A 35-year-old-young man from Guatemala presented with chronic cough and progressive fatigue. He was told that he had a “hole in his heart” when he was a child but never underwent surgical repair. His oxygen saturations at rest were 84%, heart rate of 106 bpm, and a BP of 118/78 mm Hg. He had equal saturations in all 4 extremities. He had a loud second heart sound, and a III/VI holosystolic murmur at the left sternal border (LSB) with a mild right parasternal heave on palpation and clear lungs. He had only trivial edema around his ankles. On echocardiography he was found to have a large perimembranous ventricular septal defect (VSD) with predominantly right-to-left shunting with color flow Doppler assessment (Figures 10-1A, 10-1B, and 10-2).There was no evidence of any right ventricular outflow tract obstruction. He underwent a cardiac catheterization and was found to have irreversible pulmonary vascular disease with a pulmonary vascular resistance of 14 Wood units (WU) and no reversibility with a vasodilator challenge (Figure 10-3). He was not a candidate for late surgical closure of the defect. He was treated with pulmonary vasodilators for symptomatic relief. His symptoms of chronic cough did improve. He also had significant erythrocytosis and an elevated hematocrit. He did not manifest any symptoms of hyperviscosity and therefore did not undergo any phlebotomy.

CASE EXPLANATION

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  The triad of systemic-to-pulmonary cardiovascular communication, pulmonary arterial disease, and cyanosis is called Eisenmenger syndrome. The diagnosis of Eisenmenger syndrome implies that the development of pulmonary arterial disease is a consequence of increased pulmonary blood flow, and requires exclusion of other causes of pulmonary arterial hypertension (PAH).

  
  
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  Eisenmenger syndrome (ES) is a multisystem disease and affects nearly all organs of the body, including the lungs, brain, hematologic, endocrine, and reproductive system.

  
  
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  This case vividly outlines the epidemiologic pattern of ES in developing countries where ES is common sequelae of unrepaired intracardiac shunt lesions.

  
  
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  These patients often develop markedly elevated pulmonary vascular resistance (PVR) and are more likely to be inoperable secondary to Eisenmenger physiology.

EPIDEMIOLOGY

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  ES usually develops before puberty but may develop in adolescence and early adulthood.

  
  
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  Overall prevalence of ES is unknown, but is rare in developed countries.

  
  
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  In developing nations, ES is common sequelae of unrepaired intracardiac shunt lesions. These patients may have markedly elevated PVR and are more likely to be inoperable secondary to Eisenmenger physiology.

  
  
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  Rarely, ES is first diagnosed in adulthood, after the development of symptoms of pulmonary hypertension (PH), heart failure, or arrhythmias or after symptomatic presentation of the multiorgan effects of ES.

ETIOLOGY AND PATHOPHYSIOLOGY

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  Eisenmenger syndrome can occur in patients with large, congenital cardiac, or surgically created extracardiac left-to-right shunts. These shunts cause increased pulmonary blood flow. If left uncorrected this will lead to remodeling of the pulmonary microvasculature, with subsequent obstruction to pulmonary blood flow. This is commonly referred to as pulmonary vascular obstructive disease (PVOD).

  
  
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  Eventually, the pulmonary vascular resistance exceeds systemic vascular resistance, leading to PAH, reversal of the shunt (now right to left), and resultant cyanosis.^{1, 2}

  
  
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  The incidence of PAH and development of reversed shunting depends on the specific heart defect as well as any interventions performed. The risk of developing ES is determined by the size of the initial left-to-right shunt as well as the volume of pulmonary blood flow. The volume of pulmonary blood flow is determined by the PVR, which is normally high in the neonatal period, and gradually drops over a period of about 2 months. Larger shunts have an increased risk of progressing to ES.

  
  
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  The progression to Eisenmenger syndrome is represented by a spectrum of morphologic changes in the capillary bed that progress from reversible lesions to irreversible ones. Endothelial dysfunction and smooth muscle proliferation result from the changes in flow and pressure, increasing the PVR.³

  
  
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  Unrepaired atrial septal defects (ASD) are less likely to lead to pulmonary hypertension (Figures 10-4A and 10-4B). Only 10% of unrepaired ASDs progress to PH, and PH typically develops after the third decade of life.

  
  
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  Approximately 50% of infants with a large, nonrestrictive VSD (Figures 10-1A, 10-1B, and 10-2) or patent ductus arteriosus (PDA) (Figure 10-5) develop pulmonary hypertension within the first year of life, if the shunt is not surgically closed. Almost 40% of patients develop pulmonary hypertension within the first year of life if they have unrepaired VSD or PDA and transposition of the great arteries. Virtually all patients with truncus arteriosus (with unrestricted pulmonary blood flow) and patients with common atrioventricular (AV) canal defect, if unrepaired in infancy, will develop irreversible pulmonary vascular disease by the second year of life.⁴ Rarely an unrepaired aortopulmonary (AP) window is found in adults who have developed ES (Figure 10-6).

