BONOW ET AL., ACC/AHA TASK FORCE REPORT
JACC Vol. 32, No. 5, November 1998:1486-1588
ACC/AHA
Guidelines for the Management of Patients With Valvular
Heart Disease
III.
Specific Valve Lesions
A.
Aortic Stenosis
1.
Introduction. The most common cause of AS in adults
is a degenerative-calcific process that produces an
immobilization of the aortic valve cusps. This calcific
disease progresses from the base of the cusps to the
leaflets, eventually causing a reduction in the effective
valve area; true commissural fusion may not occur. A
congenital malformation of the valve may also result
in stenosis and is the more common cause in young adults.
The management of congenital AS in adolescents and young
adults is discussed in section VI.A. of these guidelines.
Over several decades, progressive fibrosis and calcification
of the congenitally abnormal valve (often bicuspid)
produce a deformity that resembles the degenerative-calcific
lesion. Rheumatic fever results in AS due to fusion
of the commissures with scarring and eventual calcification
of the cusps. Thus, calcification is a common feature
of AS in older adults regardless of the primary cause
(41-43).
An
ejection systolic murmur may be heard in the presence
of a normal valve, one that is thickened and minimally
calcified, and one that is stenotic (41,44).
The 3 conditions must be distinguished.
a.
Grading the Degree of Stenosis. The aortic valve
area must be reduced to one fourth its normal size before
significant changes in the circulation occur. Because
the orifice area of the normal adult valve is ~3.0 to
4.0 cm2, an area >0.75 to 1.0 cm2
is usually not considered severe AS (44,45).
Historically, the definition of severe AS is based on
the hydraulic orifice-area formulae developed by Gorlin
and Gorlin, which indicate that large pressure gradients
accompany only modest increments in flow when the valve
area is <0.75 cm2 (46).
However, in large patients, a valve area of 1.0 cm2
may be severely stenotic, whereas a valve area of 0.7
cm2 may be adequate for a smaller patient.
On
the basis of a variety of hemodynamic and natural history
data, in these guidelines we graded the degree of AS
as mild (area >1.5 cm2), moderate (area
>1.0 to 1.5 cm2), or severe (area <1.0
cm2) (46a).
When stenosis is severe and cardiac output is normal,
the mean transvalvular pressure gradient is generally
>50 mm Hg. Some patients with severe AS remain asymptomatic,
whereas others with only moderate stenosis develop symptoms.
Therapeutic decisions, particularly those related to
corrective surgery, are based largely on the presence
or absence of symptoms. Thus, the absolute valve area
(or transvalvular pressure gradient) is not usually
the primary determinant of the need for aortic valve
replacement (AVR).
2.
Pathophysiology. In adults with AS, the obstruction
develops gradually--usually over decades. During this
time, the left ventricle adapts to the systolic pressure
overload through a hypertrophic process that results
in increased LV wall thickness while a normal chamber
volume is maintained (47-49).
The resulting increase in relative wall thickness is
usually enough to counter the high intracavitary systolic
pressure, and as a result, LV systolic wall stress (afterload)
remains within the range of normal. The inverse relation
between systolic wall stress and ejection fraction is
maintained; as long as wall stress is normal, the ejection
fraction is preserved (50).
However, if the hypertrophic process is inadequate and
relative wall thickness does not increase in proportion
to pressure, wall stress increases and the high afterload
causes a decrease in ejection fraction (50-52).
The depressed contractile state of the myocardium may
also be responsible for a low ejection fraction, but
a combination of excessive afterload and depressed contractility
contributes to a low ejection fraction in many patients
(53). When low ejection
fraction is caused by depressed contractility, corrective
surgery will be less beneficial than in patients with
a low ejection fraction caused by high afterload (54).
As
a result of increased wall thickness, low volume/mass
ratio, and diminished compliance of the chamber, LV
end-diastolic pressure increases without chamber dilatation
(55-58).
Thus, increased end-diastolic pressure usually reflects
diastolic dysfunction rather than systolic dysfunction
or failure (59). A forceful
atrial contraction that contributes to an elevated end-diastolic
pressure plays an important role in ventricular filling
without increasing mean left atrial or pulmonary venous
pressure (60). Loss
of atrial contraction such as that which occurs with
atrial fibrillation is often followed by serious clinical
deterioration.
The
development of concentric hypertrophy appears to be
an appropriate and beneficial adaptation to compensate
for high intracavitary pressures. Unfortunately, this
adaptation often carries adverse consequences. The hypertrophied
heart may have reduced coronary blood flow per gram
of muscle and also exhibit a limited coronary vasodilator
reserve, even in the absence of epicardial CAD (61,62).
The hemodynamic stress of exercise or tachycardia can
produce a maldistribution of coronary blood flow and
subendocardial ischemia, which can contribute to systolic
or diastolic dysfunction of the left ventricle. Hypertrophied
hearts also exhibit an increased sensitivity to ischemic
injury, with larger infarcts and higher mortalities
than are seen in the absence of hypertrophy (63-65).
Another problem that is particularly common in elderly
patients, especially women, is an excessive or inappropriate
degree of hypertrophy; wall thickness is greater than
necessary to counterbalance the high intracavitary pressures
(66-69).
As a result, systolic wall stress is low, ejection fraction
is high, and the ventricle resembles that seen in patients
with hypertensive hypertrophic cardiomyopathy of the
elderly (70). Such inappropriate
LV hypertrophy has been associated with high perioperative
morbidity and mortality (66,68).
3.
Natural History. The natural history of AS in the
adult consists of a prolonged latent period during which
morbidity and mortality are very low. The rate of progression
of the stenotic lesion has been estimated in a variety
of hemodynamic studies performed largely in patients
with moderate AS (71).
Cardiac catheterization studies indicate that some patients
have a decrease in valve area of 0.1 to 0.3 cm2
per year; the systolic pressure gradient across the
valve may increase by as much as 10 to 15 mm Hg per
year (72-78).
However, more than half of the reported patients show
little or no progression over a 3- to 9-year period.
Doppler echocardiographic data obtained over several
years are consistent with those obtained with cardiac
catheterization. Some patients exhibit a significant
increase in transvalvular pressure gradient (~15 to
19 mm Hg per year) and a decrease in valve area; others
show little or no change (79-83).
The average rate of change is ~0.12 cm2 per
year (84). Although
it appears that the progression of AS can be more rapid
in patients with degenerative calcific disease than
in those with congenital or rheumatic disease (41,73),
it is not possible to predict the rate of progression
in an individual patient. For this reason, careful clinical
follow-up is mandatory in all patients with moderate
to severe AS.
Eventually,
symptoms of angina, syncope, or heart failure develop
after a long latent period, and the outlook changes
dramatically. After the onset of symptoms, average survival
is less than 2 to 3 years (85-90).
Thus, the development of symptoms identifies a critical
point in the natural history of AS. Management decisions
are based largely on these natural history data; many
clinicians treat asymptomatic patients conservatively,
whereas corrective surgery is generally recommended
in patients with symptoms thought to be due to AS.
Sudden
death is known to occur in patients with severe AS and
rarely has been documented to occur without prior symptoms
(85,88,91).
These older retrospective studies emphasize the possibility
of sudden death in asymptomatic patients. However, prospective
echocardiographic studies provide important data on
the rarity of sudden death in asymptomatic patients
(Table 11). In one report,
51 asymptomatic patients with severe AS were followed
for an average of 17 months. In this study, 2 patients
died; symptoms preceded death in both cases (90).
In another report of 113 patients followed for 20 months,
there were no cases of sudden death without preceding
symptoms; in this study, survival was no different from
that of an age- and sex-matched control group (92).
In this latter study, all patients had Doppler velocities
across the aortic valve >4 m/s. However, only
one third had aortic valve velocities >5 m/s,
and a number of patients were not included in the follow-up
analysis because they underwent AVR at the discretion
of the clinician. In a third report of 123 patients
followed for an average of 30 months, there were no
cases of sudden death (84).
These findings were similar in 2 smaller studies (77,81).
Therefore, although sudden death occasionally does occur
in the absence of preceding symptoms in patients with
AS (85,88,93),
it must be an uncommon event--probably <1% per year.
4.
Management of the Asymptomatic Patient. Many asymptomatic
patients with severe AS develop symptoms within a few
years and require surgery. In one series, the incidence
of angina, dyspnea, or syncope in 113 asymptomatic patients
with Doppler outflow velocities >4 m/s was
14% after 1 year and 38% after 2 years (92).
In another report of 123 asymptomatic patients, the
rate of symptom development was 38% at 3 years for the
total group but 79% at 3 years in patients with Doppler
outflow velocity >4 m/s (84).
Therefore, patients with severe AS require careful monitoring
for development of symptoms and progressive disease.
a.
Initial Evaluation. The diagnosis of severe AS can
usually be made on the basis of the systolic outflow
murmur, delayed and diminished carotid upstrokes, sustained
LV impulse, and reduced intensity of the aortic component
of the second heart sound. Paradoxical splitting of
the second sound may be present. In the elderly, the
pulsus tardus and parvus may be absent because of the
effects of aging on the vasculature. Patients presenting
with the physical findings of AS should undergo selected
laboratory examinations, including an ECG, a chest x-ray,
and an echocardiogram. The 2-D echocardiogram is valuable
for confirming the presence of aortic valve disease
and determining the LV response to pressure overload.
In most patients, the severity of the stenotic lesion
can be defined with Doppler echocardiographic measurements
of a mean transvalvular pressure gradient and a derived
valve area, as discussed in the ACC/AHA Guidelines for
the Clinical Application of Echocardiography (2).
The mean pressure gradient may be underestimated if
the Doppler beam is not parallel to the velocity jet;
however, it may occasionally overestimate the transvalvular
gradient, especially in the patient with a small aortic
root and/or high cardiac output. Thus, the pressure
gradient and derived valve area require meticulous attention
to measurement of LV outflow tract area and velocity.
Echocardiography is also used to assess LV size and
function, degree of hypertrophy, and presence of other
associated valvular disease.
In
some patients, it may be necessary to proceed with cardiac
catheterization and coronary angiography at the time
of initial evaluation. For example, this is appropriate
if there is a discrepancy between clinical and echocardiographic
examinations or if the patient is symptomatic and AVR
is planned.
Exercise
testing in adults with AS has been discouraged largely
because of concerns about safety. Furthermore, when
used to assess the presence or absence of CAD, the test
has limited diagnostic accuracy. Presumably, this is
due to the presence of an abnormal baseline ECG, LV
hypertrophy, and limited coronary flow reserve. Certainly,
exercise testing should not be performed in symptomatic
patients. However, in asymptomatic patients, exercise
testing is safe and may provide information that is
not uncovered during the initial clinical evaluation
(94-97).
Exercise testing in asymptomatic patients should be
performed only under the supervision of an experienced
physician with close monitoring of blood pressure and
the ECG. Such testing can identify patients with a limited
exercise capacity or even exercise-induced symptoms
despite a negative medical history. Although the prognostic
significance of electrocardiographic ST depression is
unknown, an abnormal hemodynamic response (eg, hypotension)
in a patient with severe AS is sufficient reason to
consider AVR. Finally, in selected patients, the observations
made during exercise may provide a basis for advice
about physical activity.
The
frequency of follow-up visits to the physician depends
on the severity of the valvular stenosis and in part
on the presence of comorbid conditions. Recognizing
that an optimal schedule for repeated medical examinations
has not been defined, many physicians perform an annual
history and physical examination on patients with mild
AS. Those with moderate and severe AS should be examined
more frequently. Patients should be advised to promptly
report the development of any exertional chest discomfort,
dyspnea, lightheadedness, or syncope.
Recommendations
for Echocardiography in Aortic Stenosis
b.
Serial Testing. Echocardiographic studies can be
an important part of an integrated approach that includes
a detailed history, physical examination, and in some
patients a carefully monitored exercise test. Recognizing
that the rate of progression varies considerably, clinicians
often perform an annual echocardiogram on patients known
to have moderate to severe AS. However, current understanding
of the natural history of AS and indications for surgical
intervention do not support the use of annual echocardiographic
studies to assess changes in valve area as such. However,
serial echocardiograms are helpful for assessing changes
in LV hypertrophy and function. Therefore, in patients
with severe AS, an echocardiogram every year may be
appropriate. In patients with moderate AS, serial studies
performed every 2 years or so are satisfactory, and
in patients with mild AS, serial studies can be performed
every 5 years. Echocardiograms should be performed more
frequently if there is a change in clinical findings.
In patients with echocardiograms of suboptimal quality,
cardiac magnetic resonance imaging may be used to assess
LV volume, wall thickness, mass, and systolic function
(98-102)
as well as severity of AS (103,104).
In centers with specific expertise in cardiac magnetic
resonance imaging, serial magnetic resonance imaging
may be performed in place of serial echocardiograms.
c.
Medical Therapy. Antibiotic prophylaxis is indicated
for prevention of infective endocarditis and, in those
with rheumatic AS, recurrent episodes of rheumatic fever.
Patients with associated systemic arterial hypertension
should be treated cautiously with appropriate antihypertensive
agents. With these exceptions, there is no specific
medical therapy for patients who have not yet developed
symptoms, and patients who develop symptoms require
surgery, not medical therapy. Most asymptomatic patients
lead a normal life, although restriction of physical
activity should be advised in most patients with moderate
or severe AS.
d.
Physical Activity and Exercise. Recommendations
for physical activity are based on the clinical examination,
with special emphasis on the hemodynamic severity of
the stenotic lesion. The severity can usually be judged
by Doppler echocardiography, but in borderline cases,
diagnostic cardiac catheterization may be necessary
to accurately define the degree of stenosis.
Recommendations
on participation in competitive sports have been published
by the Task Force on Acquired Valvular Heart Disease
of the 26th Bethesda Conference (105).
Physical activity is not restricted in asymptomatic
patients with mild AS; these patients can participate
in competitive sports. Patients with moderate AS should
avoid competitive sports that involve high dynamic and
static muscular demands. Other forms of exercise can
be performed safely, but it is advisable to evaluate
such patients with an exercise test before they begin
an exercise or athletic program. Patients with severe
AS should be advised to limit their activity to relatively
low levels.
5.
Indications for Cardiac Catheterization. In patients
with AS, the indications for cardiac catheterization
and angiography are essentially the same as in other
conditions, namely to assess the coronary circulation
and confirm or clarify the clinical diagnosis. In preparation
for AVR, coronary angiography is indicated in patients
suspected of having CAD, as discussed in detail in section
VIII of these guidelines. If the clinical and echocardiographic
data are typical of severe isolated AS, coronary angiography
may be all that is needed before AVR. A complete left-
and right-heart catheterization may be necessary to
assess the hemodynamic severity of the AS if there is
a discrepancy between clinical and echocardiographic
data or there is evidence of associated valvular or
congenital disease or pulmonary hypertension.
The
pressure gradient across a stenotic valve is related
to the valve orifice area and the transvalvular flow
(106). Thus, in the
presence of depressed cardiac output, relatively low
pressure gradients are frequently obtained in patients
with severe AS. On the other hand, during exercise or
other high flow states, systolic gradients can be measured
in minimally stenotic valves. For these reasons, complete
assessment of AS requires (1) measurement of transvalvular
flow, (2) determination of the transvalvular pressure
gradient, and (3) calculation of the effective valve
area. Careful attention to detail with accurate measurements
of pressure and flow is important, especially in patients
with low cardiac output or a low transvalvular pressure
gradient.
Recommendations
for Cardiac Catheterization in Aortic Stenosis
a.
Low-Gradient Aortic Stenosis. Patients with severe
AS and low cardiac output often present with only modest
transvalvular pressure gradients (ie, <30 mm Hg).
Such patients can be difficult to distinguish from those
with low cardiac output and only mild to moderate AS.
In the former (true anatomically severe AS), the stenotic
lesion contributes to an elevated afterload, decreased
ejection fraction, and low stroke volume. In the latter,
primary contractile dysfunction is responsible for the
decreased ejection fraction and low stroke volume; the
problem is further complicated by reduced valve opening
forces that contribute to limited valve mobility and
apparent stenosis. In both situations, the low-flow
state and low-pressure gradient contribute to a calculated
effective valve area that can meet criteria for severe
AS. The standard valve area formula is less accurate
and is known to underestimate the valve area in low-flow
states, and under such conditions, it should be interpreted
with caution. In theory, Doppler-derived valve areas
should be less susceptible to low flow, but this does
not appear to be borne out in clinical practice. It
has been suggested that valve resistance might provide
a better separation between critical and noncritical
AS, particularly in patients with low transvalvular
pressure gradients (107,108).
Although valve resistance is less sensitive to flow
than valve area, the resistance calculations have not
been proved to be substantially better than valve area
calculations.
In
patients with low-gradient stenosis and what appears
to be moderate to severe AS, it may be useful to determine
the transvalvular pressure gradient and to calculate
valve area and resistance during a baseline state and
again during exercise or pharmacological (ie, dobutamine
infusion) stress (97,109-111).
This approach is based on the notion that patients who
do not have true, anatomically severe stenosis exhibit
an increase in the valve area during an increase in
cardiac output (109,110).
Thus, if a dobutamine infusion produces an increment
in stroke volume, an increase in valve area, and a decrease
in valve resistance, it is likely that the baseline
calculations overestimated the severity of the stenosis.
In patients with severe AS, these changes may result
in a calculated valve area that is higher than the baseline
calculation but one that remains in the severe range,
whereas in patients without severe AS, the calculated
valve area with dobutamine will fall outside the severe
range and indicate that severe AS is not present.
6.
Indications for Aortic Valve Replacement. In the
vast majority of adults, AVR is the only effective treatment
for severe AS. However, younger patients may be candidates
for valvotomy (see section
VI.A. of these guidelines). Although there is some
lack of agreement about the optimal timing of surgery,
particularly in asymptomatic patients, it is possible
to develop rational guidelines for most patients. Particular
consideration should be given to the natural history
of symptomatic and asymptomatic patients and to operative
risks and outcomes after surgery.
a.
Symptomatic Patients. Patients with angina, dyspnea,
or syncope exhibit symptomatic improvement and an increase
in survival after AVR (86,112-116).
These salutary results of surgery are partly dependent
on the state of LV function. The outcome is similar
in patients with normal LV function and in those with
moderate depression of contractile function. The depressed
ejection fraction in many of the patients in this latter
group is caused by excessive afterload (afterload mismatch
[52]), and LV
function improves after AVR in such patients. If LV
dysfunction is not caused by afterload mismatch, then
improvement in LV function and resolution of symptoms
may not be complete after valve replacement (116).
Survival is still improved in this setting (112),
with the possible exception of patients with severe
LV dysfunction caused by CAD (116).
Therefore, in the absence of serious comorbid conditions,
AVR is indicated in virtually all symptomatic patients
with severe AS. However, patients with severe LV dysfunction,
particularly those with so-called low gradient AS, create
a difficult management decision (117)
(see above). AVR should not be performed in such patients
if they do not have anatomically severe AS. In patients
who do have severe AS, even those with a low transvalvular
pressure gradient, AVR results in hemodynamic improvement
and better functional status.
b.
Asymptomatic Patients. Many clinicians are reluctant
to proceed with AVR in an asymptomatic patient (118),
whereas others are concerned about following a patient
with severe AS. Although insertion of a prosthetic aortic
valve is associated with low perioperative morbidity
and mortality, long-term morbidity and mortality can
be appreciable for mechanical and bioprosthetic valves.
Significant complications occur at the rate of at least
2% to 3% per year, and death due directly to the prosthesis
occurs at the rate of ~1% per year (119-124).
Thus, even if surgical mortality can be minimized, the
combined risk of surgery and the late complications
of a prosthesis exceed the possibility of preventing
sudden death and prolonging survival in all asymptomatic
patients, as discussed previously. Despite these considerations,
some difference of opinion persists among clinicians
regarding the indications for corrective surgery in
asymptomatic patients. Some argue that irreversible
myocardial depression and/or fibrosis may develop during
a prolonged asymptomatic stage and that this may preclude
an optimal outcome. Such irreversibility has not been
proved, but this concept has been used to support early
surgery (114,125).
Still others attempt to identify patients who may be
at especially high risk of sudden death without surgery,
although data supporting this approach are limited.
Patients in this subgroup include those who have an
abnormal response to exercise (eg, hypotension), those
with LV systolic dysfunction or marked/excessive LV
hypertrophy, or those with evidence of very severe AS.
However, it should be recognized that such "high-risk"
patients are rarely asymptomatic.
c.
Patients Undergoing Coronary Artery Bypass Surgery.
Patients with severe AS, with or without symptoms, who
are undergoing coronary artery bypass surgery should
undergo AVR at the time of the revascularization procedure.
Similarly, patients with severe AS undergoing surgery
on other valves (such as mitral valve repair) or the
aortic root should also undergo AVR as part of the surgical
procedure, and it is generally accepted practice to
perform AVR in patients with moderate AS (for example,
gradient >30 mm Hg) who are undergoing mitral
valve or aortic root surgery, as discussed in sections
III.F.6. and III.F.7.
of these guidelines. Such patients with moderate AS
may also warrant AVR at the time of coronary artery
bypass surgery, but there are limited data to support
this policy. Greater controversy persists regarding
the indications for concomitant AVR at the time of coronary
artery bypass surgery in patients with milder forms
of AS, as discussed in section
VIII.D. of these guidelines.
Recommendations
for Aortic Valve Replacement in Aortic Stenosis
7.
Aortic Balloon Valvotomy. Percutaneous balloon aortic
valvotomy is a procedure in which one or more balloons
are placed across a stenotic valve and inflated to decrease
the severity of stenosis (126-128).
This procedure has an important role in treating adolescents
and young adults with AS (see section
VI.A.) but a very limited role in older adults.
