Valvular Heart Disease: Changing Concepts in

Disease Management

Left Ventricular Response to Mitral Regurgitation

Implications for Management
William H. Gaasch, MD; Theo E. Meyer, MD, PhD

M itral regurgitation (MR) burdens the left ventricle with

a volume load that leads to a series of left ventricular
(LV) compensatory adaptations and adjustments that vary
considerably during the prolonged clinical course of MR.1– 4
The early compensatory changes observed in acute MR (ie,
utilization of the Frank-Starling mechanism) are gradually
replaced by a chronic remodeling process with enlargement
of the LV chamber. Eventually, these compensatory adapta-
tions fail, LV dysfunction develops, and transition to a
decompensated phase of chronic MR occurs (Table). In the
present report, the LV response to MR will be described, the
evolution from a compensated to a decompensated state will
be discussed, and the therapeutic implications of these events
will be considered. Published guidelines provide detailed
recommendations for the evaluation and treatment of patients
with MR, including those with a variety of comorbidities.5,6
The present review is limited to a discussion of the changes
in LV size and function that develop as a result of degener-
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an orifice varies by the square root of the pressure gradient
across the orifice, the duration of flow, and a discharge
coefficient. Thus, the principal determinants of the regurgi-
tant volume (and the primary therapeutic targets) are the
regurgitant orifice area and the systolic pressure gradient
between the ventricle and left atrium. It should be recognized
that systemic vascular resistance, LV afterload, and myocar-
dial contractile state are not direct determinants of regurgitant
volume.
In many, if not most, patients with MR, the regurgitant
orifice area is not fixed and can exhibit dynamic variations
that are closely related to changes in LV pressure, volume,
and geometry.9 Variations in the systolic pressure gradient
across the valve can also affect the severity of the regurgitant
volume, but the impact of the pressure gradient is blunted by
the presence of a square root sign in the orifice equation.
Thus, a 10% to 15% decrease in the pressure gradient results
in only a 7% decrease in the regurgitant volume.10 Such a

ative disease of the mitral valve (recognized clinically as

severe mitral valve prolapse with or without partial flail
leaflet) or, less commonly, rheumatic mitral valve disease.
Our primary goal is to review the rationale for the use of
measurements of LV size and function as guides to the
management of patients with MR.
modest impact of the pressure gradient on regurgitant volume
is likely responsible, at least in part, for the lack of a clinical
benefit of vasodilating drugs or angiotensin-converting en-
zyme inhibitors in asymptomatic patients with chronic com-
pensated MR.5

Mitral Regurgitant Volume Assessment of Severity

The clinical impact of MR is determined by the magnitude of
the regurgitant leak (ie, the regurgitant volume) and the time
course of development of the regurgitation. Patients with the
abrupt onset of severe MR generally present with markedly
elevated pulmonary venous pressure, whereas those with
chronic MR exhibit prominent ventricular enlargement with
increased chamber compliance and lower pulmonary venous
pressure.2,7 In this section, the determinants of regurgitant
flow will be defined and the assessment of its severity
discussed.
Determinants of Regurgitant Volume
The determinants of the mitral regurgitant volume are best
explained in the context of the orifice equation.8 This equa-
tion, based on the Torricelli principle, states that flow through
The diagnosis of severe MR is made when ⬎50% of the total
stroke volume is diverted to regurgitant flow. Moderate MR
is said to be present when this fraction is 30% to 50%, and if
the regurgitant fraction is ⬍30% the diagnosis of mild MR is
made. The regurgitant volume and fraction, and even the
regurgitant orifice area, can be determined with quantitative
echocardiography-Doppler techniques, but these methods are
largely restricted to clinical investigation, and unfortunately,
they are not widely applied. The severity of MR is best
determined from a combination of 2D echocardiography with
Doppler measurements and clinical observations.11,12 With
the possible exception of coexisting conditions that might
limit ventricular enlargements, the diagnosis of chronic se-
vere MR should be questioned if the ventricle is not enlarged.