  
  
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  Iatrogenic ES can occur after placement of a surgical systemic-to-pulmonary artery shunt, such as a Blalock-Taussig-Thomas shunt. The risk of PAH depends on the diameter and length of the shunt as well as the anatomic location. Ten percent of patients with a classic Blalock-Taussig-Thomas shunt (subclavian artery–to–pulmonary artery anastomosis) have been found to develop PAH. Waterston (ascending aorta to pulmonary artery) and Potts (descending aorta to pulmonary artery) shunts, which are no longer performed, had a much higher incidence of PAH. Newer modifications to shunt procedures have significantly decreased the risk of acquired PAH.

  
  
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  The extent of intracardiac shunting is assessed as the ratio of measured pulmonary blood flow (Qp) to systemic blood flow (Qs). In a normal heart, where no shunting exists, the Qp:Qs ratio is 1:1. A net left-to-right shunt (acyanotic physiology) results in a Qp:Qs greater than 1, whereas a net right-to-left shunt (cyanotic physiology) results in a Qp:Qs less than 1. The Qp:Qs can be calculated based on differential oxygen saturations in the catheterization laboratory (Fick equation) or estimated by a variety of noninvasive imaging techniques which are beyond the scope of this chapter.

DIAGNOSIS

Cardiac/Pulmonary Historical Features

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  If a patient has known congenital heart disease (CHD) with suspected PAH, it is important to obtain records of all prior surgical and catheter-based interventions.⁵

  
  
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  Patients who develop Eisenmenger syndrome may be asymptomatic for long periods of time. The elevated PVR prevents pulmonary overcirculation and the symptoms of heart failure. This can result in a delay in diagnosis.

  
  
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  Patients with ES may present with a multitude of symptoms including dyspnea, fatigue, severely reduced exercise tolerance with a prolonged recovery phase, presyncope, and syncope. Patients may also have symptoms suggestive of heart failure including exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, and ascites.

Historical Features From Extracardiac Organ Involvement

Other symptoms are caused by various multisystem complications associated with cyanotic congenital heart disease as listed below:

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  Hematologic symptoms secondary to erythrocytosis that may include myalgia, muscle weakness, paresthesias of the digits and lip, visual changes due to retinal involvement including episodes of transient visual loss and spontaneous hyphemas, headaches, and dizziness.

  
  
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  Hyperviscosity may lead to thromboembolic events, cerebrovascular complications, gout, chest pain from pulmonary infarction, and hemoptysis. Most of the symptoms are nonspecific and are confirmed if they are relieved by phlebotomy.

  
  
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  Symptoms of a tendency toward bleeding include mild mucocutaneous bleeding, epistaxis, hemoptysis, and rarely pulmonary hemorrhage.

  
  
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  Vascular symptoms of presyncope or syncope can arise from systemic vasodilation.

  
  
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  Symptoms of cholelithiasis include abdominal or right upper quadrant pain, biliary colic, pale stool and jaundice.

  
  
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  Patients can also suffer from nephrolithiasis giving rise to renal colic, secondary gout and joint pain and swelling.

  
  
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  Joint symptoms that can arise include long bone pain and tenderness.

Physical Examination

Cardiovascular findings include the following:

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  Central cyanosis (differential cyanosis in the case of a patient with a PDA).

  
  
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  Digital clubbing can often be pronounced.

  
  
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  Elevated jugular venous pulse wave suggestive of prominent central venous pressures. There may be a dominant A-wave. In the presence of a significant tricuspid regurgitation, the V-wave may be prominent.

  
  
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  Precordial palpation reveals a right ventricular heave and, frequently, a palpable S2.

  
  
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  A pulmonary ejection click with a loud P2, can be heard.

  
  
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  High-pitched early diastolic murmur of pulmonic insufficiency.

  
  
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  Peripheral edema is common in advanced stages of right heart failure due to ES.

  
  
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  Ascites and hepatomegaly are common.

Noncardiac examination findings include the following:

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  Respiratory findings of cyanosis and tachypnea.

  
  
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  Hematologic findings may include bruising and bleeding.

  
  
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  Ocular examination can reveal conjunctival injection and rubeosis iridis. Changes from retinal hyperviscosity on funduscopic examination reveal engorged vessels, papilledema, microaneurysms, and blot hemorrhages secondary to erythrocytosis.

  
  
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  Abdominal signs include jaundice, right upper quadrant tenderness, and positive Murphy sign that may signify acute cholecystitis.

  
  
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  Rarely there can be vascular findings of postural hypotension and focal ischemia from paradoxical embolus.

  
  
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  Findings of hypertrophic osteoarthropathy include clubbing, small joint tenderness, and joint effusions.

  
  
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  A hallmark of the transition to Eisenmenger physiology can be a seemingly improving clinical condition, despite the absence of change in therapy for congestive heart failure. It represents a physiologically normalized condition caused by the progressively worsening pulmonary vascular obstructive disease (PVOD), with resolution of pulmonary over circulation and heart failure.

Electrocardiogram

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  Frontal plane QRS right-axis deviation (Figure 10-7).

  
  
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  Right or biventricular hypertrophy with associated ST-T wave changes.

  
  
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  Right atrial abnormality (tall, narrow P-wave—also called P-pulmonale).

  
  
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  Left-axis deviation is seen in patients with an atrioventricular septal defect.