Eisenmenger Syndrome

Eisenmenger syndrome refers to any untreated congenital cardiac defect with intracardiac
communication that leads to pulmonaryhypertension, reversal of flow, and cyanosis.[1, 2, 3] The
previous left-to-right shunt is converted into a right-to-left shunt secondary to elevated
pulmonary artery pressures and associated pulmonary vascular disease. (See Etiology,
Treatment, and Medication.)
Lesions in Eisenmenger syndrome, such as large septal defects, are characterized by high
pulmonary pressure and/or a high pulmonary flow state. Development of the syndrome
represents a point at which pulmonary hypertension is irreversible and is an indication that the
cardiac lesion is likely inoperable (see the image below). (See Etiology, Workup, and
Treatment.)

Eisenmenger syndrome was initially described in 1897, when Victor Eisenmenger

reported on a patient with symptoms of dyspnea and cyanosis from infancy who
subsequently developedheart failure and succumbed to massive hemoptysis.[4] An
autopsy revealed a large ventricular septal defect (VSD) and an overriding aorta. This
was the first description of a link between a large congenital cardiac shunt defect and
the development of pulmonary hypertension. (See Presentation and Workup.)
Advances in the medical treatment of patients with severe pulmonary hypertension may
improve survival in patients with Eisenmenger syndrome and may potentially reverse
the process in selected patients to a point at which they again become candidates for
surgical repair. (See Treatment and Medication.) [5]

Pulmonary hypertension
Pulmonary hypertension is defined as a mean pulmonary artery pressure of more than 25 mm Hg at rest
or more than 30 mm Hg during exercise. The World Health Organization (WHO) has published a
classification system of various etiologies of pulmonary hypertension; the most recent update was
published in 2013.[6]Eisenmenger syndrome is considered part of the group 1 causes of pulmonary
hypertension, according to the Venice classification.

Intracardiac communication
An intracardiac communication allows high pulmonary artery pressures to develop and produces right-toleft intracardiac blood flow. Originally described in association with a large VSD, Eisenmenger syndrome
can also manifest with a patent ductus arteriosus (PDA) or, less frequently, with other congenital cardiac
anomalies.
Examples of congenital heart disease subtypes that may cause pulmonary vascular disease and proceed
to Eisenmenger syndrome include the following:

Increased pulmonary arterial flow - Atrial septal defect (ASD), systemic arteriovenous fistulae,
total anomalous pulmonary venous return
Increased pulmonary arterial pressure and flow - Large VSD, large PDA, truncus arteriosus,
single ventricle with unobstructed pulmonary blood flow
Elevated pulmonary venous pressure - Mitral stenosis, cor triatriatum, obstructed pulmonary
venous return

Epidemiology
Eisenmenger syndrome usually develops before puberty but may develop in adolescence and early
adulthood.
Patients in underdeveloped countries are more likely to present late with uncorrected congenital cardiac
lesions and a markedly elevated pulmonary vascular resistance (PVR). They are more likely to be
inoperable secondary to Eisenmenger physiology.

Etiology
Eisenmenger syndrome occurs in patients with large, congenital cardiac or surgically created extracardiac
left-to-right shunts. These shunts initially cause increased pulmonary blood flow.
If left unchecked, increased pulmonary blood flow and/or elevated pulmonary arterial pressure can result
in remodeling of the pulmonary microvasculature, with subsequent obstruction to pulmonary blood flow.
This is commonly referred to as pulmonary vascular obstructive disease (PVOD).
According to Ohms law, flow (Q) is inversely related to resistance (R) and is directly proportional to
pressure (P), as represented by the equation Q = P/R. Any increase in flow, as is observed in patients
with intracardiac defects and initial left-to-right shunts, results in increased pulmonary artery pressures.
Additionally, any increase in resistance, as occurs in PVOD, results in a decrease in effective flow at the
same pressure.
The progression to Eisenmenger physiology 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. [7]
The cellular and molecular mechanisms remain fully uncharacterized, representing pathways of
inflammation, cell proliferation, vasoconstriction, and fibrosis. [8] The mechanism of pulmonary hypertension
in congenital heart disease may share characteristics with other mechanisms of pulmonary hypertension,
but the pathways remain complex.
In 1958, Heath and Edwards proposed a histologic classification to describe the changes in Eisenmenger
syndrome.[9] Stages I and II represent disease that is most likely reversible. Stage III disease may still be
reversible, but in progressing to stages IV-VI, the disease is thought to become irreversible. Pulmonary
biopsies are rarely performed today for this condition.

Natural history
Failure to reduce pulmonary pressures in the first 2 years of life may result in the failure of the normal
regression of the intimal smooth muscle. This is followed by the progressive changes described by Heath
and Edwards.[9] The condition then advances to irreversible pulmonary hypertension, defined as
unresponsiveness to inhalation of 100% oxygen or nitric oxide. This point usually correlates to a PVR of
more than 12 Woods units.