From the Departments of Cardiovascular Medicine, Lahey Clinic, Burlington, Mass, and University of Massachusetts Medical School, Worcester, Mass.
Correspondence to William H. Gaasch, Department of Cardiovascular Medicine, Lahey Clinic, 41 Mall Rd, Burlington, MA 01805. E-mail
William.H.Gaasch@lahey.org
(Circulation. 2008;118:2298-2303.)
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.107.755942

2298
 Gaasch and Meyer
Table. LV Structure and Function in the 3 Stages of Chronic MR
Stage 1 Chronic compensated MR with LV enlargement, eccentric
hypertrophy, and normal systolic function
Stage 2 Transitional phase with mild LV dysfunction that is reversible
after surgical correction of the regurgitant lesion
Stage 3 Decompensated MR with progressive and irreversible
structural and functional changes in the ventricle
Afterload-Shortening Relations
An understanding of the LV response to MR and the stages
outlined in the Table requires some discussion and clarifica-
tion of systolic load and myocardial shortening. The systolic
load that opposes myocardial shortening has been described
by calculating LV systolic wall stresses (afterload) or by
determining the arterial and left atrial input impedance
(hydraulic load). The latter has an impact on LV perfor-
mance, but alternations in impedance are always manifest by
variations in LV systolic wall stress that more adequately
predict changes in the ejection fraction (EF).13 According to
the Law of Laplace, LV systolic wall stress is directly
proportional to systolic pressure and chamber size and in-
versely proportional to wall thickness. An enlarged chamber
will generally manifest a high afterload, unless a proportional
increase in wall thickness occurs. Thus, systolic wall stress,
calculated according to the Laplace relation, incorporates the
effects of a variable ejection impedance, and the EF can be
interpreted accurately relative to the prevailing afterload.
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Afterload in MR
In acute MR, late systolic volume is reduced and afterload is
low, but as the ventricle enlarges and adapts to the chronic
volume overload, afterload gradually increases. Eventually,
particularly in decompensated MR, afterload exceeds normal.
Such afterload excess contributes to a decline in EF.4 Despite
evidence to the contrary (vide infra), the notion persists that
afterload is low in chronic MR. Several published studies
refute this misconception.
Using echocardiographic measures of LV volume, mass,
and geometry, Zile et al14 found that meridional end-systolic
stress was normal in compensated MR and increased in
decompensated MR. A tendency was found for peak systolic
stress to be increased in both compensated and decompen-
sated MR. Corin et al15 later confirmed these observations
with cardiac catheterization techniques. They calculated cir-
cumferential wall stress and found a modest increase in peak
systolic stress in compensated and decompensated ventricles.
End-systolic stress was increased dramatically in decompen-
sated MR. Other published data support the conclusion that
LV afterload ranges from normal to increased in chronic
MR.16,17 An understanding of these concepts of afterload in
chronic MR is important when the clinician evaluates and
assesses LV systolic performance and function. For example,
a low or borderline EF (ie, 50% to 55%) would obviously
indicate depressed LV function if afterload were low; how-
ever, it would not be appropriate to conclude that LV function
was depressed if the EF were 55% to 60% in the presence of
increased or even normal afterload.
Left Ventricular Response to Mitral Regurgitation 2299
Holosystolic MR seen in patients with partial flail leaflets
can produce substantial regurgitation prior to the time of
aortic valve opening.18 With most of the regurgitation (and a
major reduction in LV volume) occurring in early systole, the
time course of systolic wall stress would be substantially
different from that seen in patients with late systolic prolapse
and late systolic MR. It is not known whether these differ-
ences produce different effects on LV size, function, or
clinical outcomes, but it is unlikely that the regurgitant
volume in late systolic MR would be as large as that seen in
holosystolic MR.
Ejection Fraction
The EF, which represents volume strain, is calculated as
change in volume divided by initial volume or stroke volume
divided by end-diastolic volume. Thus, the EF is appropri-
ately normalized and does not require a consideration of
anthropometric issues such as body size.19 The EF is, how-
ever, sensitive to changes in LV hemodynamic loading
conditions, but this is not always a disadvantage. For exam-
ple, even if the LV contractile state remains normal, there will
be a tendency for the EF to decline if afterload increases.
Thus, a decrease in myocardial contractile state or an increase
in LV afterload (ie, during the transition from compensated to
decompensated MR) may cause a decrease in the EF. Re-
gardless of the mechanism, a depressed EF can be an
indication for surgical correction of MR.