The mechanism underlying relief of the stenotic lesion
in older adults is fracture of calcific deposits within
the valve leaflets and to some degree stretching of
the annulus and separation of the calcified or fused
commissures (129-131).
Immediate hemodynamic results include a moderate reduction
in the transvalvular pressure gradient, but the postvalvotomy
valve area rarely exceeds 1.0 cm2. Despite
the modest change in valve area, an early symptomatic
improvement is usually seen. However, serious complications
occur with a frequency >10% (132-138);
restenosis and clinical deterioration occur within 6
to 12 months in most patients (133,138-141).
Therefore, in adults with AS, balloon valvotomy is not
a substitute for AVR (141-144).
Despite
the procedural morbidity and mortality and limited long-term
results, balloon valvotomy can have a temporary role
in the management of some symptomatic patients who are
not initially candidates for AVR (144).
For example, patients with severe AS and refractory
pulmonary edema or cardiogenic shock may benefit from
aortic valvuloplasty as a "bridge" to surgery;
an improved hemodynamic state may reduce the risks of
surgery. The indications for palliative valvotomy in
patients with serious comorbid conditions are less well
established, but most patients can expect temporary
relief of symptoms despite a very limited life expectancy.
Asymptomatic patients with severe AS who require urgent
noncardiac surgery may be candidates for valvotomy,
but most such patients can be successfully treated with
more conservative measures (145,146).
Recommendations
for Aortic Balloon Valvotomy in Adults With Aortic Stenosis*
8.
Medical Therapy for the Inoperable Patient. Comorbid
conditions (eg, malignancy) or, on occasion, patient
preferences may preclude corrective surgery. Under such
circumstances, limited medical therapies are available
to control symptoms. Patients with evidence of pulmonary
congestion can benefit from treatment with digitalis,
diuretics, and angiotensin converting enzyme (ACE) inhibitors.
Indeed, a cautious reduction in central blood volume
and LV preload can be efficacious in some patients with
heart failure symptoms. It should be recognized, however,
that excessive preload reduction can depress cardiac
output and reduce systemic arterial pressure; patients
with severe AS are especially subject to this untoward
effect. Digitalis should be reserved for patients with
depressed systolic function or atrial fibrillation.
Atrial fibrillation and other atrial arrhythmias have
an adverse effect on atrial pump function and ventricular
rate; if prompt cardioversion is unsuccessful, pharmacological
control of the ventricular rate with digitalis or perhaps
amiodarone is essential. Efforts should be made to prevent
atrial fibrillation, especially development of a rapid
ventricular response. ß-Adrenergic receptor blocking
agents as well as other drugs with negative inotropic
effects should not be used in patients with heart failure
caused by AS. If angina is the predominant symptom,
cautious use of nitrates and ß-blockers can provide
relief. There is no specific medical therapy for syncope
unless it is caused by a bradyarrhythmia or tachyarrhythmia.
9.
Evaluation After Aortic Valve Replacement. AVR should
be considered a form of palliative therapy in that a
prosthetic valve with its attendant complications is
substituted for a diseased native valve (119-124).
Patients with prosthetic heart valves therefore require
periodic clinical and selected laboratory examinations.
A complete history and physical examination should be
performed at least once a year. Indications for echocardiography
are discussed in section
VII.C.3. of these guidelines.
10.
Special Considerations in the Elderly. Because there
is no effective medical therapy and balloon valvotomy
is not an acceptable alternative to surgery, AVR must
be considered in all elderly patients who have symptoms
caused by AS. Valve replacement is technically possible
at any age (147), but
the decision to proceed with such surgery depends on
many factors, including the patient's wishes and expectations.
Older patients with symptoms due to severe AS, normal
coronary arteries, and preserved LV function can expect
a better outcome than those with coronary disease or
ventricular dysfunction (87).
Certainly advanced cancer and permanent neurological
defects as a result of stroke make cardiac surgery inappropriate.
Deconditioned and debilitated patients often do not
return to an active existence, and the presence of the
other comorbid disorders may have a major impact on
outcome.
In
addition to the confounding effects of CAD and the potential
for stroke, other considerations are peculiar to older
patients. For example, a narrow LV outflow tract and
a small aortic annulus sometimes present in elderly
women may require enlargement of the annulus. Heavy
calcification of the valve, annulus, and aortic root
may require debridement. Occasionally, a composite valve-aortic
graft is needed. Likewise, excessive or inappropriate
hypertrophy associated with valvular stenosis can be
a marker for perioperative morbidity and mortality (66,68).
Preoperative recognition of elderly patients with marked
LV hypertrophy followed by appropriate perioperative
management may substantially reduce this morbidity and
mortality. There is no perfect method for weighing all
of the relevant factors and identifying specifically
high- and low-risk elderly patients (148).
The decision to proceed with valve replacement depends
on an imprecise analysis that considers the balance
between the potential for improved symptoms and survival
and the morbidity and mortality of surgery.
B.
Aortic Regurgitation
1.
Etiology. There are a number of common causes of
AR. These include idiopathic dilatation, congenital
abnormalities of the aortic valve (most notably bicuspid
valves), calcific degeneration, rheumatic disease, infective
endocarditis, systemic hypertension, myxomatous proliferation,
dissection of the ascending aorta, and Marfan syndrome.
Less common etiologies include traumatic injuries to
the aortic valve, ankylosing spondylitis, syphilitic
aortitis, rheumatoid arthritis, osteogenesis imperfecta,
giant cell aortitis, Ehlers-Danlos syndrome, Reiter's
syndrome, discrete subaortic stenosis, and ventricular
septal defects with prolapse of an aortic cusp. Recently,
anorectic drugs have also been reported to cause AR
(see section III.H. of
these guidelines). The majority of these lesions produce
chronic AR with slow, insidious LV dilatation and a
prolonged asymptomatic phase. Other lesions, in particular
infective endocarditis, aortic dissection, and trauma,
more often produce acute severe AR, which can result
in sudden catastrophic elevation of LV filling pressures
and reduction in cardiac output.
2.
Acute Aortic Regurgitation
a.
Pathophysiology. In acute severe AR, the sudden
large regurgitant volume is imposed on a left ventricle
of normal size that has not had time to accommodate
the volume overload. With an abrupt increase in end-diastolic
volume, the ventricle operates on the steep portion
of a normal diastolic pressure-volume relationship,
and LV end-diastolic and left atrial pressures may increase
rapidly and dramatically. The Frank-Starling mechanism
is used, but the inability of the ventricle to develop
compensatory chamber dilatation acutely results in a
decrease in forward stroke volume. Although tachycardia
develops as a compensatory mechanism to maintain cardiac
output, this is often insufficient. Hence, patients
frequently present with pulmonary edema and/or cardiogenic
shock. Acute AR creates especially marked hemodynamic
changes in patients with preexisting pressure overload
hypertrophy, in whom the small, noncompliant LV cavity
is set on an even steeper diastolic pressure-volume
relationship and has reduced preload reserve. Examples
of this latter situation include aortic dissection in
patients with systemic hypertension, infective endocarditis
in patients with preexisting AS, and acute regurgitation
after balloon valvotomy or surgical commissurotomy for
congenital AS.
b.
Diagnosis. Many of the characteristic physical findings
of chronic AR are modified or absent when valvular regurgitation
is acute, which may lead to underestimation of its severity.
LV size may be normal on physical examination and cardiomegaly
may be absent on chest x-ray. Pulse pressure may not
be increased because systolic pressure is reduced and
the aortic diastolic pressure equilibrates with the
elevated LV diastolic pressure. Because this diastolic
pressure equilibration between aorta and ventricle may
occur before the end of diastole, the diastolic murmur
may be short and/or soft and therefore poorly heard.
The elevated LV diastolic pressure may close the mitral
valve prematurely, reducing the intensity of the first
heart sound. An apical diastolic rumble may be present,
but it is usually brief and without presystolic accentuation.
Tachycardia is invariably present.
Echocardiography
is indispensable in confirming the presence and severity
of the valvular regurgitation, in determining its etiology,
in estimating the degree of pulmonary hypertension (if
TR is present), and in determining whether there is
rapid equilibration of aortic and LV diastolic pressure.
Evidence for rapid pressure equilibration includes a
short AR diastolic half-time (<300 ms), a short mitral
deceleration time (<150 ms), or premature closure
of the mitral valve.
Acute
AR caused by aortic root dissection is a surgical emergency
that requires particularly prompt identification and
management. Transesophageal echocardiography is indicated
when aortic dissection is suspected (149-151).
If the diagnosis remains uncertain, cardiac catheterization
and aortography should be performed. Coronary angiography
is an important component of the evaluation of aortic
dissection and acute AR and should be performed, provided
that it does not delay urgent surgery. In some patients,
other diagnostic imaging methods, such as computed tomographic
imaging or magnetic resonance imaging, may be required
if echocardiography does not provide the diagnosis and
angiography is not planned (149,150,152).
c.
Treatment. Death from pulmonary edema, ventricular
arrhythmias, electromechanical dissociation, or circulatory
collapse is common in acute severe AR, even with intensive
medical management. Early surgical intervention is recommended.
Nitroprusside and possibly inotropic agents such as
dopamine or dobutamine to augment forward flow and reduce
LV end-diastolic pressure may be helpful to manage the
patient temporarily before operation. Intra-aortic balloon
counterpulsation is contraindicated. Although ß-blockers
are often used in treating aortic dissection, these
agents should be used very cautiously if at all in the
setting of acute AR because they will block the compensatory
tachycardia. In patients with acute severe AR resulting
from infective endocarditis, surgery should not be delayed,
especially if there is hypotension, pulmonary edema,
or evidence of low output. In patients with mild acute
AR, antibiotic treatment may be all that is necessary
if the patient is hemodynamically stable. Exceptions
to this latter recommendation are discussed in section
IV.E. of these guidelines.
3.
Chronic Aortic Regurgitation
a.
Pathophysiology. The left ventricle responds to
the volume load of chronic AR with a series of compensatory
mechanisms, including an increase in end-diastolic volume,
an increase in chamber compliance that accommodates
the increased volume without an increase in filling
pressures, and a combination of eccentric and concentric
hypertrophy. The greater diastolic volume permits the
ventricle to eject a large total stroke volume to maintain
forward stroke volume in the normal range. This is accomplished
through rearrangement of myocardial fibers with the
addition of new sarcomeres and development of eccentric
LV hypertrophy (153).
As a result, preload at the sarcomere level remains
normal or near-normal, and the ventricle retains its
preload reserve. The enhanced total stroke volume is
achieved through normal performance of each contractile
unit along the enlarged circumference (154).
Thus, LV ejection performance is normal, and ejection
phase indexes such as ejection fraction and fractional
shortening remain in the normal range. However, the
enlarged chamber size, with the associated increase
in systolic wall stress, also results in an increase
in LV afterload and is a stimulus for further concentric
hypertrophy (153,155).
Thus, AR represents a condition of combined volume overload
and pressure overload (156).
As the disease progresses, recruitment of preload reserve
and compensatory hypertrophy permit the ventricle to
maintain normal ejection performance despite the elevated
afterload (157,158).
The majority of patients remain asymptomatic throughout
this compensated phase, which may last for decades.
Vasodilator therapy has the potential to reduce the
hemodynamic burden in such patients.
For
purposes of the subsequent discussion, patients with
normal LV systolic function will be defined as those
with normal LV ejection fraction at rest. It is recognized
that overall LV function is usually not "normal"
in chronic severe AR and that the hemodynamic abnormalities
noted above may be considerable. It is also recognized
that the transition to LV systolic dysfunction represents
a continuum and that there is no single hemodynamic
measurement that represents the absolute boundary between
normal LV systolic function and LV systolic dysfunction.
In
a large subset of patients, the balance between afterload
excess, preload reserve, and hypertrophy cannot be maintained
indefinitely. Preload reserve may be exhausted (158)
and/or the hypertrophic response may be inadequate (48),
so that further increases in afterload result in a reduction
in ejection fraction, first into the low normal range
and then below normal. Impaired myocardial contractility
may also contribute to this process. Patients often
develop dyspnea at this point in the natural history,
which is related to declining systolic function or elevated
filling pressures. In addition, diminished coronary
flow reserve in the hypertrophied myocardium may result
in exertional angina (159).
However, this transition may be much more insidious,
and it is possible for patients to remain asymptomatic
until severe LV dysfunction has developed.
LV
systolic dysfunction (defined as an ejection fraction
below normal at rest) is initially a reversible phenomenon
related predominantly to afterload excess, and full
recovery of LV size and function is possible with AVR
(160-171).
With time, during which the ventricle develops progressive
chamber enlargement and a more spherical geometry, depressed
myocardial contractility predominates over excessive
loading as the cause of progressive systolic dysfunction.
This can progress to the extent that the full benefit
of surgical correction of the regurgitant lesion, in
terms of recovery of LV function and improved survival,
can no longer be achieved (169,172-181).
A
large number of studies have identified LV systolic
function and end-systolic size as the most important
determinants of survival and postoperative LV function
in patients undergoing AVR for chronic AR (160-170,172-189).
Studies of predictors of surgical outcome are listed
in Table 12.
Among
patients undergoing valve replacement for chronic AR
with preoperative LV systolic dysfunction (defined as
an ejection fraction below normal at rest), several
factors are associated with worse functional and survival
results after operation. These are listed in Table
13.
b.
Natural History. (1) ASYMPTOMATIC
PATIENTS WITH NORMAL LV FUNCTION. There are no
truly large-scale studies evaluating the natural history
of asymptomatic patients in whom LV systolic function
was known to be normal as determined by invasive or
noninvasive testing. The current recommendations are
derived from 7 published series (190-197)
involving a total of 490 such patients (range, 27 to
104 patients/series) with a mean follow-up period of
6.4 years (Table 14). This
analysis is subject to the usual limitations of comparing
different clinical series with different patient selection
factors and different end points. For example, 1 series
(192) represents patients
receiving placebo in a randomized drug trial (198)
that included some patients with "early" New
York Heart Association (NYHA) functional Class II symptoms
(although none had "limiting" symptoms), and
another (196) represents
patients receiving digoxin in a long-term study comparing
the effects of nifedipine with digoxin. In another study
(197), 20% of patients
were not asymptomatic but had "early" NYHA
functional Class II symptoms, and the presence of these
symptoms was a significant predictor of death, LV dysfunction,
or development of more severe symptoms. Some patients
in this latter series had evidence of LV systolic dysfunction
(fractional shortening as low as 18%).
The
results of these 7 studies are summarized in Tables
14 and 15. The rate
of progression to symptoms and/or LV systolic dysfunction
averaged 4.3% per year. Sudden death occurred in 6 of
the 490 patients, an average mortality rate of <0.2%
per year. Six of the 7 studies reported the rate of
development of asymptomatic LV dysfunction (191-194,196,197);
36 of a total of 463 patients developed depressed systolic
function at rest without symptoms during a mean 5.9-year
follow-up period, a rate of 1.3% per year.
Despite
the low likelihood of patients developing asymptomatic
LV dysfunction, it should also be emphasized that more
than one fourth of patients who die or develop systolic
dysfunction do so before the onset of warning symptoms
(191-194,196).
Thus, careful questioning of patients regarding symptomatic
status is not sufficient in the serial evaluation of
asymptomatic patients, and quantitative evaluation of
LV function is also indispensable. Moreover, patients
at risk of future symptoms, death, or LV dysfunction
can also be identified on the basis of noninvasive testing.
Three of the natural history studies provide concordant
information on the variables associated with higher
risk (192-194).
These are age, LV end-systolic dimension (or volume),
and LV end-diastolic dimension (or volume). The LV ejection
fraction during exercise, which is also identified in
these studies, may not be an independent risk factor
as the direction and magnitude of change in ejection
fraction from rest to exercise is related not only to
myocardial contractility (199)
but also severity of volume overload (193,200-202)
and exercise-induced changes in preload and peripheral
resistance (203). In
a multivariate analysis (193),
only age and end-systolic dimension on initial study
were independent predictors of outcome, as were the
rate of increase in end-systolic dimension and decrease
in resting ejection fraction during serial longitudinal
studies. During a mean follow-up period of 8 years,
patients with initial end-systolic dimensions >50
mm had a likelihood of death, symptoms, and/or LV dysfunction
of 19% per year. In those with end-systolic dimensions
of 40 to 50 mm, the likelihood was 6% per year, and
when the dimension was <40 mm, it was zero (193).
(2)
ASYMPTOMATIC PATIENTS WITH DEPRESSED SYSTOLIC FUNCTION.
The limited data in asymptomatic patients with depressed
LV ejection fraction indicate that the majority develop
symptoms warranting operation within 2 to 3 years (204-206).
The average rate of symptom onset in such patients is
>25% per year (Table 15).
(3)
SYMPTOMATIC PATIENTS. There are no recent large-scale
studies of the natural history of symptomatic patients
with chronic AR because the onset of angina or significant
dyspnea is usually an indication for valve replacement.
The data developed in the presurgical era indicate that
patients with dyspnea, angina, or overt heart failure
have a poor outcome with medical therapy, analogous
to that of patients with symptomatic AS. Mortality rates
of >10% per year have been reported in patients with
angina pectoris and >20% per year in those with heart
failure (207-209).
LV function was not measured in these patients, so it
is unclear whether symptomatic patients with normal
ejection fractions have the same adverse outcome as
symptomatic patients with LV dysfunction. However, more
recent data indicate a poor outcome of symptomatic patients
with medical therapy, even among those with preserved
LV systolic function (195,210).
c.
Diagnosis and Initial Evaluation of the Asymptomatic
Patient. The diagnosis of chronic severe AR can
usually be made on the basis of the diastolic murmur,
displaced LV impulse, wide pulse pressure, and the characteristic
peripheral findings reflecting wide pulse pressure.
A third heart sound is often heard as a manifestation
of the volume load and is not necessarily an indication
of heart failure. An Austin-Flint rumble is a specific
finding for severe AR (211,212).
In many patients with more mild to moderate AR, the
physical examination will identify the regurgitant lesion
but will be less 2accurate in determining its severity.
When the diastolic murmur of AR is louder in the third
and fourth right intercostal spaces compared with the
third and fourth left intercostal spaces, the AR likely
results from aortic root dilatation rather than from
a deformity of the leaflets alone (213).
The chest x-ray and ECG are helpful in evaluating overall
heart size and rhythm, evidence of LV hypertrophy, and
evidence of conduction disorders.
Echocardiography
is indicated to confirm the diagnosis of AR if there
is an equivocal diagnosis based on physical examination;
assess the cause of AR as well as valve morphology;
provide a semiquantitative estimate of the severity
of regurgitation; assess LV dimension, mass, and systolic
function; and assess aortic root size. In asymptomatic
patients with preserved systolic function, these initial
measurements represent the baseline information with
which future serial measurements can be compared. Quantitative
measurements of LV cavity size and systolic function
from 2-D-guided M-mode tracings are more reproducible
than and hence preferable to quantitative measurements
made directly from 2-D images. In addition to semiquantitative
assessment of the severity of regurgitation by color
flow jet area and width by Doppler echocardiography,
indirect measures of severity of regurgitation are helpful,
using the rate of decline in regurgitant gradient measured
by the slope of diastolic flow velocity, the degree
of reversal in pulse wave velocity in the descending
aorta, and the magnitude of LV outflow tract velocity
(2,214,215).
Comparison of stroke volumes at the aortic valve compared
with another uninvolved valve may provide a quantitative
measurement of regurgitant fraction (216),
but this measurement should be made only in experienced
laboratories.
LV
wall stress may also be estimated from blood pressure
and echocardiographic measurements. However, such wall
stress measurements are difficult to reproduce, have
methodological and conceptual problems, and should not
be used for diagnosis or management decision making
in clinical practice.
For
purposes of the subsequent discussion of management
of patients with AR, severe AR is defined
as clinical and Doppler evidence of severe regurgitation
(with the semiquantitative methods noted above) in addition
to LV cavity dilatation.
If
the patient is asymptomatic and leads an active lifestyle
and the echocardiogram is of good quality, no other
testing is necessary. If the patient has severe AR and
is sedentary or has equivocal symptoms, exercise testing
is helpful to assess functional capacity, symptomatic
responses, and hemodynamic effects of exercise (Figure
2). If the echocardiogram is of insufficient quality
to assess LV function, radionuclide angiography should
be used in asymptomatic patients to measure LV ejection
fraction at rest and estimate LV volumes. In patients
who are symptomatic on initial evaluation, it is reasonable
to proceed directly to cardiac catheterization and angiography
if the echocardiogram is of insufficient quality to
assess LV function or severity of AR.
The
exercise ejection fraction and the change in ejection
fraction from rest to exercise are often abnormal, even
in asymptomatic patients (190,192-194,197,200-202,206,217-222).
However, these have not been proved to have independent
diagnostic or prognostic value when LV function at rest
and severity of LV volume overload by echocardiography
are already known. One study that did identify the LV
ejection fraction response to exercise as a predictor
of symptomatic deterioration or LV dysfunction (197)
included many patients with NYHA functional Class II
symptoms, LV systolic dysfunction (fractional shortening
as low as 18%), and severe LV dilatation (end-diastolic
and end-systolic dimensions as high as 87 mm and 65
mm, respectively). Hence, the predictive nature of this
response in asymptomatic patients with normal LV systolic
function and without severe LV dilatation has not been
demonstrated.
Recommendations
for Echocardiography in Aortic Regurgitation
Recommendations
for Exercise Testing in Chronic Aortic Regurgitation*
Recommendations
for Radionuclide Angiography in Aortic Regurgitation
d.
