John F. Rhodes, Ziyad M. Hijazi and Robert J.

Sommer
Lesions
Pathophysiology of Congenital Heart Disease in the Adult, Part II: Simple Obstructive
Print ISSN: 0009-7322. Online ISSN: 1524-4539
Copyright 2008 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Circulation
doi: 10.1161/CIRCULATIONAHA.107.742072
2008;117:1228-1237 Circulation.
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Pathophysiology of Congenital Heart Disease in the
Adult, Part II
Simple Obstructive Lesions
John F. Rhodes, MD; Ziyad M. Hijazi, MD, MPH; Robert J. Sommer, MD
W
ith the successes in cardiothoracic surgery over the
past 3 decades, adults with congenital heart disease
(CHD) outnumber, for the first time, their pediatric counter-
parts.
1,2
As a result, adult patients with CHD are beginning to
appear more frequently in the practices of adult cardiologists.
This series is designed to provide a review of the pathophys-
iology and natural history of common congenital heart
problems that are now being seen by adult cardiologists. In
the first part, simple shunt lesions were reviewed. This
section will examine the physiology and natural history of
some of the more common congenital obstructive lesions that
may be seen by adult cardiologists, as well as indications for
intervention. Principally, these lesions will include ventricu-
lar outflow obstructions that may or may not have undergone
prior intervention. Congenital obstructions of systemic and
pulmonary venous return, congenital intra-atrial obstructions,
and congenital atrioventricular valve stenosis will not be
included in this review because they are far less common and
present clinically predominantly in childhood.
Congenital Obstructive Lesions
In the normal circulation, the ventricular outflow tracts,
semilunar valves, and great arteries present no obstruction to
flow. Congenital narrowing of any of these pathways in-
creases ventricular afterload and in more distal lesions causes
maldistribution of flow (see individual defects below). In
response to the increased afterload, physiological ventricular
hypertrophy occurs, which results in thicker chamber walls,
reduced chamber compliance, and higher filling pressures in
the atrium. With severe noncompliance (diastolic dysfunc-
tion) venous congestion may occur, with exertion or even at
rest, which limits cardiac output and physical activity in this
population. A reduced stroke volume may also be a direct
consequence of increased afterload and may be particularly
important in the face of increased demands.
All patients with hemodynamically significant obstructions
of large ventriculoarterial pathways will present with a heart
murmur, the result of the turbulent flow created as blood
passes, under pressure, through the stenosis. For lesions of the
outflow tracts, valves, and proximal great arteries, echocar-
diography generally remains the diagnostic modality of choice
to establish both the site and the severity of the obstruction.
Magnetic resonance imaging (MRI) and computed tomogra-
phy are superior for imaging the more distal anatomy of the
aortic arch and the branch pulmonary arteries (PAs).
Symptoms, in general, are related to the severity of
obstruction. The pressure gradient across the lesion reflects
the degree of obstruction, as estimated either by Doppler or
by MRI techniques or as measured directly in the catheter-
ization laboratory; however, this value cannot be used in
isolation. The pressure drop is a reflection of both the degree
of pathway narrowing and the amount of flow across the
narrowed portion (Ohms law: pressureflowresistance).
The degree of obstruction could be underestimated signifi-
cantly by the pressure gradient alone, for example, in a patient
with low cardiac output or in a patient with a shunt lesion that
removes blood from a chamber proximal to the obstruction.
Similarly, small resting gradients may increase substantially
with exercise or any other state that produces a physiological
increase in flow across the lesion.
Conditions With Increased Right
Ventricular Afterload
Congenital obstruction may occur in the outlet portion of the
right ventricle (RV) proximal to the pulmonary valve (sub-
valvar stenosis), at the valve itself (valvar pulmonary steno-
sis), distal to the valve in the main pulmonary artery (MPA;
supravalvar stenosis), or more peripherally in the branch PAs.
In the absence of left-sided disease, PA pressure is normal
distal to the obstructive lesion. With increased afterload, the
RV hypertrophies, and right atrial filling pressures rise. Mild
proximal obstructions and isolated distal lesions are tolerated
easily without symptoms. In more severe cases in which there
is RV noncompliance but normal systolic performance, pa-
tients are well at rest but may experience substantial increases
in right atrial filling pressures with transient venous conges-
From the Department of Pediatrics, Division of Pediatric Cardiology, Duke University Medical Center, Durham, NC (J.F.R.); Department of Pediatrics
and Medicine, Rush Center for Congenital and Structural Heart Disease, Rush University Medical Center, Chicago, Ill (Z.M.H.); and Center for
Interventional Vascular Therapy, Cardiovascular Research Foundation, Columbia University Medical Center, New York, NY (R.J.S.).
This article is Part II in a 3-part series. Part I appeared in the February 26, 2008, issue and part III will appear in the March 11, 2008, issue of
Circulation.
Correspondence to Robert J. Sommer, MD, Director, Invasive Adult Congenital Heart Disease, Assistant Professor of Clinical Medicine and Pediatrics,
Cardiovascular Research Foundation, Columbia University Medical Center, 161 Fort Washington Ave, HIP 522, New York, NY 10032.