In MR, other indices of systolic function appear to be less
useful than the EF. For example, the end-systolic dimension
may not be as accurate in predicting postoperative heart
failure and survival as the EF.20,21 This could be due at least
in part to the requirement for anthropometric normalization of
the linear end-systolic dimension; the optimal method for
such normalization has not been established.19 In addition, a
given end-systolic dimension could suggest depressed or
normal LV function depending on the diastolic dimension.
Indeed, if end-diastolic diameter ranged from 55 to 65 mm,
an end-systolic diameter of 40 mm would indicate an EF
ranging from the lows 50s to the high 60s. The former could
be taken as an indication for surgery, whereas the latter would
not. Certainly, end-systolic size is not a pure index of systolic
function. It is an amalgam of end-diastolic size and contrac-
tile function, neither of which is independent of hemodynam-
ic loading conditions. The end-systolic stress-volume ratio
might be more useful than the end-systolic volume alone, but
in chronically remodeled hearts, this ratio, like systolic
elastance, requires consideration of body size and LV geom-
etry.16,22 These and other indices of function certainly can be
useful in many circumstances, but the EF appears to be the
most clinically relevant index of LV systolic function in MR,
and it provides a scientifically valid and clinically reliable
index on which to base management decisions.
Acute MR
With the abrupt onset of MR, the major circulatory impact is
on the pulmonary venous pressure. The central circulation is
overloaded, but a normal LV compliance limits the increase
in end-diastolic volume to a modest rise. This increment in
volume produces a preload-dependent increase in LV stiff-
 2300 Circulation November 25, 2008
Figure 1. LV stress-volume loop in acute MR. The early adapta-
tion to acute MR consists of an increase in end-diastolic vol-
ume, a systolic unloading that is characteristic of acute MR, and
a decrease in end-systolic volume; as a result, the total stroke
volume increases.
ness, which adds to the pulmonary venous hypertension. LV
preload reserve is exploited, and the Frank-Starling mecha-
nism contributes to an increase in the total stroke volume. At
the same time, the low-pressure runoff into the left atrium
effects a systolic unloading, which also contributes to an
increase in stroke volume (Figure 1). Despite these major
alterations in the central circulation and the LV, the hemo-
dynamic burden of acute MR is well tolerated by the
myocardium. Almost a century ago, Evans and Matsuoka23
found that increased flow work added little to the energy
requirements of the heart. Later, Urschel and associates24
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demonstrated that myocardial oxygen consumption increased
only minimally during experimental MR, despite a doubling
of the total stroke volume.
Thus, the LV response to acute MR includes an increase in
preload, a decrease in afterload, an increased EF, and an
increased total stroke volume. Although many, if not most,
patients with acute MR require urgent surgery, some evolve
to a chronic state that has a gradual progression and pro-
longed natural history.25
Chronic MR
The natural history of chronic MR is characterized in its early
phases by a compensated hemodynamic state, during which
most patients remain free of symptoms. Gradually, a progres-
sive and malefic LV remodeling leads to a decompensated
stage of chronic MR (Figure 2). This late stage is usually
heralded by the development of symptoms, but the progres-
sion may be insidious and clinically silent. Thus, it is
extremely important to identify deleterious structural and
functional remodeling of the LV before the development of
irreversible LV dysfunction and to recommend surgical
correction of the regurgitant lesion before the decompensated
stage is established. To this end, it is necessary to describe
and clarify the definitions of the compensated, transitional,
and decompensated stages of MR.
Early descriptions of compensated and decompensated
stages of MR were based largely on reversibility of the LV
dilatation and eccentric hypertrophy, as well as the mainte-
nance of systolic function after surgical correction.14,26 Later,
a broad spectrum of clinical data that included functional
Figure 2. LV stress-volume loops in the 3 stages of chronic MR.
As the ventricle adapts to the chronic hemodynamic burden, a
progressive increase in LV end-diastolic volume and systolic
wall stress occurs. EF progressively declines from 65% in com-
pensated MR, to 55% during the transitional stage, and finally
to 45% (or lower) in decompensated MR.
status and exercise tolerance were added, and the definitions
of compensated and decompensated MR were refined and
utilized in published guidelines.5,6 The following discussion
of the pathophysiology and ventricular remodeling in MR
emphasizes ventricular size and function in compensated
MR (in which the remodeling is reversible) and in decom-
pensated MR (in which the eccentric hypertrophic remod-
