The New England Journal of Medicine

Clinical Practice
Volume 345:740-746

September 6, 2001

Number 10
Evaluation and Management of Chronic Mitral Regurgitation
Catherine M. Otto, M.D.
This Journal feature begins with a case vignette highlighting a common
clinical problem. Evidence supporting various strategies is then presented,
followed by a review of formal guidelines, when they exist. The article ends
with the author's clinical recommendations.
A 56-year-old man with no history of cardiac disease and no cardiac symptoms
has a holosystolic murmur at the apex that radiates to the axilla.
Echocardiography shows moderate mitral regurgitation with mild left
ventricular dilatation. How should this patient's care be managed?
There are about 500,000 discharge diagnoses of mitral-valve disease annually
in the United States. 1
<http://content.nejm.org/cgi/content/short/345/10/#R1>  However, estimates
of the prevalence of mitral regurgitation are confounded by the presence of
benign flow murmurs in many adults and by the small amount of physiologic
regurgitation detected on echocardiography in 80 percent of adults. Only
about 18,000 patients undergo mitral-valve surgery annually, suggesting that
most patients with a diagnosis of mitral regurgitation never need surgical
intervention. Thus, the challenge for the clinician is first to determine
which patients have pathologic mitral regurgitation and then to provide them
with appropriate care.
The Clinical Problem
Causation
Normal mitral-valve function depends on the complex interactions of all the
components of the valve apparatus ( Figure 1
<http://content.nejm.org/cgi/content/short/345/10/#F1> ). In surgical
series, the most common causes of severe mitral regurgitation are
mitral-valve prolapse (20 to 70 percent of cases), ischemia (13 to 30
percent), rheumatic heart disease (3 to 40 percent), and endocarditis (10 to
12 percent). 2 <http://content.nejm.org/cgi/content/short/345/10/#R2>
Although mitral-valve prolapse is common in surgical series, most patients
with mitral-valve prolapse have only mild disease and never need surgery.
Mitral-valve prolapse and ischemic disease are also common in patients with
milder regurgitation, but the most common causes are ventricular dilatation
and systolic dysfunction. In the elderly, mitral regurgitation may be due to
annular calcification; typically, regurgitation in older persons is mild to
moderate and intervention is rarely necessary. Accurate identification of
the mechanism of mitral regurgitation is essential because the clinical
outcome, the medical therapy prescribed, and the potential need for surgical
intervention depend as much on the cause as on the severity of disease.


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Figure 1. Mitral Valve.
The mitral valve consists of the mitral annulus, anterior and posterior
leaflets, chordae tendineae, and the papillary muscles. Mitral regurgitation
may be due to a disease that primarily affects the valve leaflets, such as
mitral-valve prolapse or rheumatic mitral-valve disease, or may result from
alterations in the function or structure of the left ventricle, such as
those induced by ischemic disease or dilated cardiomyopathy.

Pathophysiological Process
Chronic left ventricular volume overload as a result of mitral regurgitation
leads to compensatory dilatation of the left ventricle. Although this
response initially maintains cardiac output, myocardial decompensation
eventually results in symptoms of heart failure and an increased risk of
sudden death. 3 <http://content.nejm.org/cgi/content/short/345/10/#R3>  In
some patients, left ventricular contractility is irreversibly impaired in
the absence of symptoms. 4
<http://content.nejm.org/cgi/content/short/345/10/#R4>  In addition,
backflow into the left atrium results in enlargement of the left atrium,
atrial fibrillation, and elevated pulmonary pressures.
Diagnosis
Mitral regurgitation may be diagnosed on the basis of the presence of a
systolic murmur in asymptomatic adults or incidentally when echocardiography
is performed for other indications. Some patients with primary disease of
the valve leaflets present with symptoms of heart failure, atrial
fibrillation, or endocarditis. The symptoms may be precipitated by a
superimposed hemodynamic stress, such as that induced by pregnancy, anemia,
or an infection. In patients with secondary regurgitation, valve dysfunction
is most often identified during an evaluation of the underlying disease
process.
On physical examination, the murmur of mitral regurgitation is classically
an apical holosystolic murmur that radiates to the axilla. However, physical
examination is not always reliable in distinguishing mitral regurgitation
from other types of systolic murmurs and does not provide an accurate
measure of the severity of regurgitation. 5
<http://content.nejm.org/cgi/content/short/345/10/#R5>  On
electrocardiography and chest radiography, evidence of enlargement of the
left atrium, left ventricle, or both is seen only late in the course of
disease and is not sensitive or specific for the diagnosis of mitral
regurgitation.
Echocardiography
Echocardiography allows accurate evaluation of the presence or absence,
severity, and cause of mitral regurgitation. Echocardiography is indicated
in patients who have a systolic murmur and any cardiac symptoms, a loud
murmur (>=grade 3/6) alone, or other cardiac findings on physical
examination. In most cases, the cause of mitral regurgitation can be deduced
from the two-dimensional images ( Figure 2
<http://content.nejm.org/cgi/content/short/345/10/#F2> ). Although Doppler
echocardiography provides several methods of quantifying the severity of
regurgitation, none have been shown to predict the clinical outcome. Most
centers grade regurgitation as mild, moderate, or severe using a combination
of color flow, continuous, and pulsed-wave Doppler imaging. 6
<http://content.nejm.org/cgi/content/short/345/10/#R6>