(Circulation. 2008;117:1228-1237.)
2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.742072
1228
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tion as flow through the right heart increases with exertion. At
that point, pulmonary blood flow can be increased no further,
the left ventricle (LV) will become relatively preload re-
duced, and systemic cardiac output will be limited. In cases
with even more severe obstruction, critical afterload eleva-
tions may lead to RV myocardial systolic dysfunction, which
creates the usual picture of right heart failure with hepatic
congestion, jugular venous distension, ascites, and peripheral
edema. Ischemia may contribute to exercise intolerance. With
significant RV hypertrophy, myocardial oxygen requirements
are increased, whereas high intraventricular diastolic pres-
sures may impair perfusion of the RV myocardium. In severe
cases, ventricular arrhythmia, syncope, and sudden cardiac
death may be seen.
Subvalvar Pulmonary Stenosis in Adults
Natural History and Physiology
Obstruction within the RV outflow tract is rare in isolation.
Most often, isolated subvalvar pulmonary obstruction in
adults is a residuum of earlier surgical intervention (ie, for
tetralogy of Fallot), but it can be seen in adult patients with
CHD who have not undergone surgery.
Severe subvalvar obstruction can present de novo in adults
with a double-chambered RV. In the double-chambered RV,
a muscular band obstructs the RV outflow tract, dividing the
chamber into a high-pressure inflow portion (proximal to
the obstruction) and a low-pressure outflow chamber (dis-
tal). The diagnosis presents most frequently in childhood as a
complex that includes the subvalvar muscular obstruction and
a perimembranous ventricular septal defect.
3
Membranous
subaortic stenosis will also be present in a small percentage of
patients. When the subpulmonary obstruction is relatively
mild, the child presents with an asymptomatic heart murmur;
however, as patients with a double-chambered RV age, the
degree of muscular obstruction tends to progress, whereas the
ventricular septal defect often closes spontaneously.
4
For
patients with access to regular medical care, the harsh systolic
murmur associated with the outflow obstruction should bring
them to attention long before the increasing afterload reaches
critical levels. However, if not diagnosed previously, these
patients may present with exercise intolerance as young
adults due to RV systolic or diastolic dysfunction. With more
severe obstruction and hypertrophy, ventricular arrhythmia,
syncope, and sudden cardiac death may be the first presenting
sign.
Indications for Intervention
Patients with clinical symptoms, patients with RV systolic
pressures approaching that of the aortic pressure, and those
with global RV hypertrophy, especially with reduced systolic
function, should be considered for intervention. RV outflow
obstruction can be assessed by Doppler (transthoracic echo-
cardiography usually gives superior angles of interrogation
compared with transesophageal echocardiography), by MRI,
or by diagnostic catheterization. In the catheterization labo-
ratory, an end-hole catheter pulled back from the PA across
the obstruction yields a typical tracing (Figure 1) that local-
izes the obstruction within the ventricle.
Surgical muscle resection with or without patching of the
outflow tract remains the standard of care,
5
although medical
management can be useful in alleviating presenting symp-
toms. Patients respond both to increasing intravascular vol-
ume to dilate the outlet pathway and to a reduction in
ventricular contractility with -blockers or calcium channel
blockers. Diuretics and afterload-reducing agents are contra-
indicated in this population. Although a number of pediatric
case reports involve the use of angioplasty to palliate subval-
var pulmonary obstruction,
6,7
no evidence exists that such an
intervention is beneficial in the adult with severe muscular
hypertrophy.
Valvar Pulmonary Stenosis
Natural History and Physiology
Isolated valvar pulmonary stenosis is present in 8% to 10% of
patients with CHD.
8
In the Second Natural History Study of
congenital heart defects,
9
patients with mild degrees of obstruc-
tion (30 mm Hg peak-to-peak gradient at catheterization)
who did not undergo surgery had a course that was indistin-
guishable from a control group with respect to survival,
symptoms, and need for therapy. More severe obstructive
gradients increase RV afterload and lead to chamber hyper-
trophy. As noted above, symptomatic patients tend to present
with symptoms of exercise intolerance. The occurrence of
symptoms and serious dysrhythmic events is generally related
to the peak-to-peak gradient across the valve.
9
Interestingly,
we, and others,
10
have observed that moderate valvar gradi-
ents, which may be very well tolerated in children, appear to
Figure 1. A, Pullback from MPA to RV inow in a patient with
double-chamber RV. On pullback from MPA to RV (second to
third beat), no systolic gradient is present, although the diastolic
pressure falls, which indicates entrance into the ventricle. On
further catheter withdrawal, a large gradient is present within the
body of the ventricle (fourth to fth beat). A pullback in a patient
with subvalvar aortic obstruction would have a mirror-image
tracing. B, Angiographic image of the subvalvar obstruction in
the RV (arrows) in a patient with double-chamber RV. RVOT
indicates RV outow tract.
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become more important clinically with aging in adults. This
may be due to the normal ventricular myocardial stiffening
frequently associated with aging. Changes in inherent com-
pliance in addition to the long-standing afterload may lead to
even higher RV filling pressures and more readily to venous
congestion.