Medical Therapy. Therapy with vasodilating agents
is designed to improve forward stroke volume and reduce
regurgitant volume. These effects should translate into
reductions in LV end-diastolic volume, wall stress,
and afterload, resulting in preservation of LV systolic
function and reduction in LV mass. The acute administration
of sodium nitroprusside, hydralazine, or nifedipine
reduces peripheral vascular resistance and results in
an immediate augmentation in forward cardiac output
and a decrease in regurgitant volume (223-231).
With nitroprusside and hydralazine, these acute hemodynamic
changes lead to a consistent reduction in end-diastolic
volume and an increase in ejection fraction (223-226).
This is an inconsistent finding with a single oral dose
of nifedipine (228-231).
Reduced end-diastolic volume and increased ejection
fraction have also been observed in small numbers of
patients receiving long-term oral therapy with hydralazine
and nifedipine for periods of 1 to 2 years (198,232);
with nifedipine, these effects are associated with a
reduction in LV mass (196,232).
Less consistent results have been reported with ACE
inhibitors, depending on the degree of reduction in
arterial pressure and end-diastolic volume (233-235).
Reduced blood pressure with enalapril and quinapril
has been associated with decreases in end-diastolic
volume and mass but no change in ejection fraction (234,235).
There
are 3 potential uses of vasodilating agents in chronic
AR. It should be emphasized that these criteria apply
only to patients with severe AR. The first is long-term
treatment of patients with severe AR who have symptoms
and/or LV dysfunction who are considered poor candidates
for surgery because of additional cardiac or noncardiac
factors. The second is improvement in the hemodynamic
profile of patients with severe heart failure symptoms
and severe LV dysfunction with short-term vasodilator
therapy before proceeding with AVR. In such patients,
vasodilating agents with negative inotropic effects
should be avoided. The third is prolongation of the
compensated phase of asymptomatic patients who have
volume-loaded left ventricles but normal systolic function.
Only
1 study, which compared long-acting nifedipine with
digoxin therapy in a total of 143 patients followed
for 6 years, has evaluated whether vasodilating therapy
alters the long-term natural history of chronic asymptomatic
AR in a favorable manner (196).
Patients receiving nifedipine had a more gradual rate
of attrition due to onset of symptoms and/or LV dysfunction;
long-acting nifedipine reduced the need for valve replacement
over 6 years from 34% to 15%. Moreover, when patients
receiving nifedipine did undergo AVR because of symptoms
or impaired systolic function, all survived surgery,
and LV size and function improved considerably in all
patients (196). Thus,
nifedipine does not appear to obscure the development
of important signs and symptoms that precede the development
of irreversible LV dysfunction. Whether ACE inhibitors
would provide similar long-term results is unclear because
plasma renin and peripheral ACE activity may not be
increased in asymptomatic patients with uncomplicated
chronic AR with normal LV function.
The
goal of vasodilator therapy is to reduce systolic blood
pressure, and drug dosage should be increased until
there is a measurable decrease in systolic blood pressure
or the patient develops side effects. It is rarely possible
to decrease systolic blood pressure to normal because
of the increased LV stroke volume, and drug dosage should
not be increased excessively in an attempt to achieve
this goal. Vasodilator therapy is of unknown benefit
and is not indicated in patients with normal blood pressure
and/or normal LV cavity size.
Vasodilator
therapy is not recommended for asymptomatic patients
with mild AR and normal LV function in the absence of
systemic hypertension, as these patients have an excellent
outcome with no therapy. In patients with severe AR,
vasodilator therapy is not an alternative to surgery
in asymptomatic or symptomatic patients with LV systolic
dysfunction; such patients should be considered surgical
candidates rather than candidates for long-term medical
therapy unless AVR is not recommended because of additional
cardiac or noncardiac factors. Whether symptomatic patients
who have preserved systolic function can be treated
safely with aggressive medical management and whether
aggressive medical management is as good or better than
AVR have not been determined. It is recommended that
symptomatic patients undergo surgery rather than long-term
medical therapy.
There
is scant information about long-term therapy with drugs
other than vasodilators in asymptomatic patients with
severe AR and normal LV function. Thus, there are no
data to support the long-term use of digoxin, diuretics,
nitrates, or positive inotropic agents in asymptomatic
patients.
Recommendations
for Vasodilator Therapy for Chronic Aortic Regurgitation
e.
Physical Activity and Exercise. There are no data
suggesting that exercise, in particular strenuous periodic
exercise, will contribute to or accelerate the progression
of LV dysfunction in AR. Asymptomatic patients with
normal LV systolic function may participate in all forms
of normal daily physical activity, including mild forms
of exercise and in some cases competitive athletics.
Isometric exercise should be avoided. Recommendations
regarding participation in competitive athletics were
published by the Task Force on Acquired Valvular Heart
Disease of the 26th Bethesda Conference (105).
Before participation in athletics, exercise testing
to at least the level of exercise required by the proposed
activity is recommended so that the patient's tolerance
for this degree of exercise can be evaluated. This does
not necessarily evaluate the long-term effects of strenuous
exercise, which are unknown.
f.
Serial Testing. The aim of serial evaluation of
asymptomatic patients with chronic AR is to detect the
onset of symptoms and objectively assess changes in
LV size and function that can occur in the absence of
symptoms. In general, the stability and chronicity of
the regurgitant lesion and the LV response to volume
load need to be established when the patient first presents
to the physician, especially if AR is moderate to severe.
If the chronic nature of the lesion is uncertain and
the patient does not present initially with one of the
indications for surgery, repeat physical examination
and echocardiography should be performed within 2 to
3 months after the initial evaluation to ensure that
a subacute process with rapid progression is not under
way. Once the chronicity and stability of the process
has been established, the frequency of clinical reevaluation
and repeat noninvasive testing depends on the severity
of the valvular regurgitation, the degree of LV dilatation,
the level of systolic function, and whether previous
serial studies have revealed progressive changes in
LV size or function (Figure
2). In most patients, serial testing during the
long-term follow-up period should include a detailed
history, physical examination, and echocardiography.
Serial chest x-rays and ECGs have less value but are
helpful in selected patients.
Asymptomatic
patients with mild AR, little or no LV dilatation, and
normal LV systolic function can be seen on a yearly
basis with instructions to alert the physician if symptoms
develop in the interim. Yearly echocardiography is not
necessary unless there is clinical evidence that regurgitation
has worsened. Routine echocardiography can be performed
every 2 to 3 years in such patients.
Asymptomatic
patients with normal systolic function but severe AR
and significant LV dilatation (end-diastolic dimension
>60 mm) require more frequent and careful reevaluation,
with a history and physical examination every 6 months
and echocardiography every 6 to 12 months, depending
on the severity of dilatation and stability of measurements.
If stable, echocardiographic measurements are not required
more frequently than every 12 months. In patients with
more advanced LV dilatation (end-diastolic dimension
>70 mm or end-systolic dimension >50 mm), for
whom the risk of developing symptoms or LV dysfunction
ranges between 10% and 20% per year (193,194),
it is reasonable to perform serial echocardiograms as
frequently as every 4 to 6 months. Serial chest x-rays
and ECGs have less value but are helpful in selected
patients.
Chronic
AR may develop from disease processes involving the
proximal ascending aorta. In patients with aortic root
dilatation, serial echocardiograms are indicated to
evaluate aortic root size as well as LV size and function.
This is discussed in section
III.B.4. of these guidelines.
Repeat
echocardiograms are also recommended when the patient
has onset of symptoms, there is an equivocal history
of changing symptoms or exercise tolerance, or there
are clinical findings suggesting worsening regurgitation
or progressive LV dilatation. Patients with echocardiographic
evidence of progressive ventricular dilatation or declining
systolic function have a greater likelihood of developing
symptoms or LV dysfunction (193)
and should have more frequent follow-up examinations
(every 6 months) than those with stable LV function.
In
some centers with expertise in nuclear cardiology, serial
radionuclide ventriculograms to assess LV volume and
function at rest may be an accurate and cost-effective
alternative to serial echocardiograms. However, there
is no justification for routine serial testing with
both an echocardiogram and a radionuclide ventriculogram.
Serial radionuclide ventriculograms are also recommended
in patients with suboptimal echocardiograms, patients
with suggestive but not definite echocardiographic evidence
of LV systolic dysfunction, and patients for whom there
is discordance between clinical assessment and echocardiographic
data. In centers with specific expertise in cardiac
magnetic resonance imaging, serial magnetic resonance
imaging may be performed in place of radionuclide angiography
for the indications listed above. In addition to accurate
assessment of LV volume, mass, wall thickness, and systolic
function (98-102),
cardiac magnetic resonance imaging may also be used
to quantify the severity of valvular regurgitation (236-240).
Serial
exercise testing is also not recommended routinely in
asymptomatic patients with preserved systolic function.
However, exercise testing may be invaluable to assess
functional capacity and symptomatic responses in patients
with equivocal changes in symptomatic status. Serial
exercise imaging studies to assess LV functional reserve
are not indicated in asymptomatic patients or those
in whom symptoms develop.
g.
Indications for Cardiac Catheterization. Cardiac
catheterization is not required in patients with chronic
AR unless there are questions about the severity of
AR, hemodynamic abnormalities, or LV systolic dysfunction
that persist despite physical examination and noninvasive
testing or unless AVR is contemplated and there is a
need to assess coronary anatomy. The indications for
coronary arteriography are discussed in section
VIII of these guidelines. In some patients undergoing
left-heart catheterization for coronary angiography,
additional aortic root angiography and hemodynamic measurements
may provide useful supplementary data.
Hemodynamic
and angiographic assessment of severity of AR and LV
function may be necessary in some patients being considered
for surgery when there are conflicting data between
clinical assessment and noninvasive tests. Less commonly,
other asymptomatic patient subgroups may also require
invasive measurement of hemodynamics and/or determination
of severity of AR for occupational purposes or for providing
recommendations for physical activity and exercise when
this information cannot be obtained accurately from
noninvasive tests.
Hemodynamic
measurements during exercise are occasionally helpful
for determining the effect of AR on LV function or making
decisions regarding medical or surgical therapy. In
selected patients with severe AR, borderline or normal
LV systolic function, and LV chamber enlargement that
is approaching the threshold for operation (defined
below), measurement of cardiac output and LV filling
pressures at rest and during exercise with a right-heart
catheter may be valuable for identifying patients with
severe hemodynamic abnormalities in whom surgery is
warranted.
Recommendations
for Cardiac Catheterization in Chronic Aortic Regurgitation
h.
Indications for Aortic Valve Replacement. In patients
with pure, chronic AR, AVR should be considered only
if AR is severe. Patients with only mild AR are not
candidates for valve replacement, and if such patients
have symptoms or LV dysfunction, other etiologies should
be considered, such as CAD, hypertension, or cardiomyopathic
processes. If the severity of AR is uncertain after
a review of clinical and echocardiographic data, additional
information may be needed, such as invasive hemodynamic
and angiographic data. The following discussion applies
only to those patients with pure, severe AR.
(1)
SYMPTOMATIC PATIENTS WITH NORMAL LV SYSTOLIC FUNCTION.
AVR is indicated in patients with normal systolic function
(defined as ejection fraction >0.50 at rest)
who have NYHA functional Class III or IV symptoms. Patients
with Canadian Heart Association functional Class II
to IV angina pectoris should also be considered for
surgery. In many patients with NYHA functional Class
II dyspnea, the etiology of symptoms is often unclear,
and clinical judgment is required. Patients with well-compensated
AR often have chronic mild dyspnea or fatigue, and it
may be difficult to differentiate the effects of deconditioning
or aging from true cardiac symptoms. In such patients,
exercise testing may be valuable. If the etiology of
these mild symptoms is uncertain and they are not severe
enough to interfere with the patient's lifestyle, a
period of observation may be reasonable. However, new
onset of mild dyspnea has different implications in
severe AR, especially in patients with increasing LV
chamber size or evidence of declining LV systolic function
into the low normal range. Thus, even if patients have
not achieved the threshold values of LV size and function
recommended for surgery in asymptomatic patients, development
of mild symptoms is an indication for operation in a
patient who is nearing these values.
(2)
SYMPTOMATIC PATIENTS WITH LV DYSFUNCTION. Patients
with NYHA functional Class II, III, or IV symptoms and
with mild to moderate LV systolic dysfunction (ejection
fraction 0.25 to 0.49) should undergo AVR. Patients
with functional Class IV symptoms have worse postoperative
survival rates and lower likelihood of recovery of systolic
function compared with patients with less severe symptoms
(170,176,177,179),
but AVR will improve ventricular loading conditions
and expedite subsequent management of LV dysfunction
(163).
Symptomatic
patients with advanced LV dysfunction (ejection fraction
<0.25 and/or end-systolic dimension >60 mm) present
difficult management issues. Some patients will manifest
meaningful recovery of LV function after operation,
but many will have developed irreversible myocardial
changes. The mortality associated with valve replacement
approaches 10%, and postoperative mortality over the
subsequent few years is high. Valve replacement should
be considered more strongly in patients with NYHA functional
Class II and III symptoms, especially if (1) symptoms
and evidence of LV dysfunction are of recent onset and
(2) intensive short-term therapy with vasodilators,
diuretics, and/or intravenous positive inotropic agents
results in substantial improvement in hemodynamics or
systolic function. However, even in patients with NYHA
functional Class IV symptoms and ejection fraction <0.25,
the high risks associated with AVR and subsequent medical
management of LV dysfunction are usually a better alternative
than the higher risks of long-term medical management
alone (241).
(3)
ASYMPTOMATIC PATIENTS. AVR in asymptomatic patients
remains a controversial topic, but it is generally agreed
(158,242-246)
that valve replacement is indicated in patients with
LV systolic dysfunction. As noted previously, for the
purposes of these guidelines, LV systolic dysfunction
is defined as an ejection fraction below normal at rest.
The lower limit of normal will be assumed to be 0.50,
realizing that this lower limit is technique dependent
and may vary among institutions. The committee also
realizes that there may be variability in any given
measured LV dimension or ejection fraction. Therefore,
the committee recommends that 2 consecutive measurements
be obtained before proceeding with a decision to recommend
surgery in the asymptomatic patient. These consecutive
measurements could be obtained with the same test repeated
in a short time period (for example, a second echocardiogram
after an initial echocardiogram) or with a separate
independent test (for example, a radionuclide ventriculogram
or a contrast left ventriculogram after an initial echocardiogram).
Valve
replacement is also recommended in patients with severe
LV dilatation (end-diastolic dimension >75 mm or
end-systolic dimension >55 mm), even if ejection
fraction is normal. The majority of patients with this
degree of dilatation will have already developed systolic
dysfunction because of afterload mismatch and will thus
be candidates for valve replacement on the basis of
the depressed ejection fraction. The elevated end-systolic
dimension in this regard is often a surrogate for systolic
dysfunction. The relatively small number of asymptomatic
patients with preserved systolic function despite severe
increases in end-systolic and end-diastolic chamber
size should be considered for surgery, as they appear
to represent a high risk group with an increased incidence
of sudden death (193,247),
and the results of valve replacement in such patients
have thus far been excellent (189).
In contrast, postoperative mortality is considerable
once patients with severe LV dilatation develop symptoms
and/or LV systolic dysfunction (189).
The data regarding the risk of sudden death and postoperative
outcome with severe LV dilatation have been developed
with an LV end-diastolic dimension >80 mm,
but the committee recommends surgery before the left
ventricle achieves this degree of dilatation and recommends
AVR for patients with LV end-diastolic dimension >75
mm.
Patients
with severe AR in whom the degree of dilatation has
not reached but is approaching these threshold values
(for example, LV end-diastolic dimension of 70 to 75
mm or end-systolic dimension of 50 to 55 mm) should
be followed carefully with frequent echocardiograms
every 4 to 6 months, as noted previously (Figure
2). In addition, it is reasonable to recommend AVR
in such patients if there is evidence of declining exercise
tolerance or abnormal hemodynamic responses to exercise,
for example, an increase in pulmonary artery wedge pressure
>25 mm Hg with exercise.
Several
patient subgroups develop LV systolic dysfunction with
less marked LV dilatation than observed in the majority
of patients with uncomplicated AR. These include patients
with long-standing hypertension in whom the pressure-overloaded
ventricle has reduced compliance and a limited potential
to increase its chamber size; patients with concomitant
CAD, in whom myocardial ischemia may develop with increasing
myocardial wall stress, resulting in ventricular dysfunction;
and patients with concomitant MS, in whom the left ventricle
will not dilate to the same extent as in patients with
pure AR (248). In such
patients, it is particularly important that systolic
function and not merely systolic dimension be monitored.
Women also tend to develop symptoms and/or LV dysfunction
with less LV dilatation than men (249);
this appears to be related to body size as these differences
are not apparent when LV dimensions are corrected for
body surface area. Hence, LV dimensions alone may be
misleading in small patients of either gender, and the
threshold values of end-diastolic and end-systolic dimension
recommended above for AVR in asymptomatic patients (75
mm and 55 mm, respectively) may need to be reduced in
such patients. There are no data with which to derive
guidelines for LV dimensions corrected for body size,
and clinical judgment is required.
A
decrease in ejection fraction during exercise should
not be used as an indication for AVR in asymptomatic
patients with normal systolic function at rest, because
the exercise ejection fraction response is multifactorial
and the strength of evidence is limited. The ejection
fraction response to exercise has not proved to have
independent prognostic value in patients undergoing
surgery (179). The
change in ejection fraction with exercise is a relatively
nonspecific response related to both severity of volume
load (193,200-202)
and exercise-induced changes in preload and peripheral
resistance (203) that
develop early in the natural history of AR. Valve replacement
should also not be recommended in asymptomatic patients
with normal systolic function merely because of evidence
of LV dilatation as long as the dilatation is not severe
(end-diastolic dimension <75 mm or end-systolic dimension
<55 mm).
Patients
who demonstrate progression of LV dilatation or progressive
decline in ejection fraction on serial studies represent
a higher-risk group who require careful monitoring (193),
but such patients often reach a new steady state and
may do well for extended periods of time. Hence, valve
replacement is not recommended until the threshold values
noted above are reached or symptoms or LV systolic dysfunction
develop.
The
surgical options for treating AR are expanding, with
growing experience in aortic homografts, pulmonary autografts,
unstented tissue valves, and aortic valve repair. If
these techniques are ultimately shown to improve long-term
survival or reduce postoperative valve complications,
it is conceivable that the thresholds for recommending
operation may be reduced. Until such data are available,
the indications for operation for AR should not vary
with the operative technique to be used.
Recommendations
for Aortic Valve Replacement in Chronic Severe Aortic
Regurgitation
4.
Concomitant Aortic Root Disease. In addition to
causing acute AR, diseases of the proximal aorta may
also contribute to chronic AR. The valvular regurgitation
may be less important in decision making than the primary
disease of the aorta, such as Marfan syndrome, dissection,
or chronic dilatation of the aortic root caused by hypertension.
In such patients, if the AR is mild and/or the left
ventricle is only mildly dilated, management should
focus on treating the underlying aortic root disease,
which is beyond the scope of these guidelines. In many
patients, however, AR may be severe and associated with
severe LV dilatation and/or systolic dysfunction, in
which case decisions regarding medical therapy and timing
of the operation must consider both conditions. In general,
AVR and aortic root reconstruction are indicated in
patients with disease of the proximal aorta and AR of
any severity when the degree of aortic root dilatation
reaches or exceeds 50 mm by echocardiography (250).
5.
Evaluation of Patients After Aortic Valve Replacement.
After AVR, careful follow-up is necessary during the
early and long-term postoperative course to evaluate
prosthetic valve function and assess LV function, as
discussed in detail in section
VII.C.3. An echocardiogram should be performed soon
after surgery to assess the results of surgery on LV
size and function and to serve as a baseline against
which subsequent echocardiograms may be compared. This
could be performed either before hospital discharge
or preferably at the first outpatient reevaluation.
Within the first few weeks of surgery, there is little
change in LV systolic function, and ejection fraction
may even deteriorate compared with preoperative values
because of the reduced preload (251),
even though ejection fraction may increase over the
subsequent several months. Thus, persistent or more
severe systolic dysfunction early after operation is
a poor predictor of subsequent improvement in LV function
in patients with preoperative LV dysfunction. A better
predictor of subsequent LV systolic function is the
reduction in LV end-diastolic dimension, which declines
significantly within the first week or two of operation
(165,170,252).
This is an excellent marker of the functional success
of valve replacement because 80% of the overall reduction
in end-diastolic dimension observed during the long-term
postoperative course occurs within the first 10 to 14
days after AVR (165,170,252),
and the magnitude of reduction in end-diastolic dimension
after surgery correlates with the magnitude of increase
in ejection fraction (170).
After
the initial postoperative reevaluation, the patient
should be seen and examined again at 6 months and 12
months and then on a yearly basis if the clinical course
is uncomplicated. If the patient is asymptomatic and
the early postoperative echocardiogram demonstrates
substantial reduction in LV end-diastolic dimension
and LV systolic function is normal, serial postoperative
echocardiograms after the initial early postoperative
study are usually not indicated. However, repeat echocardiography
is warranted at any point at which there is evidence
of a new murmur, questions of prosthetic valve integrity,
or concerns about LV function. Patients with persistent
LV dilatation on the initial postoperative echocardiogram
should be treated as any other patient with symptomatic
or asymptomatic LV dysfunction, including treatment
with ACE inhibitors. In such patients, repeat echocardiography
to assess LV size and systolic function is warranted
at the 6- and 12-month reevaluations. If LV dysfunction
persists beyond this time frame, repeat echocardiograms
should be performed as clinically indicated. Management
of patients after AVR is discussed in greater detail
in section VII.C.3.
of these guidelines.
6.