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Figure 2. Echocardiographic Images (Panels A and C) and Color Doppler
(Panels B and D) in a 42-Year-Old Man with Mitral-Valve Prolapse and a
65-Year-Old Man with Idiopathic Dilated Cardiomyopathy.
The man with prolapse (Panels A and B) has severe mitral regurgitation (MR),
a partial flail posterior leaflet (arrow in Panel A), a normal-sized left
ventricle (LV), normal systolic function (ejection fraction, 0.66), moderate
enlargement of the left atrium (LA), and mild pulmonary hypertension. The
man with idiopathic dilated cardiomyopathy (Panels C and D) has enlargement
of all four chambers, with severely reduced left ventricular systolic
function (ejection fraction, 0.22), anatomically normal mitral-valve
leaflets, and moderate mitral regurgitation. RV denotes right ventricle, and
RA right atrium.

The most important aspect of the echocardiographic examination is the
quantitation of left ventricular systolic performance. Although calculation
of the ejection fraction is an imperfect means of assessing contractility,
from a practical point of view, the ejection fraction in conjunction with
the end-systolic dimension provides a clinically useful measure of
ventricular performance. Transesophageal echocardiography allows accurate
assessment of the feasibility of valve repair and should be performed before
surgical intervention. 7
<http://content.nejm.org/cgi/content/short/345/10/#R7>
Outcome
Patients with mitral regurgitation may remain asymptomatic for many years;
the average interval from diagnosis to the onset of symptoms is 16 years. 8
<http://content.nejm.org/cgi/content/short/345/10/#R8>  There are few data
on the rate of hemodynamic progression of disease in patients with
mild-to-moderate regurgitation, since most series are restricted to patients
with severe regurgitation. In addition, the available data are difficult to
interpret, since the criteria for evaluating the severity of regurgitation
vary and are not always clearly defined. Furthermore, even though the
clinical outcome is strongly dependent on the cause of the disease, patients
with diverse mechanisms of regurgitation are often included in the same
study.
In patients with severe symptomatic mitral regurgitation, the clinical
outcome is poor: survival rates are as low as 33 percent at eight years in
the absence of surgical intervention. The average mortality rate is
approximately 5 percent per year; most deaths are related to heart failure,
but there is a substantial incidence of sudden death, suggesting that
ventricular arrhythmias may be an important feature of the disease process.
8 <http://content.nejm.org/cgi/content/short/345/10/#R8> , 9
<http://content.nejm.org/cgi/content/short/345/10/#R9>  Other complications
include atrial fibrillation, cerebral ischemic events, and endocarditis.
In patients with mitral-valve prolapse, the clinical outcome depends on the
extent of leaflet disease and the severity of mitral regurgitation. The
progression of disease may be slow and insidious or may be abrupt, as a
result of a chordal rupture leading to flail leaflet. In one study of
patients with initially asymptomatic severe mitral regurgitation caused by
mitral-valve prolapse, only 28 percent required surgery within five years
because of the onset of symptoms. 10
<http://content.nejm.org/cgi/content/short/345/10/#R10>  In contrast, 90
percent of patients with a flail mitral-valve leaflet died or underwent
surgery within 10 years, whether or not they initially had symptoms. 11
<http://content.nejm.org/cgi/content/short/345/10/#R11>
Mitral regurgitation as a sequela of rheumatic fever is uncommon in the
United States and is typically associated with some degree of mitral
stenosis. 12 <http://content.nejm.org/cgi/content/short/345/10/#R12>
Ischemic mitral regurgitation encompasses several mechanisms, including
papillary-muscle dysfunction, regional ventricular dysfunction, and left
ventricular dilatation. The outcome is related to the severity of symptoms
at presentation and the extent of underlying coronary disease. 13
<http://content.nejm.org/cgi/content/short/345/10/#R13>  In patients with
dilated cardiomyopathy, mitral regurgitation has diverse causes, including
annular dilatation, changes in the shape and size of the left ventricle, and
systolic dysfunction. 14
<http://content.nejm.org/cgi/content/short/345/10/#R14>
Strategies and Evidence
Most patients in whom chronic mitral regurgitation is diagnosed have
mild-to-moderate disease and are unlikely ever to need surgical
intervention. Management is directed toward identifying the cause and
severity of the regurgitation, treating underlying disease processes,
preventing complications, educating the patient, and evaluating risk factors
for coronary disease. In patients with primary mitral-valve disease,
periodic echocardiography allows early detection of impaired left
ventricular systolic function on the basis of the measurement of the
end-systolic dimension and ejection fraction ( Table 1
<http://content.nejm.org/cgi/content/short/345/10/#T1> ). Other
echocardiographic measures that are useful in clinical decision making
include assessment of the size of the left atrium and pulmonary systolic
pressure.