eling is irreversible).
Compensated Stage of MR
The major adaptive change that occurs during the develop-
ment of a chronic volume overload is an enlargement of the
ventricle. As this chronic compensated state develops, the
small hyperkinetic ventricle of acute MR is converted to a
large compliant ventricle that is well suited to deliver a large
stroke volume. Progressive LV enlargement is also seen
during gradual progression of the severity of the regurgita-
tion. Such compensatory enlargement comes about through a
remodeling of the extramyocardial matrix with a dissolution
of collagen weave that allows rearrangement and slippage of
myocardial fibers and chamber enlargement.4,27 New sarco-
meres are added “in series,” and at the ventricular level,
eccentric hypertrophy develops. During this process, cardio-
myocytes exhibit an increase in length, but preload at the
sarcomere level (ie, sarcomere length) does not increase
progressively. Indeed, sarcomere lengths tend to return to-
ward normal despite progressive LV enlargement.28 As a
result, preload reserve is reestablished. In addition to these
changes in the cardiomyocytes and the extramyocardial
matrix, the LV systolic unloading that is characteristic of
acute MR is gradually replaced by normal systolic wall
stress.14,15 Thus, the enhanced total stroke volume seen in
chronic compensated MR is “mediated through a normal
performance of each unit of an enlarged circumference.”2
During this compensated stage, preload (at the sarcomere
level), afterload (at the ventricular level), and both contrac-
tility and EF are normal, and total stroke volume is increased
as a result of the large end-diastolic volume.
Transitional Stage of MR
The nature of the transition from the compensated to a
decompensated stage remains an elusive and poorly under-
 Gaasch and Meyer
stood aspect of the pathophysiology of MR. This transition
may occur as a consequence of a progressive increase in the
regurgitant volume, a decrease in LV contractile function, an
increase in afterload, or some combination of these factors.
During this stage, the EF declines to 50% to 59%. Such
structural and functional remodeling of the ventricle is largely
reversible if surgical correction of the MR is accomplished
during this transitional stage, before the decompensated stage.
Decompensated Stage of MR
Decompensated MR is characterized by substantial and pro-
gressive LV dilation, elevated LV diastolic pressure, in-
creased systolic wall stress, and an EF ⬍50%. The decline in
EF is a consequence of depressed myocardial contractile
state, LV afterload excess, or both. Such malefic structural
and functional remodeling of the ventricle generally pre-
cludes an optimal result after surgical correction of the
regurgitant lesion. This does not necessarily imply that
patients with an EF in the range of 30% to 50% cannot benefit
from surgery. Indeed, corrective surgery is recommended, but
the clinical outcomes are not as favorable (or predictable) as
those in patients with higher EF.5
Patients with signs and symptoms of MR with severely
depressed systolic function (ie, EF ⬍30%) can present a
difficult diagnostic and management dilemma. It can be
difficult to establish whether the primary problem is that of
MR causing LV dilatation and dysfunction or a cardiomyo-
pathic process leading to secondary (ie, “functional”) MR.
Such a quandary should be approached by (1) an assessment
of mitral valve morphology and the mechanism of MR to
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determine whether evidence of primary valve disease exists,
such as myxomatous changes, and (2) utilization of quanti-
tative methods that provide regurgitant volume and regurgi-
tant fraction. A regurgitant fraction that is ⬍50% is not
expected to lead to severe LV dysfunction and dilatation. In
this case, consideration should be given to a diagnosis of
cardiomyopathy. It can also be helpful to determine the ratio
of regurgitant volume to the end-diastolic volume. A high
ratio indicates severe MR that is a potential target for
corrective surgery. By contrast, a low ratio suggests severe
decompensated MR or a cardiomyopathic process.29
If a patient exhibited moderate LV enlargement (end-dia-
stolic diameter of 65 mm or end-diastolic volume of 130
mL/m2), an EF of 30%, a regurgitant fraction of 50%, and a
regurgitant volume of 20 mL/m2, the ratio of regurgitant
volume to end-diastolic volume would be only 20/130, or
0.15. This should suggest severe, irreversible LV dysfunc-
tion. By contrast, a patient with the same end-diastolic
volume, an EF of 50%, and a regurgitant fraction of 50%
would have a ratio of regurgitant volume to end-diastolic
volume of 33/130, or 0.25. The higher ratio of 0.25 indicates
a potentially reversible phase of chronic MR. This ratio is
mathematically equivalent to the product of EF and regurgi-
tant fraction, which makes it possible to determine noninva-
sively and can potentially aid in the management of patients
with chronic MR.
LV Response to Corrective Surgery
Early echocardiographic studies by Schuler et al26 and Zile et