Special Considerations in the Elderly. The vast
majority of elderly patients with aortic valve disease
have AS or combined AS and AR, and pure AR is uncommon
(253). Elderly patients
with AR generally fare less well than patients in young
or middle age. Patients older than 75 are more likely
to develop symptoms or LV dysfunction at earlier stages
of LV dilatation, have more persistent ventricular dysfunction
and heart failure symptoms after surgery, and have worse
postoperative survival rates than their younger counterparts.
Many such patients have concomitant CAD, which must
be considered in the evaluation of symptoms, LV dysfunction,
and indications for surgery. Because the goal of therapy
is to improve the quality of life rather than longevity,
symptoms are the most important guide to determining
whether or not AVR should be performed. Nonetheless,
asymptomatic or mildly symptomatic patients who develop
LV dysfunction (as defined previously) should be considered
for AVR if the risks of surgery are balanced in otherwise
healthy patients against the expected improvement in
long-term outcome.
C.
Mitral Stenosis
1.
Pathophysiology and Natural History. MS is an obstruction
to LV inflow at the level of the mitral valve as a result
of a structural abnormality of the mitral valve apparatus,
preventing proper opening during diastolic filling of
the left ventricle. The predominant cause of MS is rheumatic
carditis. Isolated MS occurs in 40% of all patients
presenting with rheumatic heart disease, and a history
of rheumatic fever can be elicited from ~60% of patients
presenting with pure MS (254,255).
The ratio of women to men presenting with isolated MS
is 2:1 (254-256).
Congenital malformation of the mitral valve occurs rarely
and is observed mainly in infants and children (257).
In
patients with MS from rheumatic fever, the pathological
process causes leaflet thickening and calcification,
commissural fusion, chordal fusion, or a combination
of these processes (257,258).
The result is a funnel-shaped mitral apparatus in which
the orifice of the mitral opening is decreased in size.
Interchordal fusion obliterates the secondary orifices
and commissural fusion narrows the principal orifice
(257,258).
The
normal mitral valve area is 4.0 to 5.0 cm2.
Narrowing of the valve area to <2.5 cm2
must occur before the development of symptoms (106).
With a reduction in valve area by the rheumatic process,
blood can flow from the left atrium to the left ventricle
only if propelled by a pressure gradient. This diastolic
transmitral gradient is the fundamental expression of
MS (259) and results
in elevation of left atrial pressure, which is reflected
back into the pulmonary venous circulation. Increased
pressure and distension of the pulmonary veins and capillaries
can lead to pulmonary edema as pulmonary venous pressure
exceeds that of plasma oncotic pressure. The pulmonary
arterioles react with vasoconstriction, intimal hyperplasia,
and medial hypertrophy, which lead to pulmonary arterial
hypertension.
A
mitral valve area >1.5 cm2 usually does
not produce symptoms at rest (260).
However, if there is an increase in transmitral flow
or a decrease in the diastolic filling period, there
will be a rise in left atrial pressure and development
of symptoms. From hydraulic considerations, at any given
orifice size, the transmitral gradient is a function
of the square of the transvalvular flow rate and dependent
on the diastolic filling period (106).
Thus, the first symptoms of dyspnea in patients with
mild MS are usually precipitated by exercise, emotional
stress, infection, pregnancy, or atrial fibrillation
with a rapid ventricular response (260).
As the obstruction across the mitral valve increases,
there will be increasing symptoms of dyspnea as the
left atrial and pulmonary venous pressures increase.
Several
other factors influence symptoms in patients with MS.
As the severity of stenosis increases, cardiac output
becomes subnormal at rest (260)
and fails to increase during exercise (261).
The degree of pulmonary vascular disease is also an
important determinant of symptoms in patients with MS
(260,262,263).
A second obstruction to flow develops from increased
pulmonary arteriolar resistance (262,263),
which may protect the lungs from pulmonary edema (262,263).
In some patients, an additional reversible obstruction
develops at the level of the pulmonary veins (264,265).
The low cardiac output and increased pulmonary arteriolar
resistance, combined with adaptation of the lungs (alveolar
basement membrane thickening, adaptation of neuroreceptors,
and increased lymphatic drainage), contribute to the
ability of a patient with severe MS to remain minimally
symptomatic for prolonged periods of time (260,262,263).
The
natural history of patients with untreated MS has been
defined from studies in the 1950s and 1960s (254-256).
MS is a continuous, progressive, lifelong disease, usually
consisting of a slow, stable course in the early years
followed by a progressive acceleration later in life
(254-256,266).
In developed countries, there is a long latent period
of 20 to 40 years from the occurrence of rheumatic fever
to the onset of symptoms. Once symptoms develop, there
is another period of almost a decade before symptoms
become disabling (254).
Overall, the 10-year survival of untreated patients
presenting with MS is 50% to 60%, depending on symptoms
at presentation (255,256).
In the asymptomatic or minimally symptomatic patient,
survival is >80% at 10 years, with 60% of patients
having no progression of symptoms (255,256,266).
However, once significant limiting symptoms occur, there
is a dismal 0 to 15% 10-year survival (254-256,266,267).
Once there is severe pulmonary hypertension, mean survival
drops to <3 years (268).
The mortality of untreated patients with MS is due to
progressive heart failure in 60% to 70%, systemic embolism
in 20% to 30%, pulmonary embolism in 10%, and infection
in 1% to 5% (256,257).
In North America and Europe, this classic history of
MS has been replaced by an even milder delayed course
with the decline in incidence of rheumatic fever (266,269).
The mean age of presentation is now in the fifth to
sixth decade (266,269);
more than one third of patients undergoing valvotomy
are older than 65 years (270).
In some geographic areas, MS progresses more rapidly,
presumably due to either a more severe rheumatic insult
or repeated episodes of rheumatic carditis due to new
streptococcal infections, resulting in severe symptomatic
MS in the late teens and early twenties (266).
2.
Evaluation and Management of the Asymptomatic Patient.
a. Initial Workup. The diagnosis of MS should
be made on the basis of the history, physical examination,
chest x-ray, and ECG (Figure
3). Patients may present with no symptoms but have
an abnormal physical examination (266,269).
Although some patients may present with fatigue, dyspnea,
or frank pulmonary edema, in others, the initial manifestation
of MS is the onset of atrial fibrillation or an embolic
event (254).
The
diagnostic tool of choice in the evaluation of a patient
with MS is 2-D and Doppler echocardiography (271-276).
Echocardiography is able to identify restricted diastolic
opening of the mitral valve leaflets due to "doming"
of the anterior leaflet and immobility of the posterior
leaflet (271-274).
Other entities that can simulate the clinical features
of rheumatic MS, such as left atrial myxoma, cor triatriatum,
and a parachute mitral valve can be readily identified
by 2-D echocardiography. Planimetry of the orifice area
may be possible from the short-axis view. 2-D echocardiography
can be used to assess the morphological appearance of
the mitral valve apparatus, including leaflet mobility,
leaflet thickness, leaflet calcification, subvalvular
fusion, and the appearance of commissures (277-280).
These features may be important when considering the
timing and type of intervention to be performed (277-280).
Patients with mobile noncalcified leaflets, no commissural
calcification, and little subvalvular fusion may be
candidates for either balloon catheter or surgical commissurotomy/valvotomy
(277-280).
Chamber size and function as well as other structural
valvular, myocardial, or pericardial abnormalities can
be assessed with the 2-D echocardiographic study.
Doppler
echocardiography can be used to assess the hemodynamic
severity of the obstruction (275,276,281).
The mean transmitral gradient can be accurately and
reproducibly measured from the continuous wave Doppler
signal across the mitral valve with the modified Bernoulli
equation (275,276).
The mitral valve area can be noninvasively derived from
Doppler echocardiography with either the diastolic half-time
method (281-284)
or the continuity equation (282).
The half-time may be inaccurate in patients with abnormalities
of left atrial or LV compliance, those with associated
AR, and those who have had mitral valvotomy (283,284).
Doppler echocardiography should also be used to estimate
pulmonary artery systolic pressure from the TR velocity
signal (285) and to
assess severity of concomitant MR or AR. Formal hemodynamic
exercise testing can be done noninvasively with either
a supine bicycle or upright treadmill with Doppler recordings
of transmitral and tricuspid velocities (286-289).
This allows measurement of both the transmitral gradient
(286-288)
and pulmonary artery systolic pressure (288,289)
at rest and with exercise. Dobutamine stress with Doppler
recordings may also be performed (290).
In
the patient who presents with asymptomatic MS, an initial
clinical history, physical examination, ECG, and chest
x-ray should be performed. 2-D and Doppler echocardiography
should also be performed to confirm the diagnosis of
MS and rule out other concomitant problems that would
require further therapy, ie, myocardial or other valvular
heart disease. The morphology of the mitral valve apparatus
should be assessed. The severity of MS should be determined
by using both the mean transmitral gradient and valve
area from the Doppler echocardiogram, and pulmonary
artery pressure should be estimated when possible. A
transesophageal echocardiogram is not required unless
a question about diagnosis remains after transthoracic
echocardiography.
In
the asymptomatic patient who has documented mild MS
(valve area >1.5 cm2 and mean gradient
<5 mm Hg), no further evaluation is needed on the
initial workup (Figure 3).
These patients usually remain stable for years (255,256,266).
If there is more significant MS, a decision to proceed
further should be based on the suitability of the patient
for mitral valvotomy. In patients with pliable, noncalcified
valves with no or little subvalvular fusion and no calcification
in the commissures, percutaneous mitral valvotomy can
be performed with a low complication rate and may be
indicated if symptoms develop. Due to the slowly progressive
course of MS, patients may remain "asymptomatic"
with severe stenosis merely by readjusting their lifestyle
to a more sedentary level. Elevated pulmonary vascular
resistance and/or low cardiac output may also play an
adaptive role in preventing symptoms from occurring
in patients with severe MS (260,262,263).
Elevation of pulmonary vascular resistance is an important
physiological event in MS (262),
and the level of pulmonary pressure is an indicator
of the overall hemodynamic consequence. Patients with
moderate pulmonary hypertension at rest (pulmonary artery
systolic pressure >50 mm Hg) and pliable mitral valve
leaflets may be considered for percutaneous mitral valvotomy
even if they deny symptoms. In patients who lead a sedentary
lifestyle, a hemodynamic exercise test with Doppler
echocardiography is useful (286-289).
Objective limitation of exercise tolerance with a rise
in transmitral gradient >15 mm Hg and in pulmonary
artery systolic pressure >60 mm Hg may be an indication
for percutaneous valvotomy if the mitral valve morphology
is suitable. There is a subset of asymptomatic patients
with severe MS (valve area <1.0 cm2) and
severe pulmonary hypertension (pulmonary artery systolic
pressure >75% of systemic pressure either at rest
or with exercise). If these patients do not have a valve
morphology favorable for percutaneous mitral balloon
valvotomy or surgical valve repair, it is controversial
whether mitral valve replacement (MVR) should be performed
in the absence of symptoms to prevent right ventricular
failure, but surgery is generally recommended in such
patients.
Recommendations
for Echocardiography in Mitral Stenosis
Recommendations
for Transesophageal Echocardiography in Mitral Stenosis
b.
Medical Therapy: General. In the patient with MS,
the major problem is mechanical obstruction to inflow
at the level of the mitral valve, and no medical therapy
will specifically relieve the fixed obstruction. The
left ventricle is protected from a volume or pressure
overload, and thus no specific medical therapy is required
in the asymptomatic patient in normal sinus rhythm who
has mild MS. Because rheumatic fever is the primary
cause of MS, prophylaxis against rheumatic fever is
recommended. Infective endocarditis is uncommon but
does occur in isolated MS (255,256),
and appropriate endocarditis prophylaxis is also recommended.
In
the patient who has more than a mild degree of MS, counseling
on avoidance of unusual physical stresses is advised.
Increased flow and a shortening of the diastolic filling
period by tachycardia increase left atrial pressure
against an obstructed mitral valve. Agents with negative
chronotropic properties such as ß-blockers or calcium
channel blockers may be of benefit in patients in sinus
rhythm who have exertional symptoms if these symptoms
occur with high heart rates (291,292).
Salt restriction and intermittent administration of
a diuretic are useful if there is evidence of pulmonary
vascular congestion. Digitalis does not benefit patients
with MS in sinus rhythm unless there is left and/or
right ventricular dysfunction (293).
c.
Medical Therapy: Atrial Fibrillation. Patients with
MS are prone to developing atrial arrhythmias, particularly
atrial fibrillation and atrial flutter. Thirty to forty
percent of patients with symptomatic MS develop atrial
fibrillation (254,255).
Structural changes from the pressure and volume overload
alter the electrophysiological properties of the left
atrium (266), and the
rheumatic process itself may lead to fibrosis of the
internodal tracts and damage to the sinoatrial node.
There may be significant hemodynamic consequences resulting
from the acute development of atrial fibrillation, with
loss of atrial contribution to LV filling, and from
the rapid ventricular rate, which shortens the diastolic
filling period and causes elevation of left atrial pressure.
Atrial fibrillation occurs more commonly in older patients
(254) and is associated
with a poorer prognosis, with a 10-year survival rate
of 25% compared with 46% in patients who remain in sinus
rhythm (256). The risk
of arterial embolization, especially stroke, is significantly
increased in patients with atrial fibrillation (254,255,294-296).
Treatment
of an acute episode of rapid atrial fibrillation consists
of anticoagulation with heparin and control of the heart
rate response. Intravenous digoxin, calcium channel
blockers, or ß-blockers should be used to control
ventricular response by slowing conduction through the
atrioventricular node. If there is hemodynamic instability,
electrical cardioversion should be undertaken urgently,
with intravenous heparin before, during, and after the
procedure. Patients who have been in atrial fibrillation
longer than 24 to 48 hours without anticoagulation are
at an increased risk for embolic events after cardioversion,
but embolization may occur with <24 hours of atrial
fibrillation. The decision to proceed with elective
cardioversion is dependent on multiple factors, including
duration of atrial fibrillation, hemodynamic response
to the onset of atrial fibrillation, a documented history
of prior episodes of atrial fibrillation, and a history
of prior embolic events. If the decision has been made
to proceed with elective cardioversion in a patient
who has had documented atrial fibrillation for longer
than 24 to 48 hours and who has not been on long-term
anticoagulation, 1 of 2 approaches is recommended, based
on data from patients with nonrheumatic atrial fibrillation.
The first is anticoagulation with warfarin for >3
weeks, followed by elective cardioversion (297).
The second is anticoagulation with heparin and transesophageal
echocardiography to look for left atrial thrombus. In
the absence of left atrial thrombus, cardioversion is
performed with intravenous heparin before, during, and
after the procedure (298).
It is important to continue anticoagulation after cardioversion
to prevent thrombus formation due to atrial mechanical
inactivity and then continue long-term warfarin.
Recurrent
paroxysmal atrial fibrillation may be treated with antiarrhythmic
drugs consisting of group IC agents, group IA agents
(in conjunction with a negative dromotropic agent),
or amiodarone to try to prevent further episodes. Eventually,
atrial fibrillation becomes resistant to prevention
or cardioversion (266),
and control of ventricular response becomes the mainstay
of therapy. Digoxin slows the heart rate response in
patients with atrial fibrillation and MS (293).
However, calcium channel blockers or ß-blockers
are more effective for preventing exercise-induced increases
in heart rate. Patients with either paroxysmal or sustained
atrial fibrillation should be treated with long-term
anticoagulation with warfarin to prevent embolic events
if they do not have a strong contraindication to anticoagulation
(295,299).
It is controversial whether percutaneous mitral valvotomy
should be performed in patients with new-onset atrial
fibrillation and moderate to severe MS who are otherwise
asymptomatic.
d.
Medical Therapy: Prevention of Systemic Embolization.
Systemic embolization may occur in 10% to 20% of patients
with MS (254,255,294).
The risk of embolization is related to age and the presence
of atrial fibrillation (254,255,294-296).
One third of embolic events occur within 1 month of
the onset of atrial fibrillation and two thirds occur
within 1 year. The frequency of embolic events does
not seem to be related to the severity of MS, cardiac
output, size of the left atrium, or even the presence
or absence of heart failure symptoms (254,295,300).
An embolic event may thus be the initial manifestation
of MS (254). In patients
who have experienced an embolic event, the frequency
of recurrence is as high as 15 to 40 events per 100
patient months (295,299).
There
are no randomized trials examining the efficacy of anticoagulation
in preventing embolic events specifically in patients
with MS. Retrospective studies have shown a 4- to 15-fold
decrease in the incidence of embolic events with anticoagulation
in these patients (295,299).
This benefit applies to both systemic and pulmonary
embolism. Most trials involved patients who had [gte]1
embolus before the onset of anticoagulation therapy
(299). However, large
randomized trials have demonstrated a significant reduction
in embolic events by treatment with anticoagulation
in subsets of patients with atrial fibrillation not
associated with MS (301,302).
In these randomized trials, the subset of patients who
benefited most from anticoagulation were those with
the highest risk of embolic events (301,302).
Patients with MS at the highest risk for future embolic
events are those with prior embolic events and those
with paroxysmal or persistent atrial fibrillation (254,255,294-296,299).
Paroxysmal atrial fibrillation may be difficult to detect;
ambulatory ECG monitoring is valuable in patients with
palpitations. There are no data to support the concept
that oral anticoagulation is beneficial in patients
with MS who have not had atrial fibrillation or an embolic
event. It is controversial whether patients without
atrial fibrillation or an embolic event who might be
at higher risk for future embolic events (ie, severe
stenosis or an enlarged left atrium) should be considered
for long-term warfarin therapy (303,304).
Although
embolic events are thought to originate from left atrial
thrombi (295,296),
the presence or absence of a left atrial thrombus does
not seem to correlate with embolic events (254,294).
Left atrial thrombi are found during surgery in 15%
to 20% of patients with prior embolic events and a similar
number of patients without embolic events (254,294).
Thus, the decision to anticoagulate a patient with MS
should not be based solely on the echocardiographic
demonstration of a left atrial thrombus.
It
has been suggested that surgical commissurotomy reduces
the incidence of future embolic events (267).
There are no randomized trial data to support this hypothesis,
and the retrospective studies that have been reported
were performed before the availability of standardized
anticoagulation regimens. Other retrospective studies
have concluded that surgery does not decrease the incidence
of systemic emboli (266,305,306).
Recommendations for Anticoagulation in Mitral Stenosis
e.
Recommendations Regarding Physical Activity and Exercise.
Many patients with mild MS will remain asymptomatic
even with strenuous exercise. In more severe MS, exercise
can cause sudden marked increases in pulmonary venous
pressure from the increase in heart rate and cardiac
output, at times resulting in pulmonary edema (261,263).
The long-term effects of repeated exertion-related increases
in pulmonary venous and pulmonary artery pressures on
the lung or right ventricle remain unknown (105).
MS rarely causes sudden death (254-256).
These factors must be considered when recommending physical
activity and exercise for the patient with MS.
In
the majority of patients with MS, recommendations for
exercise are symptom limited. Patients should be encouraged
to pursue a low-level aerobic exercise program for maintenance
of cardiovascular fitness. Exertional symptoms of dyspnea
are the limiting factors in terms of exercise tolerance.
However, there is a subset of asymptomatic patients
who wish to participate in competitive athletics who
may deny symptoms. The 26th Bethesda Conference on Recommendations
for Determining Eligibility for Competition in Athletes
with Cardiovascular Abnormalities has published guidelines
for patients with MS who wish to engage in competitive
athletics (105).
f.
Serial Testing. Serial follow-up testing of a patient
with MS should be based on whether the results of a
test will dictate either a change in therapy or a recommendation
for a procedure. Patients with MS usually have years
without symptoms before the onset of deterioration (254,266).
All patients should be informed that any change in symptoms
warrants reevaluation. In the asymptomatic patient,
yearly reevaluation is recommended (Figure
3). At the time of the yearly evaluation, a history,
physical examination, chest x-ray, and ECG should be
obtained. An echocardiogram is not recommended yearly
unless there is a change in clinical status. Ambulatory
ECG monitoring to detect paroxysmal atrial fibrillation
is indicated in patients with palpitations.
3.
Evaluation of the Symptomatic Patient. a. Initial
Workup. Patients who develop symptoms should undergo
evaluation with a history, physical examination, ECG,
chest x-ray, and echocardiogram (Figures
4 and 5). 2-D and Doppler
echocardiography is indicated to evaluate mitral valve
morphology, mitral valve hemodynamics, and pulmonary
artery pressure. Patients with NYHA functional Class
II symptoms and moderate or severe stenosis (mitral
valve area <1.5 cm2 or mean gradient
>5 mm Hg) may be considered for mitral balloon
valvotomy if they have suitable mitral valve morphology.
Patients who have NYHA functional Class III or IV symptoms
and evidence of severe MS have a poor prognosis if left
untreated (254-256)
and should be considered for intervention with either
balloon valvotomy or surgery.
A
subset of patients has significant limiting symptoms
yet resting hemodynamics that do not indicate moderate
to severe MS. If there is a discrepancy between symptoms
and hemodynamic data, formal exercise testing or dobutamine
stress may be useful to differentiate symptoms due to
MS from other causes of symptoms. Exercise tolerance,
heart rate and blood pressure response, transmitral
gradient, and pulmonary artery pressure can be obtained
at rest and during exercise. This can usually be accomplished
with either supine bicycle or upright exercise with
Doppler recording of TR and transmitral velocities (286-289).
Right- and left-heart catheterization with exercise
may also be helpful (307).
Patients who are symptomatic with a significant elevation
of pulmonary artery pressure (>60 mm Hg), mean transmitral
gradient (>15 mm Hg), or pulmonary artery wedge pressure
(>25 mm Hg) on exertion (261,286-288,308)
have hemodynamically significant MS and should be considered
for further intervention. Alternatively, patients who
do not manifest elevation in either pulmonary artery,
pulmonary artery wedge, or transmitral pressures coincident
with development of exertional symptoms most likely
would not benefit from intervention on the mitral valve.
b.