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Table 1. Recommended Frequency of Echocardiography in Patients with Chronic
Mitral Regurgitation and Primary Mitral-Valve Disease.

Medical Therapy
No known medical therapies directly affect the disease process in the valve
leaflets in patients with mitral-valve prolapse or rheumatic valve disease.
There has been sustained interest in the concept of using vasodilator
therapy to decrease the severity of mitral regurgitation and the rate of
left ventricular dilatation. The rationale for vasodilator therapy is that a
reduction in the afterload may increase aortic flow and decrease mitral
backflow. To some extent, this rationale has been validated in small,
short-term studies that demonstrated a decrease in systemic vascular
resistance and regurgitant fraction and an increase in cardiac output with
vasodilator therapy, often with a decrease in ventricular volumes and
end-diastolic pressure. 15
<http://content.nejm.org/cgi/content/short/345/10/#R15> , 16
<http://content.nejm.org/cgi/content/short/345/10/#R16>  However, these
studies show that vasodilators are most effective in improving symptoms in
patients with mitral regurgitation associated with ventricular dilatation
and impaired systolic function. 17
<http://content.nejm.org/cgi/content/short/345/10/#R17>  There are no data
that support the use of vasodilator therapy in patients with asymptomatic
mitral regurgitation and normal ventricular function. 18
<http://content.nejm.org/cgi/content/short/345/10/#R18>  Most important, the
use of medical therapy should not delay consideration of surgical
intervention in patients with symptoms or evidence of left ventricular
systolic dysfunction.
Medical therapy is primarily directed toward the treatment of the
complications of mitral regurgitation and the prevention of endocarditis
with antibiotic prophylaxis. If atrial fibrillation occurs, standard
approaches to rate control, cardioversion, and anticoagulation are
indicated. 18 <http://content.nejm.org/cgi/content/short/345/10/#R18>  In
patients with mitral regurgitation as a result of ischemic disease,
prevention of ischemia with medical therapy, percutaneous transluminal
coronary intervention, or bypass grafting is appropriate. In patients with
mitral regurgitation due to dilated cardiomyopathy, medical therapy for
heart failure, including afterload reduction, often results in improvement
in left ventricular shape, size, and systolic function in association with a
reduction in the severity of regurgitation.
Mitral-Valve Surgery
The optimal surgical intervention for mitral regurgitation is valve repair.
As compared with valve replacement, successful valve repair results in
superior hemodynamics and ventricular function, avoidance of a prosthetic
valve and the need for long-term anticoagulation, and less distortion of
ventricular shape. The feasibility of valve repair is highest in patients
with mitral-valve prolapse, especially in those whose disease is confined to
the posterior leaflet. As surgical techniques improve, an increasing number