Indications for Intervention
Patients with clinical symptoms, patients with RV systolic
pressures approaching that of the aortic pressure, and those
with global RV hypertrophy, especially with reduced systolic
function, should be considered for intervention (Figure 2).
Balloon valvuloplasty has supplanted surgical valvotomy as
the treatment of choice for valvar pulmonary stenosis since
the early 1980s. In the Second Natural History Study,
9
97%
of 210 patients who underwent surgical valvotomy for pul-
monary valve stenosis were in New York Heart Association
class I at 25 years of follow-up, but 85% had some degree of
pulmonary valve incompetence by echocardiography. The
importance of pulmonary valve incompetence in adults has
become increasingly clear, not just in isolated valvar stenosis
but in all right-heart obstructive surgery. It is now accepted
that significant, long-standing pulmonary regurgitation will
lead to progressive RV dilatation and myocardial injury/
dysfunction and is an important determinant in the develop-
ment of later symptoms in adults with CHD.
1113
Extensive
study is ongoing in this population with respect to timing of
intervention for pulmonary regurgitation to avoid RV systolic
failure
14,15
and to the potential use of the new transcatheter
valve-replacement therapies.
16,17
In adults with long-standing pulmonary stenosis and RV
hypertrophy, secondary subvalvar obstruction may occur with
acute removal of the RV afterload. The contractility of the
suddenly unloaded RV outflow musculature may lead to near
obliteration of the outflow tract immediately after interven-
tion. As with double-chambered RV patients, fluid bolus
administration and -blockers can be very useful in this
setting. Careful pullbacks, with end-hole catheters, will be
able to distinguish a residual valvar obstruction from a
new-onset reactive subvalvar obstruction (Figures 1 and 2).
With elimination of the valvar obstruction, RV hypertrophy
will regress during the first few weeks of follow-up.
18
This
results in a diminishing systolic gradient across the subvalvar
RV outflow tract but may also result in increasing pulmonary
insufficiency during follow-up as the RV chamber becomes
more compliant. Surgical valvotomy or valve replacement is
reserved for patients who do not respond to balloon interven-
tions or who have already developed significant valvar
insufficiency in addition to valve obstruction.
Supravalvar Pulmonary Stenosis
Natural History
Native supravalvar pulmonary stenosis can occur as an
isolated abnormality or in association with complex cardiac
malformations such as tetralogy of Fallot, with fetal terato-
genic exposure such as rubella or toxoplasmosis, or with
genetic syndromes such as Williams or Noonan syndromes.
Stenosis of the MPA, above the valve annulus, may also be
the result of surgical scarring from operations such as a PA
band or the arterial switch operation for transposition of the
great arteries. The hemodynamic burden of this lesion is
identical to that of valvar pulmonary stenosis. In some cases,
it may be quite difficult for the echocardiographer to distin-
guish a doming, stenotic valve from a normal valve that
cannot open fully owing to its abutment against a muscular
supravalvar ridge. MRI and computed tomographic angiog-
raphy can be very useful in this setting. In the catheterization
laboratory, careful pressure measurements with an end-hole
catheter can also help distinguish between valvar and supra-
valvar obstruction (Figure 3).
Indications for Intervention and Management
As in patients with valvar pulmonary stenosis, patients with
exercise intolerance and those with significant resting gradi-
ents should be considered for intervention. Few data exist on
catheter intervention for this patient population.
19,20
Congen-
ital supravalvar obstructions occur typically at the sinotubular
junction of the MPA. Because of the elasticity of the MPA,
which makes it resistant to balloon dilation, and the proximity
to the pulmonary valve, which makes stent implantation
undesirable, these patients are most often referred for surgery
when obstruction is severe and they are symptomatic.
21
Significant potential exists in this population for the use of
experimental transcatheter, stent-based valve implants, as
mentioned above.
Postoperative Conduit Obstruction
Surgical repairs for congenital atresia or hypoplasia of the RV
outflow tract (pulmonary atresia and tetralogy of Fallot) or
Figure 2. A, Pullback from MPA to RV in an adult with valvar
pulmonic stenosis. The PA tracing is normal, with moderate pul-
monary hypertension (patient with high LV end-diastolic pres-
sures). On pullback across the valve, both systolic and diastolic
pressures change simultaneously, which indicates obstruction at
the valvar level. The peak-to-peak gradient is 50 mm Hg. In
aortic valve stenosis, the same pressure tracing morphologies
are seen. B, Echocardiographic images of a patient with valvar
pulmonary stenosis. Thickened doming valves are shown in
both systole and diastole.
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for complex lesions in which the native pulmonary valve is
used as a systemic valve to the aorta (truncus arteriosus,
double-outlet RV, and the Ross procedure) often involve
placement of a homograft or bioprosthetic conduit from the
RV to the PA. When these grafts are placed during childhood
operations, with rare exceptions, they will eventually become
obstructed. The obstruction may simply be due to growth of
the patient, which results in a pathway that cannot accommo-
date increasing flow. It may occur, with scarring, at either the
proximal or distal anastomosis site. It may result from
external compression of the conduit by the sternum or by the
aorta, from graft calcification, from excessive intimal prolif-
eration of tissue within the lumen of the conduit, or from
kinking of the conduit itself (with scarring or patient growth).
