B C E

D

RV

RA

LV

FIGURE 283-4 Electrocardiography, chest roentgenography, and two-dimensional echocardiography in advanced pulmonary arterial hypertension. A. Standard 12-lead

electrocardiogram shows peaked R waves in lead V1

 and ST-segment depression in leads V2

–V3

, suggestive of right ventricular hypertrophy with strain (arrows). B, C.

Anterior-posterior and lateral chest roentgenogram demonstrating enlargement of central pulmonary arteries and obliteration of the retrosternal space, indicative of right

ventricular hypertrophy. D, E. Apical four-chamber and two-chamber short axis views acquired by transthoracic echocardiography demonstrate right ventricular (RV) and

right atrial (RA) enlargement, as well as interventricular septal flattening in diastole consistent with pressure overload. LV, left ventricle.

Pulmonary Hypertension

2125CHAPTER 283

No

No Yes

Exclude

PH

Exclude

PH

WHO PH

Group

1, 3, 4, 5 2 2, 5

Precapillary

PH

Isolated

postcapillary PH

Combined

pre-/postcapilIary PH

Yes

Right heart catheterization

mPAP >20 mmHg?

Is PAWP >15 mmHg?

PVR ≥3.0 WU? PVR ≥3.0 WU?

No Yes

No Yes

FIGURE 283-5 Hemodynamic classification of pulmonary hypertension (PH). Data from right heart catheterization (RHC) exclude PH or inform precapillary, postcapillary, or

combined pre-/postcapillary PH phenotypes. These categories, in turn, correspond to World Health Organization (WHO) PH clinical groups as follows: group 1, pulmonary

arterial hypertension; group 2, PH from left heart disease; group 3, PH from primary lung disease and sleep-disordered breathing; group 4, chronic thromboembolic

pulmonary hypertension; group 5, selected (rare or miscellaneous) causes of PH. mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PVR,

pulmonary vascular resistance.

WHO PH Group 123 4

No

5

Focus on left heart and lung disease:

Assess risk factors, PFT+DLCO,

Chest XR, HRCT, arterial blood gas

Is RHC indicated for definitive PH diagnosis

and to assess disease severity?

Complete RHC

Alternative non-PH

causes of symptoms

mPAP >20 mmHg,

PVR ≥3.0 WU

PAWP

≤15 mmHg

No other

cause for PH

PAH PH due to left

heart disease

PH due to

lung disease CTEPH Rare PAH

subtypes

Comorbid

diseases that are

PAH risk factors

Prior PE,

abnormal

V/Q or CTA

Obstructive or

parenchymal

lung disease

PAWP

≤15 mmHg

PAWP

≤15 mmHg

PAWP

≤15 mmHg

PAWP

>15 mmHg

Suspect PH:

Clinical features, symptoms, ECG, ECHO

FIGURE 283-6 Strategy for diagnosing pulmonary hypertension (PH) in clinical practice. A high index of clinical suspicion for PH is raised based on clinical features,

symptoms, and findings on transthoracic echocardiography (ECHO). The prevalence of PH is elevated in primary lung or cardiovascular disease; therefore, an initial

assessment should be geared toward diagnosing these comorbidities. This may include emphasis on cardiovascular risk factors, pulmonary function testing (PFT), and/or

high-resolution computed tomography (HRCT) of the chest. The diagnosis of PH and assessment of disease severity are determined by findings on right heart catheterization

(RHC). Classification of PH subtype hinges on hemodynamic parameters and clinical features. Group 2 PH may be evident with PVR <3.0 WU, as detailed in Fig. 283-5. CTA,

computed tomographic angiography; CTEPH, chronic thromboembolic pulmonary hypertension; Dl

CO, diffusing capacity of carbon monoxide; ECG, electrocardiogram; mPAP,

mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PE, pulmonary embolism; PVR, pulmonary vascular

resistance; V/Q, ventilation/perfusion nuclear scan; WHO, World Health Organization; XR, x-ray.