Indications for Cardiac Catheterization. Cardiac
catheterization has been considered the standard for
determining the severity of MS. Direct measurements
of left atrial and LV pressure determine the transmitral
gradient, which is the fundamental expression of the
severity of MS (259).
Because the severity of obstruction is dependent on
both flow and gradient (263),
the hydraulic Gorlin equation has been used in the catheterization
laboratory to derive a calculated valve area (106).
Pulmonary artery pressures and resistance can be obtained
to examine the effect of MS on the pulmonary circulation.
With
the advent of Doppler echocardiography, cardiac catheterization
is no longer required for assessment of hemodynamics
in the majority of patients with isolated MS. Reliable
measurements of the transmitral gradient may be obtained
with the modified Bernoulli equation (275,276).
The potential problems of angle dependence, pressure
recovery, proximal acceleration, and inadequate velocity
signals that occur in the evaluation of other valve
lesions are not present with MS. There is often overestimation
of the transmitral gradient when catheterization is
performed with pulmonary artery wedge pressure as a
substitute for left atrial pressure, even after correction
for phase delay. Thus, the transmitral gradient derived
by Doppler echocardiography may be more accurate than
that obtained by cardiac catheterization with pulmonary
artery wedge pressure (309).
Mitral
valve area is derived from either the half-time method
or continuity equation by Doppler echocardiography.
These measurements correlate well in most instances
with valve areas from cardiac catheterization (281,282).
The Doppler half-time method may be inaccurate if there
are changes in compliance of the left atrium or left
ventricle (282,283),
especially after mitral balloon valvotomy, or if there
is concomitant AR. There are limitations to mitral valve
area calculations derived from catheter measurements,
because the Gorlin equation may not be valid under varying
hemodynamic conditions and the empirical coefficient
of discharge may be inaccurate with different orifice
shapes (265,284).
Calculation of valve area by catheterization is also
dependent on measurement of transmitral gradient and
cardiac output. Gradients may be inaccurate when pulmonary
artery wedge pressure is used, as may cardiac output
derived by the thermodilution method. Thus, there may
be inaccuracies with both Doppler and catheter-derived
valve areas, and a single valve area should not be the
sole measure of MS severity. Estimates of the severity
of MS should be based on all data, including transmitral
gradient, mitral valve area, pulmonary artery wedge
pressure, and pulmonary artery pressure.
In
most instances Doppler measurements of transmitral gradient,
valve area, and pulmonary pressure will correlate well
with each other. Catheterization is indicated to assess
hemodynamics when there is a discrepancy between Doppler-derived
hemodynamics and the clinical status of a symptomatic
patient. Absolute left- and right-side pressure measurements
should be obtained by catheterization when there is
elevation of pulmonary artery pressure out of proportion
to mean gradient and valve area. Catheterization including
left ventriculography (to evaluate severity of MR) is
indicated when there is a discrepancy between the Doppler-derived
mean gradient and valve area. Aortic root angiography
may be necessary to evaluate severity of AR. If symptoms
appear to be out of proportion to noninvasive assessment
of resting hemodynamics, right- and left-heart catheterization
with exercise may be useful. Transseptal catheterization
may rarely be required for direct measurement of left
atrial pressure if there is doubt about the accuracy
of pulmonary artery wedge pressure. Coronary angiography
may be required in selected patients who may need intervention
(see section VIII of
these guidelines).
Recommendations
for Cardiac Catheterization in Mitral Stenosis
4.
Indications for Surgical or Percutaneous Valvotomy.
The concept of mitral commissurotomy was first proposed
by Brunton in 1902, and the first successful surgical
mitral commissurotomy was performed in the 1920s. By
the late 1940s and 1950s, both transatrial and transventricular
closed surgical commissurotomy were accepted clinical
procedures. With the development of cardiopulmonary
bypass in the 1960s, open mitral commissurotomy and
replacement of the mitral valve became the surgical
procedures of choice for the treatment of MS. Percutaneous
mitral balloon valvotomy emerged in the mid 1980s. This
procedure, in which one or more large balloons is inflated
across the mitral valve by a catheter-based approach,
has become an accepted alternative to surgical approaches
in selected patients.
The
mechanism of improvement from surgical commissurotomy
or percutaneous valvotomy is related to the successful
opening of commissures that were fused by the rheumatic
process. This results in a decrease in gradient and
increase in the calculated mitral valve area, with resulting
improvement in clinical symptomatology. The extent of
hemodynamic and clinical improvement is dependent on
the underlying morphology of the mitral valve apparatus.
Patients with pliable, noncalcified valves and minimal
fusion of the subvalvular apparatus achieve the best
immediate and long-term results.
Closed
surgical commissurotomy with either a transatrial or
transventricular approach was popularized in the 1950s
and 1960s. Early and long-term postoperative follow-up
studies showed that patients had a significant improvement
in symptoms and survival compared with those treated
medically (310-312).
Closed commissurotomy remains the surgical technique
of choice in many developing countries. Open commissurotomy
has now become the accepted surgical procedure in most
institutions in the United States (313-316),
because it allows direct inspection of the mitral valve
apparatus and, under direct vision, division of the
commissures, splitting of fused chordae tendineae and
papillary muscles, and debridement of calcium deposits.
Amputation of the left atrial appendage is recommended
to reduce the likelihood of postoperative thromboembolic
events (317). The results
of the operation are dependent on the morphology of
the mitral valve apparatus and the surgeon's skill and
experience. In patients with marked deformity of the
mitral valve apparatus, a decision for MVR can be made
at the time of operation. The risk of operation is between
1% and 3%, depending on the concomitant medical status
of the patient (313-316).
Although there is an inherent bias in the large reported
surgical series, the 5-year reoperation rate is 4% to
7% and the 5-year complication-free survival rate ranges
from 80% to 90%.
Percutaneous
mitral balloon valvotomy was first performed in the
mid 1980s and became a clinically approved technique
in 1994. In the past decade, there have been major advances
in techniques and equipment as well as changes in patient
selection. A double balloon technique was the initial
procedure used by most investigators. Today, an hourglass-shaped
single balloon (Inoue balloon) is used by most centers
performing the technique. The procedure itself is technically
challenging and involves a steep learning curve. There
is a higher success rate and lower complication rate
in experienced high-volume centers (318).
Thus, the results of the procedure are highly dependent
on the experience of the operators involved, which must
be considered when making recommendations for proceeding
with this technique.
The
immediate results of percutaneous mitral valvotomy are
similar to those of mitral commissurotomy (318-323).
The mean valve area usually doubles (from 1.0 cm2
to 2.0 cm2), with a 50% to 60% reduction
in transmitral gradient. Overall, 80% to 95% of patients
may have a successful procedure, which is defined as
a mitral valve area >1.5 cm2 and a decrease
in left atrial pressure to <18 mm Hg in the
absence of complications. The most common acute complications
reported in large series include severe MR, which occurs
in 2% to 10%, and a residual atrial septal defect. A
large atrial septal defect (>1.5:1 left-to-right
shunt) occurs in <12% of patients with the
double balloon technique and <5% with the Inoue balloon
technique. Smaller atrial septal defects may be detected
by transesophageal echocardiography in larger numbers
of patients. Less frequent complications include perforation
of the left ventricle (0.5% to 4.0%), embolic events
(0.5% to 3%), and myocardial infarction (0.3% to 0.5%).
The mortality of balloon valvotomy in larger series
has ranged from 1% to 2% (318-321);
however, with increasing experience with the procedure,
percutaneous mitral valvotomy can be done in selected
patients with a mortality of <1% (322).
Follow-up
information after percutaneous balloon valvotomy is
limited. Event-free survival (freedom from death, repeat
valvotomy, or MVR) overall is 50% to 65% over 3 to 7
years, with an event-free survival of 80% to 90% in
patients with favorable mitral valve morphology (280,320,322-324).
More than 90% of patients free of events remain in NYHA
functional Class I or II after percutaneous mitral valvotomy.
Randomized trials have compared percutaneous balloon
valvotomy with both closed and open surgical commissurotomy
(325-329).
These trials, summarized in Table
16, consisted of younger patients (aged 10 to 30
years) with pliable mitral valve leaflets. There was
no significant difference in acute hemodynamic results
or complication rate between percutaneous mitral valvotomy
and surgery, and early follow-up data indicate no difference
in hemodynamics, clinical improvement, or exercise time.
However, longer-term follow-up studies at 3 to 7 years
(327,329)
indicate more favorable hemodynamic and symptomatic
results with percutaneous balloon valvotomy than with
closed commissurotomy and results equivalent to those
of open commissurotomy.
The
immediate results, acute complications, and follow-up
results of percutaneous balloon valvotomy are dependent
on multiple factors. It is of utmost importance that
this procedure be performed in centers with skilled
and experienced operators. Other factors include age,
NYHA functional class, stenosis severity, LV end-diastolic
pressure, cardiac output, and pulmonary artery wedge
pressure (320,322,323).
The underlying mitral valve morphology is the factor
of greatest importance in determining outcome (277-280,320,323,324,330),
and immediate post-valvotomy hemodynamics are predictive
of long-term clinical outcome (322).
Patients with valvular calcification, thickened fibrotic
leaflets with decreased mobility, and subvalvular fusion
have a higher incidence of acute complications and a
higher rate of recurrent stenosis on follow-up (Table
17). Because the success of the procedure is dependent
on the ability to split fused commissures, the presence
of marked fusion and severe calcification of commissures
is associated with an increased complication rate and
higher incidence of recurrent symptoms (279,280).
Alternatively, in patients with noncalcified pliable
valves and no calcium in the commissures, the procedure
can be performed with a high success rate (>90%),
low complication rate (<3%), and sustained improvement
in 80% to 90% over a 3- to 7-year follow-up period (280,320,322,324).
Relative
contraindications to percutaneous balloon valvotomy
include the presence of a left atrial thrombus and significant
(3+ to 4+) MR. Transesophageal echocardiography is frequently
performed before the procedure to determine the presence
of left atrial thrombus, specifically examining the
left atrial appendage. If a thrombus is found, 3 months
of anticoagulation with warfarin may result in resolution
of the thrombus.
In
centers with skilled, experienced operators, percutaneous
balloon valvotomy should be considered the initial procedure
of choice for symptomatic patients with moderate to
severe MS who have a favorable valve morphology in the
absence of significant MR or left atrial thrombus. In
asymptomatic patients with a favorable valve morphology,
percutaneous mitral valvotomy may be considered if there
is evidence of a hemodynamic effect on left atrial pressure
(new-onset atrial fibrillation) or pulmonary circulation
(pulmonary artery pressure >50 mm Hg at rest or >60
mm Hg with exercise); the strength of evidence for this
recommendation is low because there are no data comparing
the results of percutaneous balloon valvotomy and those
of medical therapy in such asymptomatic patients. It
is controversial whether severely symptomatic patients
with less favorable valve morphology should undergo
this catheter-based procedure (331)
(see Figure 5). Although
there is a higher acute complication rate and a lower
event-free survival rate (~50% at 5 years in these patients,
compared with 80% to 90% in patients with favorable
valve morphology), this must be weighed against the
risks and potential complications of surgical MVR.
Patients
who are being considered for an intervention should
undergo evaluation with a history, physical examination,
and 2-D and Doppler echocardiographic examination. The
appearance and mobility of the mitral valve apparatus
and commissures should be evaluated by 2-D echocardiography,
and the transmitral gradient, mitral valve area, and
pulmonary artery pressure should be obtained from the
Doppler examination. If there is a discrepancy between
symptoms and hemodynamics, a formal hemodynamic exercise
test may be performed. Patients thought to be candidates
for percutaneous mitral valvotomy should undergo transesophageal
echocardiography to rule out left atrial thrombus and
to examine the severity of MR. If a left atrial thrombus
is present, a repeat transesophageal echocardiogram
can be performed after several months of anticoagulation.
Percutaneous mitral balloon valvotomy may be safely
performed if there has been resolution of the thrombus.
If there is a suspicion that the severity of MR is 3+
or 4+ based on the physical examination and/or echocardiogram,
a left ventriculogram should be performed. Mitral balloon
valvotomy should not be performed in patients who have
grade 3+ or 4+ MR. Percutaneous mitral balloon valvotomy
should be performed only by skilled operators at institutions
with extensive experience in performing the technique
(318,321).
Thus, the decision to proceed with percutaneous balloon
valvotomy or surgical commissurotomy is dependent on
the experience of the operator and institution. Due
to the less invasive nature of percutaneous balloon
valvotomy compared with surgical intervention, appropriate
patients without symptoms or those with NYHA functional
Class II symptoms may be considered for catheter-based
therapy (Figures 3 and 4).
Recommendations
for Percutaneous Mitral Balloon Valvotomy
Recommendations
for Mitral Valve Repair for Mitral Stenosis
5.
Indications for Mitral Valve Replacement. MVR is
an accepted surgical procedure for patients with severe
MS who are not candidates for surgical commissurotomy
or percutaneous mitral valvotomy. The risk of MVR is
dependent on multiple factors, including functional
status, age, LV function, cardiac output, concomitant
medical problems, and concomitant CAD. In the young,
healthy person, MVR can be performed with a risk of
<5%. However, in the older patient with concomitant
medical problems or pulmonary hypertension at systemic
levels, the risk of MVR may be as high as 10% to 20%.
Complications of MVR include valve thrombosis, valve
dehiscence, valve infection, valve malfunction, and
embolic events. These are discussed in detail in section
VII of these guidelines. There is also the known
risk of long-term anticoagulation.
If
there is significant calcification, fibrosis, and subvalvular
fusion of the mitral valve apparatus, commissurotomy
or percutaneous balloon valvotomy is less likely to
be successful, and MVR will be necessary. Given the
risk of MVR and the potential long-term complications
of a prosthetic valve, there are stricter indications
for mitral valve operation in these patients with calcified
fibrotic valves. In the patient with NYHA functional
Class III symptoms due to severe MS or combined MS/MR,
MVR results in excellent symptomatic improvement. Postponement
of surgery until the patient reaches the functional
Class IV symptomatic state should be avoided because
operative mortality is high and long-term outcome is
suboptimal. However, if the patient presents in NYHA
functional Class IV heart failure, surgery should not
be denied because the outlook without surgical intervention
is grave. It is controversial whether asymptomatic or
mildly symptomatic patients with severe MS (valve area
<1 cm2) and severe pulmonary hypertension
(pulmonary artery systolic pressure >60 to 80 mm
Hg) should undergo MVR to prevent right ventricular
failure, but surgery is generally recommended in such
patients. It is recognized that patients with such severe
pulmonary hypertension are rarely asymptomatic.
Recommendations
for Mitral Valve Replacement for Mitral Stenosis
6.
Management of Patients After Valvotomy or Commissurotomy.
Symptomatic improvement occurs immediately after successful
percutaneous balloon valvotomy or surgical commissurotomy,
although objective measurement of maximum oxygen consumption
may continue to improve over several months postoperatively
due to slowly progressive improvement in skeletal muscle
metabolism (332). Hemodynamic
measurements before and after either percutaneous valvotomy
or surgical commissurotomy have confirmed a decrease
in left atrial pressure, pulmonary artery pressure,
and pulmonary arteriolar resistance and an improvement
in cardiac output (333-336).
Gradual regression of pulmonary hypertension over months
has been demonstrated (333,334,336).
Recurrent
symptoms after successful surgical commissurotomy have
been reported to occur in as many as 60% of patients
after 9 years (285,310,337).
However, recurrent stenosis accounts for symptoms in
<20% of patients (337).
In patients with an adequate initial result, progressive
MR and development of other valvular or coronary problems
are more frequently responsible for recurrent symptoms
(337). Thus, in patients
presenting with symptoms late after commissurotomy,
a comprehensive evaluation is required to look for other
causes. Patients undergoing percutaneous mitral valvotomy
have a higher incidence of recurrent symptoms at 1-
to 2-year follow-up if there was an unfavorable mitral
valve morphology, due to either an initial inadequate
result or restenosis (338).
The
management of patients after successful percutaneous
balloon valvotomy or surgical commissurotomy is similar
to that of the asymptomatic patient with MS. A baseline
echocardiogram should be performed after the procedure
to obtain a baseline measurement of postoperative hemodynamics
as well as to exclude significant complications such
as MR, LV dysfunction, or atrial septal defect (in the
case of percutaneous valvotomy). This echocardiogram
should be performed at least 72 hours after the procedure
because acute changes in atrial and ventricular compliance
immediately after the procedure affect the reliability
of the half-time in calculation of valve area (282,283).
Patients with severe MR or a large atrial septal defect
should be considered for early operation. However, the
majority of small left-to-right shunts at the atrial
level will close spontaneously over the course of 6
months. In patients with a history of atrial fibrillation,
warfarin should be restarted 1 to 2 days after the procedure.
A
history, physical examination, chest x-ray, and ECG
should be obtained at yearly intervals in the patient
who remains asymptomatic or minimally symptomatic. Prophylaxis
against infective endocarditis and recurrence of rheumatic
fever should be followed. If the patient is in atrial
fibrillation or has a history of atrial fibrillation,
anticoagulation is recommended, as would be the case
for all patients with MS. With recurrent symptoms, extensive
2-D and Doppler echocardiography should be performed
to evaluate the mitral valve hemodynamics and pulmonary
artery pressure as well as to rule out significant MR
or a left-to-right shunt. As with all patients with
MS, exercise hemodynamics may be indicated in the patient
with a discrepancy in clinical and hemodynamic findings.
Repeat
percutaneous balloon valvotomy can be performed in the
patient in whom there is restenosis after either a prior
surgical commissurotomy or balloon valvotomy (277,339).
The results of these procedures are less satisfactory
than the overall results of initial valvotomy because
there is usually more valve deformity, calcification,
and fibrosis than with the initial procedure (277,339).
MVR should be considered in those patients with recurrent
severe symptoms and severe deformity of the mitral apparatus.
7.
Special Considerations. a. Pregnant Patients.
MS often affects young women who are in their childbearing
years. The increased intravascular volume, increased
cardiac output, and tachycardia associated with pregnancy
may raise complex issues in the patient with MS and
are reviewed in section
V of these guidelines.
b.
Older Patients. An increasing number of older patients
now present with symptomatic MS, most likely due to
a change in the natural history of the disease (269,270).
Older patients are more likely to have heavy calcification
and fibrosis of the mitral valve leaflets, with significant
subvalvular fusion. In patients older than 65, the success
rate of percutaneous valvotomy is lower (<50%) than
in prior reports of younger patients. Procedural mortality
is 3%, and there is an increased risk of complications,
including pericardial tamponade in 5% and thromboembolism
in 3%. However, in selected patients with favorable
valve morphology, the procedure may be done safely with
good intermediate-term results (270).
D.
Mitral Valve Prolapse
1.
Pathophysiology and Natural History. MVP refers
to a systolic billowing of one or both mitral leaflets
into the left atrium with or without MR. It is the most
common form of valvular heart disease and occurs in
2% to 6% of the population. MVP often occurs as a clinical
entity with little or no MR but is also the most common
cause of significant MR in the United States. MR stemming
from MVP is frequently associated with unique clinical
characteristics when compared with other causes of MR
(340,341).
The
mitral valve apparatus is a complex structure composed
of the mitral annulus; valve leaflets; chordae tendineae;
papillary muscles; and the supporting LV, left atrial,
and aortic walls (342).
Disease processes involving any of these components
may result in dysfunction of the valve apparatus and
prolapse of the mitral leaflets toward the left atrium
during systole, when LV pressure exceeds left atrial
pressure. A classification of MVP is shown in Table
18 (343,344).
In
primary MVP, there is interchordal hooding due to leaflet
redundancy that includes both the rough and clear zones
of the involved leaflets (345).
The height of the interchordal hooding is usually >4
mm and involves at least one half of the anterior leaflet
or two thirds of the posterior leaflet. The basic microscopic
feature of primary MVP is marked proliferation of the
spongiosa, the delicate myxomatous connective tissue
between the atrialis (a thick layer of collagen and
elastic tissue forming the atrial aspect of the leaflet)
and the fibrosa or ventricularis (dense layers of collagen
that form the basic support of the leaflet). In primary
MVP, myxomatous proliferation of the acid mucopolysaccharide-containing
spongiosa tissue causes focal interruption of the fibrosa.
Secondary effects of the primary MVP syndrome include
fibrosis of the surfaces of the mitral valve leaflets,
thinning and/or elongation of chordae tendineae, and
ventricular friction lesions. Fibrin deposits often
form at the mitral valve-left atrial angle.
The
primary form of MVP usually occurs as isolated cases
but may be familial and transmitted as an autosomal
dominant trait (346,347).
It occurs with increased frequency in patients with
Marfan syndrome and in other connective tissue diseases
(345,348-350).
It has been speculated that the primary MVP syndrome
represents a generalized disease of connective tissue.
Thoracic skeletal abnormalities such as a straight thoracic
spine and pectus excavatum are commonly associated with
MVP (351). The increased
incidence of primary MVP in patients with von Willebrand's
disease and other coagulopathies, primary hypomastia,
and various connective tissue diseases has been used
to support the concept that MVP is a result of defective
embryogenesis of cell lines of mesenchymal origin (352).
Secondary
forms of MVP occur in which myxomatous proliferation
of the spongiosa portion of the mitral valve leaflet
is absent. Serial studies in patients with known ischemic
heart disease have occasionally documented unequivocal
MVP after an acute coronary syndrome that was previously
absent (353-355).
In most patients with CAD and MVP, however, the 2 entities
are coincident but unrelated.
Several
recent studies indicate that valvular regurgitation
caused by MVP may result from postinflammatory changes,
including those after rheumatic fever (356-358).