Regardless of the mechanism, the result is pathway obstruc-
tion between the RV and MPA, which creates a hemodynam-
ic burden for the RV identical to that of the patient with a
supravalvar obstruction in the native MPA.
Indications for Intervention and Management
As in other RV outflow obstructions, patients who are
symptomatic or who have significant resting gradients that
result in RV hypertrophy with or without systolic dysfunction
should be considered for intervention. Most often, adult
patients have outgrown the conduit placed previously in
childhood, and surgical conduit replacement is required. In
some cases, intraconduit balloon or stent angioplasty may be
useful in treating discreet stenoses within an RV-to-PA
conduit.
22
Although stent angioplasty may be successful in reducing
obstruction in adult patients in the short term, particularly
with noncalcified conduits, it does not address the issue of the
insufficient conduit valve, a nearly universal finding late after
implantation.
23
As such, stent angioplasty alone is not an
ideal long-term solution, even in patients with otherwise
acceptable conduits. As a surgical alternative, this group of
patients is currently the main focus of investigators working
on stent-based transcatheter pulmonary valve implantation.
This patient population is particularly attractive for this
stent-based technology, because the size of the pathway
receiving the implantable valve is known and fixed, in
contrast to the many patients with marked dilatation (often
dynamic in nature) of the native RV outflow tract related to
prior obstruction and surgical intervention.
Branch PA Stenosis
Natural History
Branch PA obstructions may be isolated or multiple in
number, or they may occur diffusely throughout the pulmo-
nary tree. Postmortem studies in children have revealed these
lesions to consist of primarily fibrous intimal proliferation,
with medial hypoplasia and loss of elastic fibers in affected
vascular segments.
24,25
Isolated congenital obstruction of the
proximal PA is rare, but when it occurs is more often the
result of prior surgical interventions (ie, Blalock-Taussig
shunt or PA banding).
26
Multiple or diffuse narrowings of the
branch PAs, especially in conjunction with other cardiac or
systemic malformations, is a marker for congenitally acquired
genetic or infectious diseases. Williams syndrome, Noonan
syndrome, congenital rubella, and Alagille syndrome all
commonly present with branch PA stenosis, hypoplasia, or
both. It is rare that these systemic diseases remain undiag-
nosed into adulthood.
Pathophysiology and Natural History
Because of the innumerable parallel pathways available in the
pulmonary tree, an isolated branch PA stenosis may not
impose a significant afterload on the ventricle. Rather, the
higher resistance of that pathway will result in blood being
redistributed among the unobstructed (or less affected) seg-
ments in a proportion that is inversely related to the resistance
of each branch pathway. Patients may be remarkably symp-
tom free, even with severe maldistribution of flow, unless
pulmonary parenchymal disease (ie, pneumonia) affects the
well-perfused segments. In that setting, with the majority of
ventilation occurring in the poorly perfused lung, the V

/Q

mismatch is maximized, and patients may become seriously

compromised.
With more diffuse branch PA disease, affecting segments
of both lungs, RV afterload and systolic pressure may be
increased significantly. In this setting, as with other obstruc-
tive lesions, the PA pressure past the most distal obstruction
will be normal (Figure 3); however, unaffected lung segments
in such a patient will be exposed to both high pressure and
high flow (redistributed from obstructed areas). These pa-
Figure 3. A, Pullback through MPA to RV in patient with branch
or supravalvar PA stenosis. Pullback from the distal MPA (rst 3
beats) to MPA shows jump in systolic pressure without change
in diastolic pressure, which indicates that the catheter is still in
the arterial tree distal to the pulmonic valve. Further pullback
(from beat 5 to beat 6) shows no obstruction at the valve as the
catheter is withdrawn into the ventricle, where diastolic pressure
falls. The tracing could be identical in branch PA stenosis,
where the obstruction is also distal to the valve. B, Angiographic
image of a patient with Williams syndrome, with multiple levels
of branch PA stenosis.
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tients are uniquely at risk of developing segmental pulmonary
vascular disease.
Although uncommon, the diagnosis of branch PA stenosis
should always be considered in patients with a history of
CHD who present with symptoms of pulmonary embolism:
dyspnea, fatigability, and segmental lung ventilation-perfusion
mismatches. In patients with symptoms or severe maldistribu-
tion of flow, intervention is indicated both to redistribute flow
more appropriately and to reduce RV afterload.
Echocardiography cannot readily identify the level of
obstruction in the PAs past the first branch point in children
or past the bifurcation of the MPA in most adults. MRI
increasingly has become used to assess PA anatomy and flow,
particularly because it allows simultaneous assessment of RV
ejection fraction and regurgitant volumes of the right-sided
valves, when needed.
27
Angiography, however, remains the
gold standard for defining PA anatomy, whereas quantita-
tive lung perfusion scans (technetium-99m) have been invalu-
able in identifying discrepancies in segmental or lobar pul-
monary flow.