Clinically, patients gradually develop the following complications of advanced pulmonary vascular
disease:

Dyspnea upon exertion

Syncope
Chest pain
Stroke
Brain abscess
Cyanosis
Congestive heart failure
Dysrhythmia
Hyperviscosity complications
Pulmonary hemorrhage/hemoptysis
Endocarditis
The time frame for this process depends on the anatomic nature of the lesion and whether conditions,
such as trisomy 21 (Down syndrome), that are known to accelerate the development of PVOD are
present.[10] Without intervention, reversal of flow may happen in early childhood or around puberty, and
progression of symptoms may lead to death by the second or third decade of life. [11, 12]Interestingly, adult
patients with Eisenmenger syndrome may have a better prognosis compared with those with other
causes of pulmonary hypertension.[13]

Causes
Causes of Eisenmenger syndrome include the following:

Large, uncorrected cardiac shunt or palliative, surgically created systemic-to-pulmonary shunt for
congenital heart disease
Large, nonrestrictive VSD
Nonrestrictive PDA
Atrioventricular septal defect, including a large ostium primum ASD without a ventricular
component
Aortopulmonary window
Palliative, surgically created systemic-to-pulmonary anastomosis for treatment of congenital heart
disease

Prognosis
Eisenmenger syndrome is uniformly fatal; however, some patients survive into the sixth decade of life.
The usual life expectancy of a patient with Eisenmenger syndrome is 20-50 years if the syndrome is
diagnosed promptly and treated with vigilance. The onset of pulmonary hemorrhage is usually the
hallmark of a rapid progression of the disease.[14]
The complications of chronic cyanotic heart disease affect multiple organ systems, including the
hematologic, skeletal, renal, and neurologic systems, causing significant morbidity and mortality.

The quality of life is poor in patients with Eisenmenger syndrome because exercise tolerance is extremely
limited (due to limited oxygen uptake resulting from an inability to increase pulmonary blood flow) and
complications are profound. Poor prognosis is predicted by syncope, elevated-right sided pressures, and
hypoxemia.
A study by Salehian et al reported that left ventricular dysfunction (defined as left ventricular ejection
fraction [LVEF] < 50%), right ventricular hypertrophy, and signs and symptoms of heart failure predict
mortality in patients with Eisenmenger syndrome.[15] A simple echocardiographic score relying on right
ventricular and right atrial characteristics was found to predict adverse outcomes in patients with
Eisenmenger syndrome that is not associated with complex congenital heart disease. [16]
Uncorrected congenital heart disease with development of Eisenmenger complex portends an insidious
progression to near complete physical disability.

Occurrence
The frequency of pulmonary hypertension and the subsequent development of reversed shunting vary
depending on the specific heart defect and operative intervention. Such variations include the following:

Large, nonrestrictive VSD or PDA - Approximately 50% of infants with one of these defects
develop pulmonary hypertension by early childhood
VSD or PDA and transposition of the great arteries - Forty percent of patients develop pulmonary
hypertension within the first year of life
Large secundum ASD - The natural history of a large secundum ASD differs in that the 10% of
cases that progress to pulmonary hypertension do so more slowly and usually not until after the third
decade of life
Persistent truncus arteriosus and unrestricted pulmonary blood flow - All patients develop severe
pulmonary hypertension by the second year of life
Common atrioventricular canal - Almost all patients develop severe pulmonary hypertension by
the second year of life
Surgically created systemic-to-pulmonary shunt - The frequency of pulmonary hypertension
varies depending on size and anatomy
Blalock-Taussig anastomosis (subclavian artery to pulmonary artery) - Ten percent of patients
develop pulmonary hypertension
Waterston (ascending aorta to pulmonary artery) or Potts (descending aorta to pulmonary artery)
shunt - Thirty percent of patients develop pulmonary hypertension.

Morbidity
Complications in Eisenmenger syndrome include the following:

Hematologic complications - These include hyperviscosity syndromes related to secondary

erythrocytosis and bleeding diatheses
Nervous system complications These include brain abscess, transient cerebral ischemia,
thrombotic stroke, and intracerebral hemorrhage
Hyperbilirubinemia - Increases the risk of gallstones
Hyperuricemia - Can cause nephrolithiasis and secondary gout
Hypertrophic osteoarthropathy - Causes bone pain and tenderness
Vision loss - Reports document transient vision loss related to peripheral retinal microvascular
abnormalities

Congestive heart failure

Dysrhythmia
Pulmonary infarction and hemorrhage
Infective endocarditis
Syncope - The systemic vascular bed is prone to vasodilation and subsequent systemic arterial
hypotension, which can cause syncope
Sudden death

Mortality
Patients with Eisenmenger syndrome usually do not survive beyond the second or third decade. Longterm survival depends on the patients age at the onset of pulmonary hypertension and the coexistence of
additional adverse features, such as Down syndrome. Survival predominantly depends on right ventricular
function. The mortality rate in pregnant patients with Eisenmenger syndrome is reported to be
approximately 50%, although it may be higher.
The most frequent terminal event in this syndrome is a combination of hypoxemia and arrhythmia in the
setting of rapid increases in pulmonary vascular resistance or decreases in systemic vascular resistance
(SVR). Death also commonly results from congestive heart failure, massive hemoptysis, or
thromboembolism.[11]
A study by Diller et al indicated that survival rates for untreated patients with Eisenmenger syndrome may
have been overestimated in previous studies and that these rates have not improved since the 1970s.
The report involved a literature review of 12 studies published between 1971 and 2013 (1131 patients
total), along with an analysis of 219 contemporary, treatment-nave patients at the investigators own
institution.[17]
The investigators stated that almost none of the studies appropriately accounted for immortal time bias
and therefore overestimated patients survival chances by as much as 20 years. When Diller and
colleagues took immortal time bias into account, they determined that the 10-year mortality rate among
untreated patients approached 30-40%. They also found no indication that the chances of survival for
these patients were better than they would have been in the 1970s, 1980s, or 1990s, although survival
prospects were found to be better than for patients in the 1950s and 1960s. [17]