In histological studies of surgically excised valves,
fibrosis with vascularization and scattered infiltration
of round cells including lymphocytes and plasmacytes
were found without myxomatous proliferation of the spongiosa.
With rheumatic carditis the anterior mitral leaflet
is more likely to prolapse.
MVP
has been observed in patients with hypertrophic cardiomyopathy
in whom posterior MVP may result from a disproportionally
small LV cavity, altered papillary muscle alignment,
or a combination of factors (359).
The mitral valve leaflet is usually normal. MVP may
occur secondary to ruptured chordae tendineae as a "flail"
or partial flail mitral leaflet, whether spontaneous
or due to infective endocarditis.
Patients
with primary and secondary MVP must be distinguished
from normal variants by cardiac auscultation and/or
echocardiography; these variations can result in an
incorrect diagnosis of MVP, particularly in patients
whose hearts are hyperkinetic or who are dehydrated
(360). Other auscultatory
findings may be misinterpreted as midsystolic clicks
or late systolic murmurs. Patients with mild to moderate
billowing of one or both nonthickened leaflet(s) toward
the left atrium with the leaflet coaptation point on
the LV side of the mitral annulus and with minimal or
no MR by Doppler echocardiography are probably normal
(361). Unfortunately,
many such patients are overdiagnosed as having the MVP
syndrome.
In
patients with MVP, there may be left atrial dilatation
and LV enlargement, depending on the presence and severity
of MR. The supporting apparatus is often involved, and
in patients with connective tissue syndromes such as
Marfan syndrome, the mitral annulus is usually dilated
and sometimes calcified and does not decrease its circumference
by the usual 30% during LV systole.
Many
studies suggest autonomic nervous system dysfunction
in many patients with primary MVP. In several studies,
measurements of serum and 24-hour urine epinephrine
or norepinephrine levels were increased in patients
with symptomatic MVP compared with age-matched controls
(362-365).
Tricuspid
valve prolapse with similar interchordal hooding and
histological evidence of mucopolysaccharide proliferation
and collagen dissolution occurs in ~40% of patients
with MVP (346). Pulmonic
valve prolapse and aortic valve prolapse occur in ~10%
and 2% of patients with MVP, respectively (345).
There is an increased incidence of secundum atrial septal
defect in patients with MVP as well as an increased
incidence of left-sided atrioventricular bypass tracts
and supraventricular arrhythmias (345).
In
most patient studies, the MVP syndrome is associated
with a benign prognosis (366,367).
The age-adjusted survival rate of both men and women
with MVP is similar to that of individuals without this
common clinical entity (346).
The gradual progression of MR in patients with MVP may
result in the progressive dilatation of the left atrium
and ventricle. Left atrial dilatation may result in
atrial fibrillation, and moderate to severe MR may eventually
result in LV dysfunction and development of congestive
heart failure (340).
Pulmonary hypertension may occur with associated right
ventricular dysfunction. In some patients, after an
initially prolonged asymptomatic interval, the entire
process may enter an accelerated phase as a result of
left atrial and LV dysfunction, atrial fibrillation,
and in certain instances ruptured mitral valve chordae
(340).
Several
long-term prognostic studies suggest that complications
occur most commonly in patients with a mitral systolic
murmur, those with thickened redundant mitral valve
leaflets, and those with increased LV or left atrial
size, especially in men older than 45 years (340,368-372).
Sudden
death is a rare complication of MVP occurring in <2%
of known cases during long-term follow-up (366-373),
with annual mortality rates <1% per year. The likely
cause is a ventricular tachyarrhythmia based on the
finding of an increased incidence of complex ventricular
ectopy on ambulatory ECG recordings in patients with
MVP who had sudden cardiac death (374,375).
Although infrequent, the highest incidence of sudden
death has been reported in the familial form of MVP;
some of these patients have also been noted to have
QT prolongation (340,376).
Infective
endocarditis is a serious complication of MVP, which
is the leading predisposing cardiovascular diagnosis
in most series of patients reported with endocarditis
(340,350,377).
Because the absolute incidence of endocarditis is extremely
low for the entire MVP population, there has been much
controversy about the risk of endocarditis in MVP (378).
As
indicated above, progressive MR occurs frequently in
patients with long-standing MVP. Fibrin emboli are responsible
in some patients for visual symptoms consistent with
involvement of the ophthalmic or posterior cerebral
circulation (379).
Several studies have indicated an increased likelihood
of cerebrovascular accidents in patients under age 45
who have MVP over what would have been expected in a
similar population without MVP (380).
2.
Evaluation and Management of the Asymptomatic Patient.
The diagnosis of MVP is most commonly made by cardiac
auscultation in asymptomatic patients or echocardiography
performed for another purpose. The patient may be evaluated
because of a family history of cardiac disease or occasionally
may be referred because of an abnormal resting ECG.
The
primary diagnostic evaluation of the patient with MVP
is a careful physical examination (340,381).
The principal cardiac auscultatory feature of this syndrome
is the midsystolic click, a high-pitched sound of short
duration. One or more clicks may vary considerably in
intensity and timing in systole according to LV loading
conditions and contractility. Clicks result from sudden
tensing of the mitral valve apparatus as the leaflets
prolapse into the left atrium during systole. The midsystolic
click(s) is frequently followed by a late systolic murmur,
usually medium- to high-pitched and loudest at the cardiac
apex. Occasionally, the murmur has a musical or honking
quality. The character and intensity of the murmur also
vary under certain conditions, from brief and almost
inaudible to holosystolic and loud. Dynamic auscultation
is often useful for establishing the clinical diagnosis
of the MVP syndrome (381).
Changes in LV end-diastolic volume result in changes
in the timing of the midsystolic click(s) and murmur.
When end-diastolic volume is decreased (such as with
standing), the critical volume is achieved earlier in
systole and the click-murmur complex occurs shortly
after the first heart sound. By contrast, any maneuver
that augments the volume of blood in the ventricle (eg,
squatting), reduces myocardial contractility, or increases
LV afterload lengthens the time from onset of systole
to initiation of MVP, and the systolic click and/or
murmur move toward the second heart sound.
Although
the ECG may provide some information in patients with
MVP, it is most often normal. Nonspecific ST-T wave
changes, T-wave inversions, prominent U waves, and prolongation
of the QT interval also occur. Continuous ambulatory
ECG recordings or event monitors may be useful for documenting
arrhythmias in patients with palpitations. They are
not indicated as a routine test for asymptomatic patients.
Most of the arrhythmias detected are not life-threatening,
and patients often complain of palpitations when the
ambulatory ECG recording shows no abnormalities.
Posterior-anterior
and lateral chest roentgenograms usually show normal
cardiopulmonary findings. The skeletal abnormalities
described above, such as pectus excavatum, are often
seen (351). When severe
MR is present, both left atrial and LV enlargement often
result. Various degrees of pulmonary venous congestion
are evident when left-heart failure results. Calcification
of the mitral annulus may be seen, particularly in adults
with Marfan syndrome (381).
In asymptomatic patients with MVP, a chest x-ray usually
provides no additional information.
2-D
and Doppler echocardiography is the most useful noninvasive
test for defining MVP. The M-mode echocardiographic
definition of MVP includes >2 mm posterior
displacement of one or both leaflets or holosystolic
posterior "hammocking" >3 mm. On 2-D echocardiography,
systolic displacement of one or both mitral leaflets
in the parasternal long-axis view, particularly when
they coapt on the atrial side of the annular plane,
indicates a high likelihood of MVP. There is disagreement
concerning the reliability of echocardiographic diagnosis
of MVP when observed in only the apical 4-chamber view
(382,383).
The diagnosis of MVP is even more certain when the leaflet
thickness is >5 mm. Leaflet redundancy is often associated
with an enlarged mitral annulus and elongated chordae
tendineae (340). On
Doppler echocardiography, the presence or absence of
MR is an important consideration, and MVP is more likely
when MR is detected as a high-velocity eccentric jet
in late systole (361).
At
present, there is no consensus on the 2-D echocardiographic
criteria for MVP. Because echocardiography is a tomographic
cross-sectional technique, no single view should be
considered diagnostic. The parasternal long-axis view
permits visualization of the medial aspect of the anterior
mitral leaflet and middle scallop of the posterior leaflet.
If the findings of prolapse are localized to the lateral
scallop in the posterior leaflet, they would be best
visualized by the apical 4-chamber view. All available
echocardiographic views should be used with the provision
that billowing of the anterior leaflet alone in the
4-chamber apical view is not evidence of prolapse; however,
a displacement of the posterior leaflet or the coaptation
point in any view, including the apical view, suggests
the diagnosis of prolapse. The echocardiographic criteria
for MVP should include structural changes such as leaflet
thickening, redundancy, annular dilatation, and chordal
elongation.
Patients
with echocardiographic evidence for MVP but without
evidence of thickened/redundant leaflets or definite
MR are more difficult to classify. If such patients
have clinical auscultatory findings of MVP, then the
echocardiogram usually confirms the diagnosis.
Although
the echocardiogram is a confirmatory test for diagnosing
MVP, it is not always abnormal. Nevertheless, echocardiography
is useful for defining left atrial size, LV size and
function, and the extent of mitral leaflet redundancy
for detecting patients at high risk for complications
and for detecting associated lesions such as secundum
atrial septal defect. Doppler echocardiography is helpful
for detection and semiquantitation of MR. Although there
is controversy concerning the need for echocardiography
in patients with classic auscultatory findings of MVP,
the usefulness of echocardiography for risk stratification
in patients with MVP has been demonstrated in >6
published studies (Table 19)
(368,382,
384-387).
All patients with MVP should have an initial echocardiogram.
Serial echocardiograms are not usually necessary in
the asymptomatic patient with MVP unless there are clinical
indications of severe or worsening MR.
The
use of echocardiography as a screening test for MVP
in patients with and without symptoms who have no systolic
click or murmur on serial, carefully performed auscultatory
examinations is not recommended. The likelihood of finding
a prolapsing mitral valve in such patients is extremely
low. Most patients with or without symptoms who have
a negative dynamic cardiac auscultation and "mild
MVP" by echocardiography should not be diagnosed
as having MVP.
Reassurance
is a major part of the management of patients with MVP,
most of whom are asymptomatic or have no cardiac symptoms
and lack a high-risk profile. These patients with mild
or no symptoms and findings of milder forms of prolapse
should be reassured of the benign prognosis. A normal
lifestyle and regular exercise is encouraged (340,381).
Antibiotic
prophylaxis for the prevention of infective endocarditis
during procedures associated with bacteremia is recommended
for most patients with a definite diagnosis of MVP (388)
as indicated in section
II.B. of these guidelines. There has been some disagreement
concerning whether patients with an isolated systolic
click and no systolic murmur should undergo endocarditis
prophylaxis. Patients with only a systolic click who
have echocardiographic evidence of a higher-risk profile
for endocarditis, such as leaflet thickening, elongated
chordae, left atrial enlargement, or LV dilatation,
should receive endocarditis prophylaxis (368,382,384-387).
Recommendations
for Echocardiography in Mitral Valve Prolapse*
Recommendations
for Antibiotic Endocarditis Prophylaxis for Patients
With Mitral Valve Prolapse Undergoing Procedures Associated
With Bacteremia*
3.
Evaluation and Management of the Symptomatic Patient.
Some patients consult their physicians about one or
more of the common symptoms that occur with this syndrome;
palpitations, often reported at a time when continuous
ambulatory ECG recordings show no arrhythmias; atypical
chest pain that rarely resembles classic angina pectoris;
dyspnea and fatigue, when objective exercise testing
often fails to show any impairment in exercise tolerance;
and neuropsychiatric complaints, with many patients
having panic attacks and similar syndromes (340).
Transient cerebral ischemic episodes occur with increased
incidence in patients with MVP, and some patients develop
stroke syndromes. Reports of amaurosis fugax, homonymous
field loss, and retinal artery occlusion have been described;
occasionally the visual loss persists (380,389-391).
The
roles of cardiac auscultation and echocardiography in
the assessment of symptomatic patients with MVP are
the same as for patients without symptoms. The indications
for antibiotic prophylaxis to prevent endocarditis are
also unchanged.
Patients
with MVP and palpitations associated with mild tachyarrhythmias
or increased adrenergic symptoms and those with chest
pain, anxiety, or fatigue often respond to therapy with
ß-blockers (392).
In many cases, however, the cessation of stimulants
such as caffeine, alcohol, and cigarettes may be sufficient
to control symptoms. In patients with recurrent palpitations,
continuous or event-activated ambulatory ECG recordings
may reveal the presence or absence of arrhythmias at
the time of symptoms and indicate appropriate treatment
of existing arrhythmias. The indications for electrophysiological
testing are similar to those in the general population
(eg, aborted sudden death, recurrent syncope of unknown
cause, and symptomatic or sustained ventricular tachycardia)
(393).
Cardiac
catheterization is not required for the diagnosis of
MVP. It is helpful in evaluating associated conditions
(eg, CAD and atrial septal defect) and may be needed
to assess the hemodynamic effects of severe MR (as well
as coronary artery anatomy) before consideration for
valve repair or replacement.
Orthostatic
symptoms due to postural hypotension and tachycardia
are best treated with volume expansion, preferably by
liberalizing fluid and salt intake. Mineralocorticoid
therapy or clonidine may be needed in severe cases,
and wearing support stockings may be beneficial.
Daily
aspirin therapy (80 to 325 mg/d) is recommended for
MVP patients with documented focal neurological events
who are in sinus rhythm with no atrial thrombi. Such
patients also should avoid cigarettes and oral contraceptives.
Long-term anticoagulation therapy with warfarin is recommended
for post-stroke patients with MVP and MVP patients with
recurrent transient ischemic attacks on aspirin therapy
(INR 2 to 3). In MVP patients with atrial fibrillation,
warfarin therapy is indicated in patients aged >65
years and those with MR, hypertension, or a history
of heart failure (INR 2 to 3). Aspirin therapy is satisfactory
in patients with atrial fibrillation who are <65
years, have no MR, and have no history of hypertension
or heart failure (394,395).
Daily aspirin therapy is often recommended for patients
with high-risk echocardiographic characteristics.
A
normal lifestyle and regular exercise are encouraged
for most patients with MVP, especially those who are
asymptomatic (370,396).
Restriction from competitive sports is recommended when
moderate LV enlargement, LV dysfunction, uncontrolled
tachyarrhythmias, long QT interval, unexplained syncope,
prior sudden death, or aortic root enlargement is present
individually or in combination (340).
A familial occurrence of MVP should be explained to
the patient and is particularly important in those with
associated disease who are at greater risk for complications.
There is no contraindication to pregnancy based on the
diagnosis of MVP alone.
Asymptomatic
patients with MVP and no significant MR can be evaluated
clinically every 3 to 5 years. Serial echocardiography
is not necessary in most patients and is obtained only
in patients who have high-risk characteristics on the
initial echocardiogram and those who develop symptoms
consistent with cardiovascular disease or have a change
in physical findings suggesting development of significant
MR. Patients who have high-risk characteristics, including
those with moderate to severe MR, should be followed
once a year.
Patients
with severe MR with symptoms and/or impaired LV systolic
function require cardiac catheterization and evaluation
for mitral valve surgery. The thickened, redundant mitral
valve can often be repaired rather than replaced with
a low operative mortality and excellent short- and long-term
results (391-393,397,398).
Follow-up studies also suggest lower thrombotic and
endocarditis risk with valve repair than with prosthetic
valves.
Recommendations
for Aspirin and Oral Anticoagulants in Mitral Valve
Prolapse
4.
Surgical Considerations. Management of MVP may require
valve surgery, particularly in those patients who develop
a flail mitral leaflet due to rupture of chordae tendineae
or their marked elongation. Most such valves can be
repaired successfully by surgeons experienced in mitral
valve repair, especially when the posterior leaflet
of the mitral valve is predominantly affected. Symptoms
of heart failure, severity of MR, presence or absence
of atrial fibrillation, LV systolic function, LV end-diastolic
and end-systolic volumes, and pulmonary artery pressure
(rest and exercise) all influence the decision to recommend
mitral valve surgery. Recommendations for surgery in
patients with MVP and MR are the same as for those with
other forms of nonischemic severe MR, as indicated in
section III.E.4. of
these guidelines.
E.
Mitral Regurgitation
1.
Etiology. The common etiologies for MR include MVP
syndrome, rheumatic heart disease, CAD, infective endocarditis,
and collagen vascular disease. Recently, anorectic drugs
have also been reported to cause MR (see section
III.H. of these guidelines). In some cases, such
as ruptured chordae tendineae or infective endocarditis,
MR may be acute and severe. Alternatively, MR may worsen
gradually over a prolonged period of time. These 2 ends
of the spectrum have quite different clinical presentations.
2.
Acute Severe Mitral Regurgitation.
a.
Pathophysiology. In acute severe MR, a sudden volume
overload is imposed on the left ventricle. Acute volume
overload increases LV preload, allowing for a modest
increase in total LV stroke volume (399).
However, in the absence of compensatory eccentric hypertrophy
(which has had no time to develop), forward stroke volume
and cardiac output are reduced. At the same time, the
unprepared left atrium and left ventricle cannot accommodate
the regurgitant volume, resulting in pulmonary congestion.
In this phase of the disease, the patient has both reduced
forward output (even shock) and simultaneous pulmonary
congestion. In severe MR, the hemodynamic overload often
cannot be tolerated, and mitral valve repair or replacement
must often be performed urgently.
b.
Diagnosis. The patient with acute severe MR is almost
always symptomatic. Physical examination of the precordium
may be misleading because a normal-sized left ventricle
does not produce a hyperdynamic apical impulse. The
systolic murmur of MR, which may or may not be holosystolic,
and a third heart sound may be the only abnormal physical
findings present. A fourth heart sound is also common
in acute MR because the patient is usually still in
sinus rhythm. Transthoracic echocardiography may demonstrate
the disruption of the mitral valve and help provide
semiquantitative information on lesion severity. However,
transthoracic echocardiography may underestimate lesion
severity by inadequate imaging of the color flow jet.
Because transesophageal echocardiography can more accurately
assess the color flow jet (400),
transesophageal imaging should be performed if mitral
valve morphology and regurgitant severity are still
in question after transthoracic echocardiography. Transesophageal
echocardiography is also helpful in demonstrating the
anatomic cause of MR and directing successful surgical
repair. Indeed, assessment of valve anatomy is a major
goal of transesophageal imaging.
If
ischemia is not the cause of MR and there is no reason
to suspect CAD, mitral valve repair can usually be performed
without the need for cardiac catheterization. However,
if CAD is suspected or there are risk factors for CAD
(see Section VIII. B.),
coronary arteriography is necessary before surgery because
myocardial revascularization should be performed during
mitral valve surgery in those patients with concomitant
CAD (401,402).
c.
Medical Therapy. In acute severe MR, the goal of
nonsurgical therapy is to diminish the amount of MR,
in turn increasing forward output and reducing pulmonary
congestion. In the normotensive patient, administration
of nitroprusside may effectively accomplish all 3 goals.
Nitroprusside increases forward output not only by preferentially
increasing aortic flow but also by partially restoring
mitral valve competence as LV size diminishes (403,404).
In the patient rendered hypotensive because of a severe
reduction in forward output, nitroprusside should not
be administered alone, but combination therapy with
an inotropic agent (such as dobutamine) and nitroprusside
is of benefit in some patients. In such patients, aortic
balloon counterpulsation increases forward output and
mean arterial pressure while diminishing regurgitant
volume and LV filling pressure and can be used to stabilize
the patient while preparing for surgery. If infective
endocarditis is the cause of acute MR, identification
and treatment of the infectious organism are essential.
3.
Chronic Asymptomatic Mitral Regurgitation.
a.
Pathophysiology. In chronic severe MR, there has
been time for development of eccentric cardiac hypertrophy
in which new sarcomeres are laid down in series, increasing
the length of individual myocardial fibers (153,399).
The resulting increase in LV end-diastolic volume is
compensatory because it permits an increase in total
stroke volume, allowing for restoration of forward cardiac
output (405). At the
same time, the increase in LV and left atrial size allows
accommodation of the regurgitant volume at a lower filling
pressure, and the symptoms of pulmonary congestion abate.
In this phase of compensated MR, the patient may be
entirely asymptomatic, even during vigorous exercise.
It should be noted that in the compensatory phase, augmented
preload and reduced or normal afterload (provided by
the unloading of the left ventricle into the left atrium)
facilitate LV ejection, resulting in a large total stroke
volume and a normal forward stroke volume.
The
duration of the compensated phase of MR is variable
but may last for many years. However, the prolonged
burden of volume overload may eventually result in LV
dysfunction. In this phase, contractile dysfunction
impairs ejection and end-systolic volume increases.
There may be further LV dilatation and increased LV
filling pressure. These hemodynamic events result in
reduced forward output and pulmonary congestion. However,
the still favorable loading conditions often maintain
ejection fraction in the low normal range (0.50 to 0.60)
despite the presence of significant muscle dysfunction
(399,406,407).
Correction of MR should occur before the advanced phases
of LV decompensation.
b.
Diagnosis. In evaluating the patient with chronic
MR, a careful history is invaluable. A well-established
estimation of baseline exercise tolerance is important
in gauging the subtle onset of symptoms at subsequent
evaluations. Physical examination should demonstrate
displacement of the LV apical impulse, which indicates
that MR is severe and chronic, producing cardiac enlargement.
A third heart sound is usually present and does not
necessarily indicate heart failure. Findings consistent
with pulmonary hypertension are worrisome because they
indicate advanced disease with worsened prognosis (408).
An ECG and chest x-ray are useful in establishing rhythm
and heart size, respectively. An initial echocardiogram
including Doppler interrogation of the mitral valve
is indispensable in the management of the patient with
MR. The echocardiogram provides a baseline estimation
of LV and left atrial volume, an estimation of LV ejection
fraction, and approximation of the severity of regurgitation.