28
Of course, without invasive hemodynamic
data, neither a lung scan nor an MRI can distinguish a
significant segmental obstructive lesion from an unobstructed
lung segment with pulmonary vascular disease and high
resistance.
Indications for Intervention
Indications for catheter intervention include symptoms, a
significant decrease in pulmonary blood flow to the left or
right lung (or a specific lobe), or elevated RV afterload as
determined by the ratio of RV systolic to systemic systolic
pressures.
29,30
Although most proximal stenoses of the pre-
hilar area can be repaired surgically, more distal branch PA
obstructions are difficult for the surgeon to reach without the
potential for extensive pulmonary parenchymal injury. As a
result, the management of branch PA stenosis has been
predominantly the domain of the interventionalist since
1983.
29
Current techniques have been best applied to isolated
lesions and involve balloon angioplasty, stent angioplasty,
and the use of cutting balloons when standard balloons have
failed.
3134
Outcomes in patients with diffuse pulmonary obstructions
(Williams, Noonan, and Alagille syndromes and rubella)
have been generally poor.
35
This can be attributed to 2
factors. First, given the large number of vessels typically
involved, successful dilation of even a few significant lesions
will not result in an immediate decrease in RV afterload.
Second, when angioplasty is successful, the newly unob-
structed lung segment will suddenly face high flow, as blood
is redirected from unobstructed segments, as well as high
pressure. This may result acutely in a reperfusion injury
with significant segmental pulmonary edema that may require
ventilatory support.
36
This does not occur when the proximal
PA pressures are normal after intervention, such as in valvar
pulmonary stenosis.
Conditions With Increased LV Afterload
Similar to congenital obstructions on the right side of the
heart, left-sided congenital obstructive disease may occur at
the subvalvar, valvar, or supravalvar levels and peripherally
in the aorta (coarctation of the aorta). Although LV obstruc-
tive lesions may occur in isolation, they may also be a part of
a number of genetic syndromes. For example, hypertrophic
cardiomyopathy (subaortic stenosis) is associated with Noon-
ans syndrome, supravalvar aortic stenosis is virtually always
associated with Williams syndrome, and coarctation of the
aorta is part of Turners syndrome.
37
Left-sided obstructive
lesions may not occur in isolation. Shones complex presents
with multiple left-sided obstructive lesions and may include a
supravalvar mitral ring, parachute mitral valve deformity,
subaortic stenosis, valvar obstruction (typically bicommis-
sural or unicommissural valves), and distal aortic arch
obstructions.
38
As on the right side, with significant obstruction of the LV
outflow, chamber hypertrophy leads to reduced compliance
and higher atrial filling pressures. On the left side, higher
venous pressure and congestion may result in pulmonary
edema, particularly in higher-output states. Thus, dyspnea on
exertion is the most frequent presenting sign of clinically
important left-heart obstructive disease. Ventricular arrhyth-
mia and sudden cardiac death may also occur. Rarely,
patients may present with angina/coronary insufficiency,
when LV myocardial oxygen requirements are increased
(with increased wall thickness), and when elevated ventricu-
lar diastolic pressures or early atherosclerotic changes may
limit coronary flow.
Subvalvar Aortic Stenosis
Pathophysiology and Natural History
Subvalvar aortic stenosis comprises a spectrum of obstructive
processes in the LV outflow tract that range from a discrete
subaortic membranous obstruction to a fibromuscular tunnel-
type obstruction to the more familiar hypertrophic cardiomy-
opathy. Regardless of the presenting anatomic features, each
of these lesions tends to be progressive during childhood.
In patients with discrete subaortic stenosis, a thin fibrous
membrane stretches across the LV outflow tract from the
septal surface to the anterior leaflet of the mitral valve. The
membrane may be of variable thickness and of variable distance
below the aortic valve annulus. The membrane typically has a
central lumen that narrows the LV outflow pathway proximal
to the aortic valve. In children, the progression of obstruction
may be rapid. They may develop progressive aortic insuffi-
ciency, a result of the distortion of the valve anatomy as the
membrane extends onto the valve leaflets.
39
In adults, ob-
struction progression is much slower, with less change in the
degree of aortic regurgitation over time.
40
With the tunnel-type obstructive lesion, a thick fibromus-
cular tubular narrowing diffusely reduces the diameter of the
outflow tract. At any given time, the degree of obstruction in
both discrete and tunnel LV outflow obstruction is fixed,
with the gradient across the outflow increasing proportion-
ately to the increase in cardiac output. These lesions will
present with heart murmurs long before hypertrophy and
reduced LV compliance lead to symptoms of pulmonary
venous congestion.
In contrast to membranous and fibromuscular obstructions,
hypertrophic cardiomyopathy features a dynamic muscular
obstruction of the outflow tract. In this population, the
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gradient may increase dramatically with decreased afterload
41
or with an increase in contractility (inotropic state). The
dynamic nature of this obstruction is easily demonstrated in
the catheterization laboratory by the Brockenbrough-
Braunwald-Morrow sign (Figure 4), which occurs with the
cardiac cycle immediately after a premature ventricular
contraction.