of patients are becoming candidates for this procedure. When valve repair is
not technically possible, every effort is made to maintain the integrity of
the mitral chordal apparatus. With chordal preservation, there is little
change in the ejection fraction after surgery, as compared with an average
decline of 10 ejection-fraction units in patients with transected chords.
The operative mortality rate is lower for mitral-valve repair than for valve
replacement (2 to 4 percent vs. 5 to 10 percent). In patients with
mitral-valve prolapse, long-term clinical outcome is excellent, with
survival rates of 80 to 94 percent at 5 to 10 years with valve repair as
compared with 40 to 60 percent with valve replacement. 19
<http://content.nejm.org/cgi/content/short/345/10/#R19> , 20
<http://content.nejm.org/cgi/content/short/345/10/#R20>
In patients with symptoms due to mitral regurgitation, surgical intervention
is indicated, unless they have severe left ventricular dysfunction. In
asymptomatic patients with severe mitral regurgitation, the outcome is
improved if surgery is performed before the onset of irreversible
ventricular dysfunction. No randomized trials have assessed the optimal
timing of intervention for asymptomatic severe mitral regurgitation, and the
ideal measure of ventricular contractility remains elusive. However, a
consensus has been reached that left ventricular end-systolic dimension and
ejection fraction can be used to identify early systolic dysfunction. The
evidence supporting this approach is derived from studies in patients who
were undergoing valve surgery for severe mitral regurgitation that assessed
the value of preoperative variables as predictors of postoperative
ventricular performance. 4
<http://content.nejm.org/cgi/content/short/345/10/#R4> , 21
<http://content.nejm.org/cgi/content/short/345/10/#R21> , 22
<http://content.nejm.org/cgi/content/short/345/10/#R22> , 23
<http://content.nejm.org/cgi/content/short/345/10/#R23>  Indicators of early
systolic dysfunction are an end-systolic dimension of 45 mm or more or an
ejection fraction of 0.60 or less. Systolic dysfunction is most likely when
both values are abnormal and sequential studies show a progressive
deterioration. Other factors that may affect the timing of surgical
intervention include the feasibility of valve repair, the onset of atrial
fibrillation, and the development of progressive pulmonary hypertension
 Figure 3 <http://content.nejm.org/cgi/content/short/345/10/#F3> ). There
are two noteworthy features of these criteria: the degree of ventricular
dilatation seen with isolated volume overload due to mitral regurgitation is
much less than that seen in aortic regurgitation, a condition characterized
by combined pressure and volume overload, and these criteria only apply to
patients with severe mitral regurgitation.


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Figure 3. Management of Chronic Severe Mitral Regurgitation.
Modified from the American College of Cardiology–American Heart Association
guidelines. 18 <http://content.nejm.org/cgi/content/short/345/10/#R18>

