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Congenital heart defects (CHDs) associated with large
systemic-to- pulmonary shunts, (eg, atrial septal defect,
ventricular sep-tal defect, patent ductus arteriosus)
can lead to pulmonary vas-cular disease, which is characterized
by bidirectional shunting or reversal of the shunt. This
phenomenon, which is associated with progressive cyanosis,
polycythemia, and ultimately, func-tional limitation,
was first described in 1897 by Viktor Eisenmenger and
later termed the Eisenmenger syndrome (ES). If it is not
corrected before fixed vascular disease develops, the
patient is a poor surgical candidate as the failing right
ventricle cannot tolerate closure of the defect. Approximately
one third of all patients with CHD who have not undergone
corrective procedures or who die of other causes, will
die from pulmonary vascular disease.1 The course of the
disease, however, is usu-ally more favorable than for
patients with primary pulmonary hypertension (PPH). Today,
while there have been many advances in our understanding
of the pathophysiology and treatment of ES in adults,
there is still no cure for this progres-sive condition
once it is established, aside from lung or heart-lung
transplantation which is associated with significant mor-bidity
and mortality.2
Natural History
The natural history of ES is highly variable, although
overall sur-vival is significantly better than for patients
with PPH. Actuarial survival without transplantation is
97% at 1 year, 89% at 2 years, and 77% at 3 years for
patients with ES and 77%, 69%, and 35%, respectively,
for patients with PPH,3 (Fig 1).
Most patients survive into the third to fourth decade
of life, and there are rare case reports of patients living
into the seventh decade. The Second Congenital Heart Disease
Natural History Study (1993) demontrated that patients
with ES can survive for sev-eral decades following diagnosis.
In this study, 54% of 98 unoperated patients with ventricular
septal defects and ES were alive 20 years after diagnosis.4
Further, in a retrospective study of 109 adults with ES,
the median survival was 52.6 years of age.5 Some risk
factors that have been associated with earlier mortality
in ES patients have included trisomy 21, syncope, hemoptysis,
elevated right atrial (RA) pressure, lower systemic arterial
oxygen saturation, supraventricular arrhythmia, earlier
age at presentation, electrocardiographic evidence of
RVH, poor functional class, pregnancy, and ventricular
or aortopulmonary shunt vs intraatrial shunt.5-7
Pathophysiology
The pathophysiologic mechanisms, which lead to the histopathologic
changes seen in ES, are not completely under-stood. Increased
shear stress, flow, and pressure contribute to the pathobiology
of pulmonary vascular disease. In patients with large
left-to-right shunts, the pulmonary vascular bed is subjected
to ongoing shear stress. This leads to the histopatho-logic
changes seen in pulmonary arterial hypertension (PAH),
which include pulmonary arteriolar medial hypertrophy,
intimal fibrosis, and plexiform lesions (Figs. 2, 3).
In ES patients, this may be the result of increased flow
across the pulmonary vascular bed causing peripheral extension
of muscle from differentiating pericytes and intermediate
cells in precapillary vessels. In addition, damage to
the pulmonary vascular endothelium from a mechanical stretch
injury sets a series of events in motion at the cellular
level (implicated in the pathogenesis of pulmonary vascular
disease).6,8 As a result of these events, pulmonary vascular
resistance increases and ultimately leads to a decrease
in left to right shunting. Eventually, when the resistance
becomes significantly elevated, shunting becomes bi-directional
and at later stages becomes predomi-nantly right to left.
The long-term outlook for patients with ele-vated pulmonary
vascular resistance who undergo closure of their defect(s)
is worse than for unrepaired ES patients with the same
lesion(s).9 This may be related to the absence of a com-munication
between the right and left circulations, which may serve
as a “pop-off valve” in patients who are at risk for pul-monary
hypertensive crises.10 Systemic cardiac output is greater
in patients with ES than in those with PPH, presumably
secondary to the presence of their pop-off valve. In contrast
to PPH patients, right ventricular function is typically
preserved and heart failure is uncommon in patients with
ES, until the end stages of the disease.11,12
Diagnosis
Clinical History/Symptoms: Timely diagnosis
of a large systemic to pulmonary shunt is critical in
the prevention of ES. Defects closed within the first
two years of life are unlikely to lead to pulmonary vascular
obstructive disease.4 Infants with large, unrestrictive
defects usually present initially with signs of con-gestive
heart failure, and failure to thrive. Following years
of continued exposure to high shear stress from the left
to right shunting, the pulmonary vascular resistance increases,
usually to systemic levels, leading to reversed shunting.
Cyanosis then follows, which can be severe. In rare cases,
the history of con-gestive heart failure or failure to
thrive in infancy is absent. In these patients, reversal
of flow may have occurred within the first two years of
life. This group may represent a subset of patients who
may have never had the normal physiologic fall in the
pulmonary vascular resistance after birth or perhaps may
represent a subset of patients with an increased susceptibility
to pulmonary vascular disease. Eventually, all adults
with ES develop cyanosis and suffer from some of its inherent
complications, eg, polycythemia, headaches, blurry vision,
cerebral abscesses and/or strokes. In addition, most patients
develop progressive shortness of breath, dys-pnea on exertion,
and exercise intolerance. Patients may also complain of
chest pain. Hemoptysis is more common with advancing age.
Physical Signs
On physical examination, ES patients may appear cyanotic
at rest. In the early stages of the disease, they may
only develop cyanosis with exertion. Virtually all ES
patients will become progressively more cyanotic with
exertion. Clubbing of the digits may be pres-ent. Most
patients have normal jugular venous pressure on physical
examination. On cardiac examination a right ventricular
lift, a loud, palpable single S2, a high-pitched diastolic
murmur of pulmonary insufficiency, and a pansystolic murmur
of tricuspid insuf-ficiency may also be present. If there
is con-gestive heart failure, peripheral edema, ascites,
and hepatosplenomegaly may be present.
Diagnostic Testing
The electrocardiogram in patients with ES typically demon-strates
right axis deviation and right ventricular hypertrophy.
A right ventricular strain pattern may also be present,
with asso-ciated ST-T segment changes (Fig 4). The chest
x-ray may demonstrate right ventricular enlargement and
enlarged central pulmonary arteries with “pruning” of
the peripheral pulmonary vessels. The peripheral pruning
is usually a late finding. The central pulmonary arteries
often appear severely enlarged in patients with atrial
septal defects. Two-dimensional echocar-diography may
demonstrate any of the following: a dilated right ventricle
and atrium, right ventricular hypertrophy, diminished
right ventricular function, tricuspid regurgitation, pulmonary
insufficiency, flattening or posterior bowing of the interventric-ular
septum, and bidirectional or right-to-left shunting across
the cardiac defect.
Right and left heart catheterization may be performed
to assess “operability”. The patient is usually considered
“inoper-able” if the pulmonary vascular resistance is
greater than 10 Wood units /m 2 despite the administration
of acute pulmonary vasodilator agents such as inhaled
nitric oxide, intravenous epoprostenol, intravenous adenosine,
or inhaled iloprost. Laboratory testing should include
hemoglobin, hematocrit, and iron studies to determine
the extent of polycythemia and need for supplemental iron.
A coagulation profile should be per-formed at baseline
prior to consideration of anticoagulation.
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