Changes from these baseline values are subsequently
used to guide the timing of mitral valve surgery. In
addition, the echocardiogram can often disclose the
anatomic cause of the patient's condition. In the presence
of even mild TR, interrogation of the tricuspid valve
yields an estimate of pulmonary artery pressure by measurement
of the gradient from the right ventricle to the right
atrium (409).
In
some patients, Doppler studies show that MR worsens
with exercise, possibly reconciling exercise-induced
symptoms with resting echocardiograms that show only
mild or moderate regurgitation (410).
c.
Serial Testing. The aim of serial follow-up of the
patient with MR is to subjectively assess changes in
symptomatic status and objectively assess changes in
LV function and exercise tolerance that can occur in
the absence of symptoms. Asymptomatic patients with
mild MR and no evidence of LV enlargement, LV dysfunction,
or pulmonary hypertension can be followed on a yearly
basis with instructions to alert the physician if symptoms
develop in the interim. Yearly echocardiography is not
necessary unless there is clinical evidence that regurgitation
has worsened. In patients with moderate MR, clinical
evaluations should be performed annually, and echocardiograms
are not necessary more than once per year.
Asymptomatic
patients with severe MR should be followed with history,
physical examination, and echocardiography every 6 to
12 months to assess symptoms or transition to asymptomatic
LV dysfunction. Serial chest x-rays and ECGs have less
value but are helpful in selected patients. Exercise
stress testing may be used to add objective evidence
regarding symptoms and changes in exercise tolerance.
Exercise testing is especially important if a good history
of the patient's exercise capacity cannot be obtained.
Assessment
of LV function in the patient with MR is made difficult
because the loading conditions present in MR facilitate
ejection and increase ejection fraction, the standard
guide to LV function. Nonetheless, several studies indicated
that the preoperative ejection fraction is an important
predictor of postoperative survival in patients with
chronic MR (406,408,411,412).
Ejection fraction in a patient with MR with normal LV
function is usually >0.60. Consistent with
this concept, postoperative survival is reduced in patients
with a preoperative ejection fraction <0.60 compared
with patients with higher ejection fractions (412).
Alternatively
or in concert, echocardiographic LV end-systolic dimension
(or volume) can be used in the timing of mitral valve
surgery. End-systolic dimension, which may be less load-dependent
than ejection fraction (413),
should be <45 mm preoperatively to ensure normal
postoperative LV function (405,413).
If patients become symptomatic, they should undergo
mitral valve surgery even if LV function is normal.
Recommendations
for Transthoracic Echocardiography in Mitral Regurgitation
Recommendations
for Transesophageal Echocardiography in Mitral Regurgitation
d.
Guidelines for Physical Activity and Exercise. Recommendations
regarding participation in competitive athletics were
published by the Task Force on Acquired Valvular Heart
Disease of the 26th Bethesda Conference (105).
Asymptomatic patients with MR in sinus rhythm who have
normal LV volumes may exercise without restriction (105).
For mildly symptomatic patients, those with LV dilatation
or atrial fibrillation, exercise should be limited to
activities with low to moderate dynamic and low to moderate
static cardiovascular demands (105).
e.
Medical Therapy. In the asymptomatic patient with
chronic MR, there is no generally accepted medical therapy.
Although intuitively the use of vasodilators may appear
to be logical for the same reasons that they are effective
in acute MR and chronic AR, there are no large long-term
studies to indicate that they are beneficial. Furthermore,
because MR with normal ejection fraction is a disease
in which afterload is not increased (155,405,414,415),
drugs that reduce afterload might produce a physiological
state of chronic low afterload with which there is very
little experience. However, in patients with MR resulting
from increased preload (ie, CAD or dilated cardiomyopathy),
there is reason to believe that preload reduction may
be beneficial (223),
and in a small series of patients with chronic MR in
NYHA functional Class I to III, 1 year of quinapril
therapy reduced LV volumes and mass and improved functional
class (416). These
data do not appear to be applicable to asymptomatic
patients. Thus, in the absence of systemic hypertension,
there is no known indication for the use of vasodilating
drugs in asymptomatic patients with preserved LV function.
In
patients with MR who develop symptoms but have preserved
LV function, surgery is the most appropriate therapy.
If atrial fibrillation develops, heart rate should be
controlled with digitalis, rate-lowering calcium channel
blockers, ß-blockers, or, rarely, amiodarone. Although
the risk of embolism with the combination of MR and
atrial fibrillation was formerly considered similar
to that of MS and atrial fibrillation, more recent studies
suggest that embolic risk may be less in MR (417,418).
Although this suggests that the intensity of anticoagulation
in such patients can probably be reduced, firm guidelines
are not yet established, and it is recommended that
the INR be maintained at 2 to 3 in this population.
f.
Indications for Cardiac Catheterization. Cardiac
catheterization, with or without exercise, is necessary
when there is a discrepancy between clinical and noninvasive
findings. Catheterization is also performed when surgery
is contemplated in cases where there is still some doubt
about the severity of MR after noninvasive testing or
when there is a need to assess extent and severity of
CAD preoperatively. In patients with MR who have risk
factors for CAD (advanced age, hypercholesterolemia,
hypertension, etc) or when there is a suspicion that
MR is ischemic in etiology (either because of known
myocardial infarction or suspected ischemia), coronary
angiography should be performed before surgery. In cases
in which no reasonable suspicion of CAD exists, coronary
angiography can be avoided.
Obviously,
patients should not undergo valve surgery unless the
valve lesion is severe. In cases of chronic MR, noninvasive
imaging should demonstrate anatomic disruption of the
valve or its apparatus, and color flow Doppler should
indicate severe MR. Both the left atrium and left ventricle
should be enlarged. Discordance between chamber enlargement
and the presumed severity of regurgitation (ie, supposedly
chronic severe MR without cardiac enlargement) raises
questions about the accuracy of the diagnosis. Such
questions should be resolved during ventriculography
at cardiac catheterization. Although the standard semiquantitative
approach to determining the severity of MR from ventriculography
has its own limitations (419),
ventriculography does provide an additional method to
assess LV dilatation and function and gauge the severity
of MR. Exercise hemodynamics and quantitative angiography
may provide additional information helpful in decision
making.
During
the catheterization procedure, a right-heart catheterization
should be performed if the severity of MR is uncertain
to obtain right-sided pressures to quantify the increase
in left atrial pressure (pulmonary artery wedge pressure)
and pulmonary artery pressure. Although much has been
written about the presence of a large V wave in the
pulmonary artery wedge pressure tracing, the presence
or absence of a large V wave has little diagnostic impact
when combined with data from the rest of the catheterization
(420).
Recommendations
for Coronary Angiography in Mitral Regurgitation
Recommendations
for Left Ventriculography and Hemodynamic Measurements
in Mitral Regurgitation
4.
Indications for Surgery. a. Types of Surgery.
Three different mitral valve operations are currently
used for correction of MR: mitral valve repair, MVR
with preservation of part or all of the mitral apparatus,
and MVR with removal of the mitral apparatus. Each procedure
has its advantages and disadvantages, and therefore
the indications for each procedure are somewhat different.
In most cases, mitral valve repair is the operation
of choice when the valve is suitable for repair and
appropriate surgical skill and expertise are available.
This procedure preserves the patient's native valve
without a prosthesis and therefore avoids the risk of
chronic anticoagulation (except in patients in atrial
fibrillation) or prosthetic valve failure late after
surgery. Additionally, preservation of the mitral apparatus
leads to better postoperative LV function and survival
than in cases in which the apparatus is removed (421-427).
Improved postoperative function occurs with repair because
the mitral apparatus is an integral part of the left
ventricle that is essential for maintenance of normal
shape, volume, and function of the left ventricle (428).
However, mitral valve repair is technically more demanding
than MVR, may require longer extracorporeal circulation
time, and may occasionally fail. Valve calcification,
rheumatic involvement, and anterior leaflet involvement
decrease the likelihood of repair, whereas uncalcified
posterior leaflet disease is almost always reparable.
The
advantage of MVR with preservation of the chordal apparatus
is that this operation ensures postoperative mitral
valve competence, preserves LV function, and enhances
postoperative survival compared with MVR in which the
apparatus is disrupted (423,429-432).
The disadvantage is the use of a prosthetic valve, with
the risks of deterioration inherent in tissue valves
or the need for anticoagulation inherent in mechanical
valves.
MVR
in which the mitral valve apparatus is destroyed should
almost never be performed. It should only be performed
in those circumstances in which the native valve and
apparatus are so distorted by the preoperative pathology
(rheumatic disease, for example) that the mitral apparatus
cannot be spared.
The
advantages of mitral valve repair make it applicable
in the 2 extremes of the spectrum of MR. Valve repair
might be possible in patients with far-advanced symptomatic
MR and depressed LV function because it preserves LV
function at the preoperative level (425);
MVR with disruption of the apparatus in such patients
could lead to worsened or even fatal LV dysfunction
after surgery. At the other extreme, in the relatively
asymptomatic patient with well-preserved LV function,
repair of a severely regurgitant valve might be contemplated.
However, failed mitral valve repair would result in
a prosthetic valve; this would represent a clear complication,
as it would impose the risks of a prosthesis on a patient
who did not previously require it. Hence, most cardiologists
would not recommend "prophylactic" surgery
in an asymptomatic patient with MR and normal LV function.
b.
Timing of Surgery for Symptomatic Patients With Normal
Left Ventricular Function. Patients with symptoms
of congestive heart failure despite normal LV function
on echocardiography (ejection fraction >0.60 and
end-systolic dimension <45 mm) require surgery. Surgery
should be performed in patients with mild symptoms and
severe MR (Figure 6), especially
if it appears that mitral valve repair rather than replacement
can be performed. The feasibility of repair is dependent
on several factors, including valve anatomy and surgical
expertise. Successful surgical repair improves symptoms,
preserves LV function, and avoids the problems of a
prosthetic valve. When repair is not feasible, MVR with
chordal preservation should relieve symptoms and maintain
LV function.
c.
Timing of Surgery for Asymptomatic or Symptomatic Patients
With Left Ventricular Dysfunction. Preoperative
variables that are predictive of postoperative survival,
symptomatic improvement, and postoperative LV function
are summarized in Table 20.
The timing of surgery for asymptomatic patients was
controversial, but most would now agree that mitral
valve surgery is indicated with the appearance of echocardiographic
indicators of LV dysfunction. These include LV ejection
fraction <0.60 and/or LV end-systolic dimension
>45 mm (Figure 6).
Surgery performed at this time will likely prevent further
deterioration in LV function and improve longevity.
This is true whether repair or replacement is performed
(412), although repair
is clearly preferred. Although some recommend a slightly
lower threshold ejection fraction (0.55), it must be
emphasized that, unlike timing of AVR for AR, LV ejection
fraction should not be allowed to fall into the lower
limit of the normal range in patients with chronic MR
(412,433-435).
The data regarding postoperative survival are much stronger
with LV ejection fraction than end-systolic dimension
(408,411,412),
whereas both ejection fraction and end-systolic dimension
strongly influence postoperative LV function and heart
failure (405,406,408,413,436).
Outcome is also influenced by LV wall thickness-to-radius
ratio (436,437).
Mitral
valve surgery should also be recommended for symptomatic
patients with evidence of LV systolic dysfunction (ejection
fraction <0.60, end-systolic dimension >45
mm).
Determining
the surgical candidacy of the symptomatic patient with
MR and far-advanced LV dysfunction is a common clinical
dilemma. The question that often arises is whether the
patient with MR has such advanced LV dysfunction that
he or she is no longer a candidate for surgery. Often
such cases present difficulty in distinguishing primary
cardiomyopathy with secondary MR from primary MR with
secondary myocardial dysfunction. In the latter case,
if mitral valve repair appears likely, surgery should
still be contemplated, provided ejection fraction is
>0.30 (Figure 6).
Even though such a patient is likely to have persistent
LV dysfunction, surgery is likely to improve symptoms
and prevent further deterioration of LV function (241).
d.
Asymptomatic Patients With Normal Left Ventricular Function.
As noted previously, repair of a severely regurgitant
valve may be contemplated in an asymptomatic patient
with normal LV function in order to preserve LV size
and function and prevent the sequelae of chronic MR.
Although there are no data with which to recommend this
approach to all patients, the committee recognizes that
some experienced centers are moving in this direction
for patients for whom the likelihood of successful repair
is high (see below). This approach is often recommended
in hemodynamically stable patients with newly acquired
severe MR, such as might occur with ruptured chordae.
Surgery is also recommended in an asymptomatic patient
with chronic MR with recent onset of episodic or chronic
atrial fibrillation in whom there is a high likelihood
of successful valve repair (see below).
e.
Atrial Fibrillation. Atrial fibrillation is a common,
potentially morbid arrhythmia associated with MR. Preoperative
atrial fibrillation is an independent predictor of reduced
long-term survival after mitral valve surgery for chronic
MR (412). The persistence
of atrial fibrillation after mitral valve surgery can
lead to thromboembolism and partially nullifies an advantage
of mitral repair by requiring anticoagulation. Predictors
of the persistence of atrial fibrillation after successful
valve surgery are the presence of atrial fibrillation
for >1 year and left atrial size >50 mm (438).
In one study, an even shorter duration of preoperative
atrial fibrillation (3 months) was a predictor of persistent
atrial fibrillation after mitral valve repair (439);
persistent atrial fibrillation after surgery occurred
in 80% of patients with preoperative atrial fibrillation
>3 months but in no patient with preoperative
atrial fibrillation <3 months. Although patients
who develop atrial fibrillation also usually manifest
other symptomatic or functional changes that would warrant
mitral valve repair or MVR, many clinicians would consider
the onset of episodic or chronic atrial fibrillation
to be an indication in and of itself for surgery (Figure
6) (432,439).
f.
Feasibility of Repair Versus Replacement. As noted
above, in many cases the type of operation, repair versus
MVR, is important in timing surgery. In fact, although
the type of surgery to be performed is never actually
established until the operation, many situations lend
themselves to preoperative prediction of the operation
that can be performed. This prediction is based on the
skill and experience of the surgeon in performing repair
and on the location and type of mitral valve disease
that caused MR. Nonrheumatic posterior leaflet prolapse
due to degenerative mitral valve disease or a ruptured
chordae tendineae can usually be repaired (440,441).
Involvement of the anterior leaflet diminishes the likelihood
of repair, and consequently the skill and experience
of the surgeon are probably the most important determinants
of the eventual operation that will be performed. In
general, rheumatic and ischemic involvement of the mitral
valve and calcification of the mitral valve leaflets
or annulus diminish the likelihood of repair even in
experienced hands.
Recommendations
for Mitral Valve Surgery in Nonischemic Severe Mitral
Regurgitation
5.
Ischemic Mitral Regurgitation. The outlook for the
patient with ischemic MR is substantially worse than
that for regurgitation from other causes (402,442).
A worse prognosis accrues from the fact that ischemic
MR is usually caused by LV dysfunction resulting from
myocardial infarction. Furthermore, the mitral valve
itself is usually anatomically normal and MR is secondary
to papillary muscle dysfunction and/or displacement
that make repair of the valve more difficult. On the
other hand, coronary artery bypass graft surgery may
improve LV function and reduce ischemic MR. In many
patients with transient severe MR due to ischemia, myocardial
revascularization can eliminate episodes of severe MR.
In
severe MR secondary to acute myocardial infarction,
hypotension and pulmonary edema often occur. Treatment
is aimed at hemodynamic stabilization, usually with
insertion of an intra-aortic balloon pump. Occasionally,
revascularization of the coronary artery supplying an
ischemic papillary muscle can lead to improvement in
mitral valve competence. However, such improvement is
rare, and correction of acute severe ischemic MR usually
requires valve surgery. Unlike nonischemic MR, in which
mitral repair is clearly the operation of choice, the
best operation for ischemic MR is controversial (443,444).
In one recent report, MVR had a better outcome than
repair, especially when annular dilatation rather than
chordal or papillary muscle rupture was the cause of
MR (444).
6.
Evaluation of Patients After Mitral Valve Replacement
or Repair. After mitral valve surgery, follow-up
is necessary to detect late surgical failure and assess
LV function, as discussed in detail in section
VII.C.3. of these guidelines. For patients in whom
a bioprosthesis has been inserted, the specter of eventual
deterioration is always present and must be anticipated.
If a mechanical valve has been inserted, anticoagulation
is required, and chronic surveillance of prothrombin
time and INR is necessary. After valve repair, follow-up
to assess the effectiveness of the repair is indicated
early, especially because most repair failures are detected
soon after surgery.
7.
Special Considerations in the Elderly. Elderly patients
with MR fare more poorly with valve surgery than do
their counterparts with AS. In general, operative mortality
increases and survival is reduced in patients >75,
especially if MVR must be performed or if the patient
has concomitant CAD (427).
In such patients, the goal of therapy is to improve
the quality of life rather than prolong it. Thus, surgery
may be performed in asymptomatic younger patients to
preserve LV function, but it is hard to argue this position
in patients older than 75. For such patients, symptoms
are an important guide in deciding whether or not surgery
is necessary. Under most circumstances, asymptomatic
patients or patients with mild symptoms should be treated
medically.
F.
Multiple Valve Disease
1.
Introduction. Remarkably few data exist to objectively
guide the management of mixed valve disease. The large
number of combined hemodynamic disturbances (and their
varied severity) yield a large number of potential combinations
to consider, and few data exist for any specific category.
Hence, each case must be considered individually and
management based on understanding the potential derangements
in hemodynamics and LV function and the probable benefit
of medical versus surgical therapy. The committee has
developed no specific recommendations in this section.
2.
Mixed Single-Valve Disease. a. Pathophysiology.
In mixed mitral or aortic valve disease, one lesion
usually predominates over the other, and the pathophysiology
resembles that of the pure dominant lesion. Thus, for
the patient with mixed AS and AR where stenosis predominates,
the pathophysiology and management resemble that of
pure AS. The left ventricle develops concentric hypertrophy
rather than dilatation. The timing of AVR is based on
symptomatic status. However, if the attendant regurgitation
is more than mild, it complicates the pathophysiology
by placing the concentrically hypertrophied and noncompliant
left ventricle on a steeper portion of its diastolic
pressure-volume curve, in turn causing pulmonary congestion.
The effect is that neither lesion by itself might be
considered severe enough to warrant surgery, but both
together produce substantial hemodynamic compromise
requiring intervention.
In
patients with severe AR and mild AS, the high total
stroke volume due to extensive regurgitation may produce
a substantial transvalvular gradient. Because the transvalvular
gradient varies with the square of the transvalvular
flow (106), a high
gradient in predominant regurgitation may be predicated
primarily on excess transvalvular flow rather than on
a severely compromised orifice area.
In
mixed mitral disease, predominant MS produces a left
ventricle of normal volume, whereas predominant MR chamber
dilatation occurs. A substantial transvalvular gradient
may exist in regurgitation-predominant disease because
of high transvalvular flow, but (as in mixed aortic
valve disease with predominant regurgitation) the gradient
does not represent severe orifice stenosis.
b.
Diagnosis. (1) 2-D
AND
DOPPLER
ECHOCARDIOGRAPHIC
STUDIES.
As noted above, chamber geometry is important in assessing
the dominant lesion (stenotic versus regurgitant), which
in turn is important in management. For instance, a
small left ventricle is inconsistent with chronic severe
regurgitation. Doppler interrogation of the aortic and
mitral valves with mixed disease should provide a reliable
estimate of the transvalvular mean gradient. However,
there may be a significant discrepancy between the Doppler-derived
maximum instantaneous gradient and catheter peak gradient
with mixed aortic valve disease. Exercise hemodynamics
derived by Doppler echocardiography have been helpful
in management of mixed valve disease. Mitral valve area
can be measured accurately by the half-time method in
mixed MS/MR. Aortic valve area would be measured inaccurately
at the time of cardiac catheterization in mixed AS/AR
if cardiac output is measured by either thermodilution
or the Fick method. The valve area can be measured more
accurately by the continuity equation from Doppler echocardiography
in mixed AS/AR. However, the continuity equation calculation
of valve area may not be completely independent of flow
(445). Although these
valve area measurements by Doppler echocardiography
are more accurate than those obtained at cardiac catheterization,
in general, the confusing nature of mixed valve disease
makes cardiac catheterization necessary to obtain additional
hemodynamic information in most patients.
(2)
CARDIAC CATHETERIZATION. Catheterization is often
necessary to fully assess hemodynamics. The diagnosis
of "moderate" mixed disease is frequently
made on the basis of noninvasive tests alone. This term
suggests that the valve disease is not severe enough
to mandate surgery. However, as noted previously, the
nondominant lesion may exacerbate the pathophysiology
of the dominant lesion and produce symptoms. In this
context, a complete hemodynamic evaluation including
exercise hemodynamics may be important. For example,
resting hemodynamics in mixed mitral disease might show
a transmitral gradient of 5 mm Hg, a valve area of 1.5
cm2, and 2+ MR with a resting pulmonary artery
wedge pressure of 15 mm. However, with exercise, the
wedge pressure may increase dramatically, identifying
a hemodynamic cause for the patient's symptoms and suggesting
that mechanical correction will be of benefit. Many
cases of mixed valve disease require hemodynamic exercise
testing to delineate proper assessment (446).