Areas of Uncertainty
Assessment of the Severity of Mitral Regurgitation
The current definition of severe mitral regurgitation is based on
angiographic and echocardiographic descriptors of the degree of backflow
across the valve. An alternative physiological definition would be mitral
regurgitation severe enough to result in dilatation of the left ventricle,
left atrium, or both. However, the best definition would be regurgitation
leading to adverse clinical outcomes. Unfortunately, prospective data based
on quantitative measures of severity are not available. Thus, it is not
certain whether some patients with moderate regurgitation have severe
disease that has not yet resulted in ventricular enlargement. The percentage
of patients with mild regurgitation who will have a progressive increase in
the severity of mitral regurgitation is also unknown.
Medical Therapy for Primary Valve Disease
In patients with severe mitral regurgitation due to primary valve disease,
there are no persuasive data that medical therapy decreases the rate of
ventricular dilatation or delays valve surgery. Some clinicians argue that
medical therapy may even be harmful if it increases the severity of
regurgitation in patients with mitral-valve prolapse, prevents normal
adaptive responses of the left ventricle, or delays the recognition of early
symptoms or ventricular dysfunction.
Timing of Surgical Intervention
When severe mitral regurgitation and severely reduced ventricular function
are both present, it can be difficult to determine whether ventricular
dysfunction is the cause or a consequence of chronic regurgitation. In
either case, the surgical outcome is poor when the ejection fraction is less
than 0.30, unless chordal continuity is preserved. In some patients, a trial
of medical therapy for heart failure and an evaluation for other causes of
left ventricular dysfunction may clarify the situation. Because the optimal
approach to these patients is controversial, clinical decision making must
be individualized on the basis of the evaluation of ventricular and valvular
function, the likelihood of valve repair, the presence of other underlying
conditions, and the patient's preferences.
Valve Repair in Patients with Secondary Mitral Regurgitation
Some studies of patients with ischemic mitral regurgitation suggest that
revascularization alone decreases the severity of regurgitation, whereas
other studies suggest that concurrent valve repair or the placement of an
annuloplasty ring is necessary. 24
<http://content.nejm.org/cgi/content/short/345/10/#R24>  Revascularization
might be effective if regurgitation is due to ischemia or if
revascularization improves the shape of the mitral valve. However, if there
is irreversible myocardial damage or if remodeling does not occur, then
mitral regurgitation may persist. In the absence of randomized clinical
trials, the surgical decision is currently individualized on the basis of
the mechanism of regurgitation in each patient.
In patients with dilated cardiomyopathy, mitral regurgitation is due to the
change in the shape of the valvular apparatus, so that the severity of
regurgitation is often decreased by medical therapy that restores the
ventricular size and shape. Some centers advocate mitral-valve surgery in
these patients, but this approach is not widely accepted. 25
<http://content.nejm.org/cgi/content/short/345/10/#R25>
Guidelines
The American College of Cardiology and the American Heart Association have
developed detailed guidelines for the evaluation, follow-up, and optimal
timing of surgical intervention in patients with severe mitral
regurgitation. 18 <http://content.nejm.org/cgi/content/short/345/10/#R18>
Appropriate candidates for mitral-valve surgery include patients with
symptoms, except those with severe ventricular dysfunction, and patients
with no symptoms who have mild or moderate ventricular dysfunction. Surgery
is indicated in asymptomatic patients with preserved ventricular function if
there is a high likelihood of valve repair or if there is evidence of
pulmonary hypertension or recent atrial fibrillation. Guidelines also
address the use of echocardiography, the prevention of rheumatic fever and
endocarditis, and indications for anticoagulation.
Conclusions and Recommendations
In the case of patients with a cardiac murmur, the threshold for
echocardiographic evaluation should be low. When the valve is anatomically
abnormal, periodic clinical and echocardiographic follow-up allows early
identification of symptoms, complications, and systolic dysfunction. In
patients with secondary mitral regurgitation, echocardiography serves as the
first step toward the evaluation and treatment of the underlying disease
process. Patient education is vital, both to ensure compliance with
follow-up and to allow the patient to participate in the decision-making
process.
In the case of the patient described in the vignette, annual
echocardiography and evaluation by a cardiologist are appropriate to monitor
the severity of mitral regurgitation, the size of the left ventricle, and
pulmonary-artery pressure. Surgical intervention in patients with severe
mitral regurgitation is indicated at the onset of symptoms or in the
presence of convincing evidence of left ventricular systolic dysfunction.
Valve repair rather than valve replacement should be performed whenever
possible. We should remain cautious in recommending valve surgery for
asymptomatic patients who are considered to have severe mitral regurgitation
but who have no evidence of consequences of hemodynamic abnormalities.
However, the excellent anatomical and clinical outcomes of valve repair make
surgical intervention appropriate earlier in the course of disease in many
patients with severe mitral regurgitation as a means of preventing chronic
volume overload.

Source Information
From the Division of Cardiology, University of Washington, Seattle.
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.