Under normal circumstances, after a premature ventricular
beat, the physiological pause before the next ventricular
contraction allows for increases in both ventricular filling and
intracellular calcium transport. With the next ventricular
contraction, stroke volume is increased, the result of in-
creased preload and contractility. In the normal heart, both
LV and aortic systolic pressure will have a corresponding
increase. In patients with discrete membranous or fibromus-
cular subaortic obstruction, the ventricular contraction after
the premature beat will increase the outflow gradient slightly,
due to the increased stroke volume of the subsequent beat,
even as aortic pressure increases or stays the same; however,
in the patient with hypertrophic cardiomyopathy, the in-
creased inotropy after the pause causes a marked increase in
muscular contraction and a sharp rise in outflow obstruction
associated with a fall in aortic pressure. Unlike the other 2
subaortic obstructions, hypertrophic cardiomyopathy may
present with sudden arrhythmic death in an otherwise healthy
and undiagnosed patient and may be unrelated to the degree
of outflow obstruction at rest.
42
Indications for Intervention
The principal effect of subaortic obstruction is increased
ventricular afterload, with the same potential hypertrophy,
arrhythmia, chamber compliance, and pulmonary venous
congestion issues seen in other left-sided obstructive lesions.
For fixed subaortic obstructive lesions, for patients who
become symptomatic, or when significant LV hypertrophy is
present, especially in the presence of systolic dysfunction,
43
intervention is indicated. Surgery remains the definitive
therapy for these lesions, although a number of authors have
published small series using balloon angioplasty in children
and in the veterinary literature.
44
Balloon angioplasty may be
effective in transiently reducing the level of obstruction in
patients with thin membranes but appears to be palliative only
because the obstruction invariably returns.
In patients with hypertrophic cardiomyopathy, the risk of
sudden arrhythmic death appears to be independent of the
degree of outflow obstruction. Underlying myocardial disor-
ganization in the affected tissues may be the primary arrhyth-
mogenic source.
42
Thus, all patients with this diagnosis
should be treated medically. -Blockers or calcium channel
blockers remain first-line therapy in this population. Implant-
able defibrillators are being used in the population at risk.
45
When obstruction becomes significant, surgical myomectomy
improves symptoms,
46
and transcatheter alcohol ablation of
the septal tissue (by infusion into the feeding coronary
branch) has developed as a promising alternative.
47
Congenital Valvar Aortic Stenosis
Pathophysiology and Natural History
Congenital aortic valve abnormalities are common in the
population. A nonobstructive bicuspid aortic valve occurs in
1% of the population, with aortic valve stenosis presenting
clinically in 3% to 8% of all CHD patients.
48
Young adults
with unobstructed bicuspid aortic valves are most often
asymptomatic and undiagnosed. Most patients are discovered
on the basis of a cardiac murmur, in the absence of other
symptoms. With significant obstruction, LV afterload in-
creases, the myocardium hypertrophies, and chamber com-
pliance is reduced, which results in higher left atrial filling
pressures. Blood pressure distal to the obstruction is normal.
Rarely, patients may present with pulmonary venous conges-
tion or coronary insufficiency with the increased output and
workload associated with exertion. Children are almost never
symptomatic, even with the most significant obstructions;
however, aortic stenosis tends to progress and becomes more
clinically significant as patients age.
49,50
When obstructed, the mechanism of aortic stenosis in
young adults is generally fibrotic rather than calcification.
51
But, these valves do tend to calcify and become obstructed or
insufficient at an earlier age than the typical senescent
tricommissural aortic valve.
52,53
In addition, patients with
bicuspid valves have been found to have abnormalities of the
connective tissues of the aorta and are prone to marked
dilation of the ascending aorta even in the absence of
significant obstruction or insufficiency.
54,55
These patients
should be followed up noninvasively to rule out rapid aortic
growth, because root replacement may be required to prevent
Figure 4. Brockenbrough-Braunwald-
Morrow sign in patient with hypertrophic
cardiomyopathy. With the physiological
pause after a premature ventricular con-
traction in a normal heart, both lling of
the ventricle and myocardial contractility
are augmented, which creates a larger
stroke volume on the next contraction
and higher aortic pressure. In a patient
with obstructive hypertrophic cardiomy-
opathy, although lling is also aug-
mented, muscular contractility at the
subvalvar level increases the degree of
obstruction, which leads to a rise in the
calculated gradient and an actual fall in
the aortic pressure on the beat after the
pause (the fth beat in this tracing).
Rhodes et al Pathophysiology of CHD, Part II 1233
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dissection. Currently, no clear consensus exists for this
population as to the size at which prophylactic aortic root
replacement should be performed.
Indications for Intervention
Currently accepted indications for intervention include symp-
toms of exercise intolerance with LV hypertrophy, with or
without systolic dysfunction, a persistent decrease in myocardial
systolic performance due to excessive afterload, or progressive
dilation of the aortic root and ascending aorta (despite medical
therapy) in association with an obstructed or regurgitant valve.