Hemodynamic
estimation of valve area requires determination of total
valve flow and transvalvular gradient. The presence
of valvular regurgitation in a primarily stenotic valve
causes forward cardiac output to underestimate total
valve flow, which is the sum of forward plus regurgitant
flow. Thus, if standard measures of forward cardiac
output (thermodilution, Fick, etc) are used to calculate
valve area, the area will be underestimated. One approach
to this problem is to use total stroke volume (angiographic
end-diastolic volume-end systolic volume) in place of
forward stroke volume (Fick or thermodilution cardiac
output/heart rate) in the Gorlin formula. Although this
approach is logically valid, it has not been clinically
tested or vetted against a gold standard. Furthermore,
angiographic stroke volume is dependent on accurate
calculation of cardiac volumes, which may be difficult
in the very large and/or spherical left ventricles encountered
in valvular regurgitation (447).
In general, the utility of this approach is limited.
Doppler pressure half-time may be very useful in this
situation.
c.
Management. Unlike the management of a severe pure
valve lesion, solid guidelines for mixed disease are
difficult to establish. The most logical approach is
to surgically correct disease that produces more than
mild symptoms or, in the case of AS-dominant aortic
valve disease, to operate in the presence of even mild
symptoms. In regurgitant dominant lesions, surgery can
be delayed until symptoms develop or asymptomatic LV
dysfunction (as gauged by markers used in pure regurgitant
disease) becomes apparent. The use of vasodilators to
forestall surgery in patients with asymptomatic mixed
disease is untested. Anticoagulants should be used in
mixed mitral disease if atrial fibrillation is present.
In mixed mitral disease with moderate or severe (3+
to 4+) regurgitation, percutaneous mitral balloon valvotomy
is contraindicated because regurgitation may worsen.
3.
Combined Mitral Stenosis and Aortic Regurgitation.
a. Pathophysiology. When both AR and MS coexist,
severe MS usually coexists with mild AR with pathophysiology
similar to that of isolated MS. However, the coexistent
AR is occasionally severe. The combination of coexistent
severe MS and severe AR may present confusing pathophysiology
and often leads to misdiagnosis. MS restricts LV filling,
blunting the impact of AR on LV volume (248).
Thus, even severe AR may fail to cause a hyperdynamic
circulation, so that typical signs of AR are absent
during physical examination. Likewise, echocardiographic
LV cavitary dimensions may be only mildly enlarged.
Doppler half-time measurements of mitral valve area
may be inaccurate in the presence of significant AR.
The picture presented by this complex combination of
lesions usually requires all diagnostic modalities,
including cardiac catheterization, for resolution.
b.
Management. Mechanical correction of both lesions
is eventually necessary in most patients. Development
of symptoms or pulmonary hypertension is the usual indication
for intervention.
When
mechanical correction is anticipated in predominant
MS, balloon mitral valvotomy followed by AVR obviates
the need for double valve replacement, which has a higher
risk of complications than single valve replacement.
In most cases, it is advisable to perform mitral valvotomy
first and then follow the patient for symptomatic improvement.
If symptoms disappear, correction of AR can be delayed.
4.
Combined Mitral Stenosis and Tricuspid Regurgitation.
a. Pathophysiology. When TR coexists with MS,
some elements of pulmonary hypertension are also usually
present. Thus, the issue arises whether TR will or will
not improve when MS is corrected and pulmonary artery
pressure decreases (448).
Unfortunately, the status of the tricuspid valve after
correction of MS is difficult to predict. In general,
if pulmonary hypertension is severe and the tricuspid
valve anatomy is not grossly distorted, improvement
in TR can be expected after correction of MS (449).
On the other hand, if there is severe rheumatic deformity
of the tricuspid valve, competence is likely to be restored
only by surgery.
b.
Diagnosis. Once TR is suspected by physical examination
to coexist with MS, both can be further evaluated by
Doppler echocardiographic studies. The presence of TR
almost guarantees that an estimation of pulmonary artery
pressure can be made by Doppler interrogation of the
tricuspid valve. An evaluation of the anatomy of both
the mitral and tricuspid valves can be made.
c.
Management. If the mitral valve anatomy is favorable
for percutaneous balloon valvotomy and there is concomitant
pulmonary hypertension, valvotomy should be performed
regardless of symptom status. After successful mitral
valvotomy, pulmonary hypertension and TR almost always
diminish (449).
If
mitral valve surgery is performed, concomitant tricuspid
annuloplasty should be considered, especially if there
are preoperative signs or symptoms of right-heart failure,
rather than risking severe persistent TR, which may
necessitate a second operation (450).
However, TR that seems severe on echocardiography but
does not cause elevation of right atrial or right ventricular
diastolic pressure will generally improve greatly after
MVR. If intraoperative assessment suggests that TR is
functional without significant dilatation of the tricuspid
annulus, it may not be necessary to perform an annuloplasty.
5.
Combined Mitral and Aortic Regurgitation. a.
Pathophysiology. As noted in the previous discussions
of isolated MR and AR, these are 2 very different diseases
with different pathophysiological effects and different
guidelines for the timing of surgery. Thus, in the patient
with double valve regurgitation, proper management becomes
problematic. The most straightforward approach is the
same as for mixed single valve disease, ie, to determine
which lesion is dominant and to treat primarily according
to that lesion. Although both lesions produce LV dilatation,
AR will produce modest systemic systolic hypertension
and a mild increase in LV wall thickness.
b.
Diagnosis. Doppler echocardiographic interrogation
shows bivalve regurgitation and an enlarged left ventricle.
2-D echocardiography is usually performed to assess
severity of AR and MR, LV size and function, left atrial
size, pulmonary artery pressure, and feasibility of
mitral valve repair.
6.
Combined Mitral and Aortic Stenosis. a. Pathophysiology.
Combined stenotic disease is almost always secondary
to rheumatic heart disease. Obstruction of flow at the
mitral valve diminishes aortic valve flow as well. Thus,
the problem of evaluating aortic valve severity in a
low flow-low gradient situation often exists.
b.
Diagnosis and Therapy. In patients with significant
AS and MS, the physical findings of AS generally dominate,
and those of MS may be overlooked, whereas the symptoms
are usually those of MS. Noninvasive evaluation should
be performed with 2-D and Doppler echocardiographic
studies to evaluate severity of AS and MS, paying special
attention to suitability for mitral balloon valvotomy
in symptomatic patients, and to assess ventricular size
and function. If the degree of AS appears to be mild
and the mitral valve is acceptable for balloon valvotomy,
this should be attempted first. If mitral balloon valvotomy
is successful, the aortic valve should then be reevaluated.
7.
Combined Aortic Stenosis and Mitral Regurgitation.
a. Pathophysiology. Combined AS and MR often
develop secondary to rheumatic heart disease. However,
congenital AS and MVP may occur in combination in younger
patients, as may degenerative AS and MR in the elderly.
If severe, AS will worsen the degree of MR. In addition,
MR may cause difficulty in assessing severity of AS
because of reduced forward flow. MR will also enhance
LV ejection performance, thereby masking the early development
of LV systolic dysfunction caused by AS. Development
of atrial fibrillation and loss of atrial systole may
further reduce forward output because of impaired filling
of the hypertrophied left ventricle.
b.
Diagnosis and Therapy. Noninvasive evaluation should
be performed with 2-D and Doppler echocardiography to
evaluate the severity of both AS and MR. Attention should
be paid to LV size, wall thickness and function, left
atrial size, right-heart function, and pulmonary artery
pressure. Particular attention should be paid to mitral
valve morphology in patients with these combined lesions.
Patients with severe AS and severe MR (with abnormal
mitral valve morphology) with symptoms, LV dysfunction,
or pulmonary hypertension should undergo combined AVR
and MVR or mitral valve repair. However, in patients
with severe AS and lesser degrees of MR, the severity
of MR may improve greatly after isolated AVR, particularly
when there is normal mitral valve morphology. Intraoperative
transesophageal echocardiography and, if necessary,
visual inspection of the mitral valve should be performed
at the time of AVR to determine whether additional mitral
valve surgery is warranted in these patients.
In
patients with mild to moderate AS and severe MR in whom
surgery on the mitral valve is indicated because of
symptoms, LV dysfunction, or pulmonary hypertension,
preoperative assessment of the severity of AS may be
difficult because of reduced forward stroke volume.
If the mean aortic valve gradient is >30 mm
Hg, AVR should be performed. In patients with less severe
aortic valve gradients, inspection of the aortic valve
and its degree of opening on 2-D or transesophageal
echocardiography as well as visual inspection by the
surgeon may be important in determining the need for
concomitant AVR.
G.
Tricuspid Valve Disease
1.
Pathophysiology. Tricuspid valve dysfunction can
occur with normal or abnormal valves. When normal tricuspid
valves develop dysfunction, the resulting hemodynamic
abnormality is almost always pure regurgitation. This
occurs with elevation of right ventricular systolic
and/or diastolic pressure, right ventricular cavity
enlargement, and tricuspid annular dilatation (451,452);
right ventricular systolic hypertension occurs in MS,
pulmonic valve stenosis, and the various causes of pulmonary
hypertension. Right ventricular diastolic hypertension
occurs in dilated cardiomyopathy and right ventricular
failure of any cause (451,452).
Abnormalities
of the tricuspid valve leading to TR can occur with
rheumatic valvulitis, infective endocarditis, carcinoid,
rheumatoid arthritis, radiation therapy, trauma, Marfan
syndrome, tricuspid valve prolapse, papillary muscle
dysfunction, or congenital disorders such as Ebstein's
anomaly (451) or a
cleft tricuspid valve as part of atrioventricular canal
malformations. Anorectic drugs may also cause TR, as
indicated in section III.H.
of these guidelines.
Tricuspid
stenosis is most commonly rheumatic in origin. On very
rare occasions, infective endocarditis (with large bulky
vegetations), congenital abnormalities, carcinoid, Fabry's
disease, Whipple's disease, or previous methysergide
therapy may be implicated (453).
Right atrial mass lesions represent a nonvalvular cause
of obstruction to the tricuspid orifice and may also
over time destroy the leaflets and cause regurgitation.
Rheumatic tricuspid involvement usually results in both
stenosis and regurgitation.
2.
Diagnosis. The clinical features of tricuspid stenosis
include a giant a wave and diminished rate of
y descent in the jugular venous pulse, a tricuspid
opening snap, and a murmur that is presystolic as well
as middiastolic and that increases on inspiration (454).
Because acute rheumatic fever is the most common cause
of tricuspid stenosis, there is usually associated mitral
and/or aortic disease, and the clinical findings include
those associated with the other 2 valves, especially
the mitral valve.
The
clinical features of TR include abnormal systolic c
and v waves in the jugular venous pulse, a lower
left parasternal systolic murmur (holosystolic or less
than holosystolic, depending on the severity of hemodynamic
derangement) that may increase on inspiration (Carvallo's
sign), a middiastolic murmur in severe regurgitation,
and systolic hepatic pulsation. In rare instances, severe
TR may produce systolic propulsion of the eyeballs (455),
pulsatile varicose veins (456),
or a venous systolic thrill and murmur in the neck (457).
Other associated clinical features are related to the
cause of TR.
Echocardiography
is valuable in assessing tricuspid valve structure and
motion, measuring annular size, and identifying other
cardiac abnormalities that might influence tricuspid
valve function. Doppler echocardiography permits estimation
of the severity of TR (458),
right ventricular systolic pressure, and the tricuspid
valve diastolic gradient. Although echocardiography
is a valuable diagnostic tool, it should be pointed
out that clinically insignificant TR is detected by
color Doppler imaging in many normal persons (18-22).
This is not an indication for either routine follow-up
or prophylaxis against bacterial endocarditis. Thus,
clinical correlation and judgment must accompany the
echocardiographic results. Systolic pulmonary artery
pressures >55 mm Hg are likely to cause TR
with anatomically normal tricuspid valves, whereas TR
occurring with systolic pulmonary artery pressures <40
mm Hg is likely to reflect a structural abnormality
of the valve apparatus. Systolic pulmonary artery pressure
estimation combined with information about annular circumference
will further improve the accuracy of clinical assessment
(452).
3.
Management. The patient's clinical status and the
etiology of the tricuspid valve abnormality usually
determine the appropriate therapeutic strategy. Medical
and/or surgical management may be required. For example,
in the patient with severe MS and pulmonary hypertension
with resulting right ventricular dilatation and TR,
relief of MS and the resulting decrease in pulmonary
artery pressure may result in substantial diminution
of the degree of TR. The timing of surgical intervention
for TR remains controversial as do the surgical techniques.
To some extent, this controversy has diminished since
the advent of 2-D and Doppler echocardiography for preoperative
diagnosis and assessment. Intraoperative transesophageal
Doppler echocardiography allows refinement of annuloplasty
techniques to optimize outcome (459-461).
At present, surgery on the tricuspid valve for TR occurs
commonly at the time of mitral valve surgery. However,
there are no long-term data regarding the value of such
an approach.
Tricuspid
valve balloon valvotomy has been advocated for tricuspid
stenosis of various etiologies (462-464).
However, severe TR is a common consequence of this procedure,
and results are poor when severe TR develops.
Patients
with severe TR of any cause have a poor long-term outcome
because of RV dysfunction and/or systemic venous congestion
(465). Tricuspid valve
and chordal reconstruction can be attempted in some
cases of TR resulting from endocarditis and trauma (466-468).
In recent years, annuloplasty has become an established
surgical approach to significant TR (469-473).
When
the valve leaflets themselves are diseased, abnormal,
or destroyed, valve replacement with a low-profile mechanical
valve or bioprosthesis is often necessary (474).
A biological prosthesis is preferred because of the
high rate of thromboembolic complications with mechanical
prostheses in the tricuspid position. In patients with
associated conduction defects, insertion of a permanent
epicardial pacing electrode at the time of valve replacement
can avoid the later need to pass a transvenous lead
across the prosthetic valve.
Recommendations
for Surgery for Tricuspid Regurgitation
H.
Valvular Heart Disease Associated With Anorectic Drugs
In
addition to the common causes of the valvular lesions
described in the preceding sections, there are a number
of uncommon causes of valvular heart disease related
to systemic diseases, drugs, and toxins. It is beyond
the scope of these guidelines to discuss the specific
pathology and natural history of valve disease stemming
from each of these many etiologies. In general, the
management strategies for patients with these disorders
are directed toward management of the underlying disease
process and diagnosis and management of the associated
valvular disease according to the guidelines developed
for each of the valvular lesions in sections
III.A. through III.G.
However,
it is appropriate to address the issue of valvular heart
disease associated with anorectic agents because of
the current widespread concern of patients and healthcare
professionals that has developed since this association
was reported in the summer of 1997. Investigators at
the Mayo Clinic and the MeritCare Medical Center in
Fargo, ND, reported 24 patients receiving the combination
of fenfluramine and phentermine in whom unusual valve
morphology and associated regurgitation were identified
in both left-sided and right-sided heart valves (475);
all had AR and/or MR, and 12 had TR. Eight patients
had associated pulmonary hypertension. Five patients
underwent valve replacement surgery, and the histopathological
findings of the excised valves included plaquelike encasement
of the leaflets and chordal structures with intact valve
architecture. The echocardiographic and histopathological
findings were similar to those described in patients
with carcinoid or ergotamine-induced valvular heart
disease (476-480).
All 24 patients were symptomatic and had heart murmurs;
thus, the frequency of valvular pathology in asymptomatic
patients receiving the combination of fenfluramine-phentermine
could not be determined. When this initial series was
published, it was accompanied by a letter to the editor
from the Food and Drug Administration (481)
reporting additional cases of valvular heart disease
in 28 patients taking the fenfluramine-phentermine combination,
as well as a few patients taking a combination of dexfenfluramine
and phentermine, fenfluramine alone, or dexfenfluramine
alone. A left-sided heart valve was involved in all
cases. A total of 85 single cases were reported to the
FDA by August 1997. In addition, the FDA also reported
5 echocardiographic prevalence surveys (482)
in which 86 of 271 patients (32%) receiving combination
fenfluramine-phentermine for 6 to 24 months had evidence
of significant AR and/or MR, as did 6 of 20 patients
(30%) receiving dexfenfluramine with or without phentermine.
The prevalence of valvular regurgitation was consistent
among the 5 reporting centers (range, 29% to 36%).
In
light of this information, the drugs fenfluramine and
dexfenfluramine were withdrawn from the market in September
1997. However, a lower prevalence of valvular abnormalities
was reported in a survey of 21 centers that performed
echocardiography in a total of 746 patients (483);
in this survey, 21 patients (8%) were reported to have
valvular regurgitation with the same threshold definitions
as in the FDA report.
The
risk of valvular heart disease associated with exposure
to fenfluramine or dexfenfluramine, alone or in combination
with phentermine, has been addressed in 3 recent peer-reviewed
studies, one of which was a case-control study (483a),
one a population-based study (483b),
and one a randomized, double-blind placebo-controlled
clinical trial (483c).
The prevalence of AR and/or MR in patients exposed to
these drugs varied widely among the 3 studies (from
as high as 26% to as low as <1%), related primarily
to differences in patient selection and study design.
The 2 studies which used Doppler echocardiography to
detect valvular regurgitation (483a,
483c) differed considerably
in terms of the prevalence of the valve lesions and
its statistical significance in comparison to control
groups, which may be related to differences in the anorectic
agents and the duration of exposure. It does appear
that the prevalence of significant valvular regurgitation
may be related to the duration of exposure to the anorectic
agents (483b, 483d)
and that patients exposed for only brief periods of
time have less risk of developing valvular regurgitation.
In
addition to the uncertainties regarding the prevalence
of valvular disease in patients receiving combination-
or single-drug therapy, the natural history of the valve
disease during anorectic drug treatment and the natural
history after drug withdrawal are unknown and await
further clinical investigation. Thus, the risk of valvular
heart disease relative to the benefit of weight reduction
in patients with morbid obesity is unknown.
Considering
these unknown variables and the rapidly evolving information
linking fenfluramine and dexfenfluramine (with or without
phentermine) to valvular heart disease, it is not possible
to derive definitive diagnostic and treatment guidelines
for patients who have received these anorectic drugs.
Hence, clinical judgment is important. The US Department
of Health and Human Services (DHHS), through the Centers
for Disease Control and Prevention and the National
Institutes of Health, published interim recommendations
on November 14, 1997 (484,485).
The DHHS recommended that,
- All
persons exposed to fenfluramine or dexfenfluramine
for any period of time, either alone or in combination
with other agents, should undergo a medical history
and cardiovascular examination by their physicians
to determine the presence or absence of cardiopulmonary
signs or symptoms.
- An
echocardiography evaluation should be performed on
all persons who were exposed to fenfluramine or dexfenfluramine
for any period of time, either alone or in combination
with other agents, and who exhibit cardiopulmonary
signs (including a new murmur) or symptoms suggestive
of valvular disease (eg, dyspnea).
- Although
the clinical importance of asymptomatic valvular regurgitation
in exposed patients and the risk for developing bacterial
endocarditis in these patients are unknown, practitioners
should strongly consider performing echocardiography
on all persons--regardless of whether they have cardiopulmonary
signs or symptoms--who have been exposed to fenfluramine
or dexfenfluramine for any period of time, either
alone or in combination with other agents, BEFORE
the patient undergoes any invasive procedure for which
antimicrobial prophylaxis is recommended by the 1997
AHA guidelines. Any echocardiographic findings that
meet the AHA criteria for prophylaxis--regardless
of whether they are attributable to possible fenfluramine
or dexfenfluramine use--should be recognized as indications
for antibiotic prophylaxis. The invasive procedures
include certain medical or dental procedures in which
antibiotic prophylaxis is recommended as defined by
the 1997 AHA guidelines. For emergency procedures
for which cardiac evaluation cannot be performed,
empirical antibiotic prophylaxis should be administered
according to the 1997 AHA guidelines.
- Because
of the prevalence of minimal degrees of regurgitation
in the general population, the current case definition
of drug-associated valvulopathy should include exposed
patients with echocardiographically demonstrated AR
of mild or greater severity and/or MR of moderate
or greater severity, based on published criteria (486,487).
The
Committee on Management of Patients With Valvular Heart
Disease adopted the majority of the DHHS recommendations.
However, the committee recommends that certain DHHS
statements remain open to interpretation by individual
physicians because of the lack of conclusive scientific
data for appropriate care of patients who have taken
these drugs. Specifically, the committee interprets
the DHHS statement that practitioners should "strongly
consider" performing echocardiography on all persons
before they undergo invasive procedures, such as dental
procedures, regardless of whether signs or symptoms
are present, as the need for the physician to consider
the findings of a patient's cardiovascular physical
examination and any other pertinent data before ordering
the test.
All
patients with a history of use of fenfluramine or dexfenfluramine
should undergo a careful history and thorough cardiovascular
physical examination. The physical examination should
include auscultation with the patient in the upright
position at end-expiration to detect AR and in the left
lateral decubitus position to detect MR. 2-D and Doppler
echocardiography should be performed in patients with
symptoms, cardiac murmurs, or other signs of cardiac
involvement (eg, widened pulse pressure or regurgitant
cv waves in the jugular venous pulse). Patients whose
body size prevents adequate cardiac auscultation should
also undergo 2-D and Doppler echocardiography. For example,
mild AR may be difficult to detect on auscultation in
an obese patient. Patients with clinical and echocardiographic
evidence of valvular heart disease should then undergo
treatment and/or further testing according to the recommendations
developed for the specific valve lesions addressed in
the earlier sections of these guidelines. Modification
of these recommendations may be necessary as more information
on the natural history of these specific valve lesions
becomes available.
In
light of the current evidence, echocardiographic screening
of all patients with a history of fenfluramine or dexfenfluramine
use, especially asymptomatic patients without murmurs
or associated findings, is not recommended. However,
because of possible progression of subclinical valvular
disease, asymptomatic patients without murmurs should
undergo repeat physical examinations in 6 to 8 months.
Recommendations
for Patients Who Have Used Anorectic Drugs*
©
1998 American College of Cardiology and American Heart
Association, Inc. Published by Elsevier
Science Inc.
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