Surgical valve replacement remains the treatment of choice for
adult patients. A group from the Toronto General Hospital has
recommended concurrent ascending aorta and/or root replace-
ment for ascending aorta dimensions in excess of 4.5 cm.
56
Balloon valvuloplasty in adults with calcific aortic stenosis
57
has
been largely abandoned as a primary therapy because of the
rapid rate of restenosis. Balloon valvuloplasty is currently
reserved as palliative therapy for a fewclinical situations in adult
patients, including patients in cardiogenic shock, symptomatic
pregnant women, and symptomatic patients who require urgent
noncardiac surgery.
58,59
Balloon valvuloplasty may also be used
as a bridge to surgical valve replacement, to assess the LV
myocardial response to afterload reduction. In children,
clinically important obstructions may present without
symptoms and without calcification. Balloon valvuloplasty
has been shown to have excellent short- and medium-term
outcomes in this population.
5761
In general, peak-to-peak
gradients of 50 mm Hg at rest (with normal cardiac output)
are accepted as the threshold for intervention in children. The
patient age at which balloon therapy is not indicated is not
well defined.
A number of percutaneous valve implants have been
developed recently and are undergoing initial clinical tri-
als.
62,63
This holds particular promise for the patient with
combined calcific aortic stenosis and regurgitation. Current
trials are limited to patients who have been refused surgery
owing to age, cardiomyopathy, or other comorbid conditions.
Supravalvar Aortic Stenosis
Pathophysiology and Natural History
Supravalvar aortic stenosis is an unusual cardiovascular
finding and is usually a marker for the Williams-Beuren
syndrome, an easily recognizable neurodevelopmental disor-
der characterized by connective tissue and central nervous
system abnormalities. Isolated supravalvar aortic stenosis
occurs at the level of the sinotubular junction in 70% of
patients with cardiovascular manifestations.
64,65
Diffuse hyp-
oplasia and stenosis of the branch PAs is the most frequent
associated finding, occurring in 41% to 57% of patients with
supravalvar aortic stenosis. Other less frequent associations
include coarctation of the aorta, valvar pulmonary stenosis,
septal defects, and atrioventricular valve prolapse.
Physiologically, the supravalvar obstruction creates an
increased afterload for the LV, depending on the severity of
the narrowing, similar to valvar aortic stenosis; however,
unlike valvar stenosis, the supravalvar lesion also imposes
high pressure on the coronary arteries. A pathology series
reported dilatation and tortuosity, as well as premature
atherosclerotic disease, in this population, similar to patients
with uncontrolled systemic hypertension,
66
although the in-
cidence of clinically severe coronary disease appears to be
very small in the population with Williams-Beuren syndrome.
Congenital stenosis of the coronary, renal, subclavian,
splanchnic, and carotid arteries has also been observed.
With a defined elastin-gene heterozygosity identified as the
cause of the arteriopathy associated with this syndrome,
67
it is
interesting to note the unusual clinical course associated with
these arterial obstructions. Mild supravalvar aortic obstruc-
tions (20 mm Hg gradient) tend to regress or remain stable,
as with aortic valve stenosis; however, some patients with
more severe supravalvar obstructions have had regression in
the degree of obstruction during long-term follow-up.
68
On
the pulmonary side, the tendency toward regression is the rule
rather than the exception.
Indications for Intervention
Because a documented chance of regression exists, isolated
supravalvar aortic stenosis without clinical or echocardiographic
findings of LV dysfunction should be monitored noninvasively.
In the setting of excessive LV afterload or with clinical symp-
toms, surgery is the treatment of choice. Interventional proce-
dures are likely to fail. The thickened elastic tissue of the aortic
root will be resistant to balloon angioplasty, like that of the
supravalvar pulmonary stenosis, and stenting has no role so close
to the aortic valve leaflets and the coronaries. In this type of
systemic syndrome, the patients overall condition, including
neurodevelopmental and endocrine status (not just the cardio-
vascular component), must be considered in making a recom-
mendation to intervene.
Coarctation of the Aorta
Coarctation of the aorta is a congenital narrowing of the aorta
that accounts for 5% to 8% of all CHD.
48
The obstructive
lesion occurs just distal to the origin of the left subclavian
artery where the fetal ductus arteriosus had previously in-
serted into the aorta. The obstruction is usually a discrete,
tubular narrowing, but common anatomic variations include
long-segment stenosis and transverse aortic arch hypoplasia
proximal to the coarctation. Histological abnormalities of the
medial layer can be seen in the affected area.
69
Between 50%
and 85% of patients with coarctation also have a bicuspid
aortic valve.
70
Obstruction of the aorta distal to the takeoff of the subclavian
and carotid arteries creates not only an afterload for the LV but
also a maldistribution of flow, similar to the branch PA obstruc-
tions. Although the proximal/upper segment of the aorta receives
blood flow normally from the LV, there will be a diminished
pressure head reaching the lower portions of the body distal to
the obstruction (Figure 5). The juxtaglomerular apparatus in the
kidneys, perceiving a low-flow condition, modulates vascular
tone and intravascular volume through the secretion of vasocon-
strictive substances to attempt to restore perfusion pressure in the
distal aorta. With the fixed obstruction at the coarctation and
maintenance of flow (cardiac output), the result is a significant
blood pressure elevation proximal to the coarctation. Over time,
the body will develop alternate pathways from the ascending to
the descending aorta in the form of collateral arterial vessels.
1234 Circulation March 4, 2008
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Small branches from the mammary and intercostal arteries will
grow substantially as flow increases. This results in the typical
rib-notching pattern seen on chest radiographs in a patient with
coarctation as the enlarged and dynamic intercostal arteries
erode/remodel the lower margins of the ribs. Significant collat-
eral flow may mask the severity of the obstruction, as
measured by the pressure gradient from the upper to the lower
segments (either by echocardiography, by MRI, or by direct
pressure measurement in the catheterization laboratory), because
only a percentage of the cardiac output actually traverses the
obstruction. In the most extreme cases, teenagers and young
adults may present with an actual interruption of the aorta. These
patients are dependent entirely on the collateral flow to the distal
aorta but are physiologically no different from patients with
severe coarctation.
Natural History
Although the disorder is most frequently diagnosed in the
child who presents with hypertension, diminished pulse
volume in the lower extremities, or a heart murmur (either
from the coarctation itself or from the associated bicuspid
aortic valve), coarctation may go undetected well into adult-
hood. Because of systemic hypertension in the upper body,
these individuals are predisposed to premature coronary
artery disease and cerebral berry aneurysm (3% to 5%).
71,72
Adults typically present with refractory hypertension but may
also complain of headaches, nosebleeds, cool extremities,
fatigue, and leg weakness/claudication with exertion. They
may also develop iatrogenic problems related to antihyper-
tensive therapy (claudication or prerenal azotemia). Less
common clinical manifestations include angina, exertional
dyspnea, and heart failure from chronically increased LV
afterload. For the adult with unrepaired, isolated coarctation,
the average survival is 35 years of age, with a 25% survival
rate beyond 50 years of age.
71
Patients may have undergone prior surgical or interven-
tional procedures for coarctation. Surgical scarring or poor
growth of the repaired segment after a childhood repair may
result in restenosis. Older surgical repairs, in which Dacron
conduits were used to bypass the obstructed segment, may
become obstructed themselves. This may occur when a child
outgrows the conduit placed, when neoendothelialization of
the prosthesis narrows the lumen significantly, or as the result
of kinking of the conduit from scarring or patient growth.
In some patients, congenital hypoplasia of the proximal aortic
arch may be unmasked as obstructive when the discreet
coarctation site is opened successfully. In any of these
recurrent coarctation situations, the clinical presentation and
the underlying physiology are the same.
Indications for Intervention
Current indications for intervention in an adult patient include
clinical symptoms, hypertension at rest, or severe hyperten-
sion with exertion. Because the hypertension associated with
coarctation is due to a mechanical obstruction in the circula-
tion, patients cannot be treated with any pharmacological
therapy that reduces vascular tone, diminishes intravascular
volume, or lessens cardiac output. The blood pressure, as
measured in the arms, may be corrected with such medical
therapy, but the result will be substantial reduction in the
perfusion pressure of the lower part of the body. Coarctation
of the aorta requires a mechanical solution to eliminate the
pressure difference between upper and lower segments.
Surgical reconstruction of the aorta was the treatment from
1945
73
until the 1980s, when balloon angioplasty became a
competitive option.
74,75
More recently, endovascular stents
for both native and recurrent coarctation of the aorta have
gained acceptance as the procedure of choice in teenagers and
young adults who have achieved full growth.
7684
Although
early and mid-term follow-up data appear to favor stent
angioplasty over balloon dilation in adults, stenting the aorta
may still be associated with serious adverse events.
8588
Long-term outcomes remain unknown.
Covered stents
89
may become the primary therapy in the
future in an effort to avoid the potential complications of
arterial dissection, tear, or rupture, but they are not yet
available in the United States in sizes large enough for a
typical aorta. No comparative studies have yet appeared that
compare covered stents with other options.
Conclusions
Obstructive disease is relatively common in the adult popu-
lation with CHD and may affect ventricular function signif-
icantly. Although most adult cardiologists are experienced
and comfortable with the pathophysiology of isolated valvar
and subvalvar aortic valve stenosis, right-sided outflow and
arterial obstructions are less common. More distal obstruc-
tions in either the right or left sides of the circulation produce
redistribution of blood flow to lower-resistance pathways,
which creates more complicated physiologies. Comfort with
Figure 5. A, Pullback from ascending to descending aorta in
patient with severe coarctation of the aorta. Pullback through
the aortic obstruction reveals a dampening of the tracing with a
signicant drop in peak systolic pressures. B, Aortic angiogram
in a patient with coarctation of the aorta. Arrow indicates
obstructed segment.
Rhodes et al Pathophysiology of CHD, Part II 1235
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the physiology of the simple obstructions is critical in
understanding the more complex congenital malformations
that will be presented in the next article in this series.
Disclosures
None.
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KEY WORDS: coarctation

heart defects, congenital

physiology
Rhodes et al Pathophysiology of CHD, Part II 1237
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