al14 described the temporal response of the left ventricle to
Left Ventricular Response to Mitral Regurgitation 2301
mitral valve replacement and suggested a predictive value of
preoperative measures of LV size and function. In most of
these patients, the LV end-diastolic dimension declined
substantially after surgery, but some failed to exhibit this
favorable decrease in LV size. In both studies, patients who
achieved a normal LV end-diastolic dimension had a better
functional result than those with persistent postoperative LV
enlargement. These disparate responses to valve replacement
provided the basis of our current terminology that emphasizes
compensated and decompensated LV function in chronic MR
and stimulated a wide search for parameters that might
predict the postoperative result and thereby aid in the optimal
timing of surgery.
The early studies also revealed a consistent decline in LV
EF after mitral valve replacement. This was thought to be a
consequence of an increase in LV afterload that was causally
related to closure of the low-impedance left atrial leak. Such
a mechanism may very well contribute to the decline in EF
that is seen in patients with decompensated MR, persistent
postoperative LV enlargement, and afterload excess. How-
ever, those patients exhibiting a postoperative normalization
of LV chamber size tend to exhibit normal or near-normal
values for systolic wall stresses before surgery and normal
values after surgery. Thus, a postoperative decline in EF
(with valve replacement in compensated MR) does not appear
to be a consequence of afterload excess.14
An alternative explanation for the postoperative decline in
EF can be developed by comparing the different functional
results of total valve replacement (with and without preser-
vation of the subvalvular apparatus) with those of valve repair
and preservation of the subvalvular apparatus.30,31 When the
valve, including the subvalvular apparatus, is replaced with a
prosthesis, the ventricle becomes more spherical, long-axis
shortening declines, and the EF falls. By contrast, valve repair
or replacement with preservation of the subvalvular apparatus
is not associated with a significant fall in the EF. By
preserving the continuity between the mitral apparatus and
the LV wall, systolic function is preserved despite closure of
the low-impedance left atrial leak. Thus, the LV response to
corrective surgery depends largely on the functional state of
the ventricle before surgery and the surgical procedure that is
performed.
Predictive Value of Preoperative Data
Having described the LV response to corrective surgery in
compensated and decompensated MR, it appeared to be
possible to predict the postoperative results from preoperative
data. Angiographic and echocardiographic data that appeared
to provide prognostic information included (1) a subnormal
EF or low fractional shortening and (2) a large end-systolic
volume or dimension. These early studies were later ex-
panded to include prediction of postoperative heart failure
and even survival.20,21 Such predictive and prognostic clues
do not directly identify an optimal time for corrective surgery,
but they certainly should influence our decisions about
surgery. Indeed, the published guidelines rely heavily on such
information.5
A most important prospective outcome study by Rosenhek
et al32 confirms the utility of the published guidelines. These
 2302 Circulation November 25, 2008
investigators used a “watchful waiting” approach in 132
patients with severe MR and recommended surgery only if
the patients met the criteria outlined in the guidelines. Their
indications for surgery were (1) the development of cardiac
symptoms that were thought to be caused by MR; (2) an EF
⬍60% or fractional shortening of the minor-axis diameter
⬍32%, which is equivalent to an EF that is ⬍60%33,34; (3) an
end-systolic diameter of 45 mm or 26 mm/m2; or (4)
pulmonary hypertension or atrial fibrillation. Thirty-five pa-
tients were treated surgically in the first 5 years, and no
postoperative deaths occurred. Only 4 patients exhibited
postoperative LV dysfunction; 2 of these had undergone
mitral valve replacement, and the other 2 had coronary bypass
surgery with reduced LV function before surgery. During the
follow-up period, only 2 deaths were thought to be related to
MR, and overall survival did not differ from the “expected
cumulative survival.” This study provides strong support for
the use of the published guidelines for the management of
chronic MR.5,6
An Unresolved Issue
Current guidelines for the management of patients with
valvular heart disease are based in part on the information
reviewed herein. Unfortunately, most such data, particularly
surgical outcomes, were obtained decades ago. In the modern
era, a remarkable improvement in surgical techniques, par-
ticularly mitral valve repair, has resulted in improved out-
comes.35 This may be a rationale for considering earlier
surgery, but it may also be a rationale for reconsidering the
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EF limit of 60% that is recommended in the guidelines. For
example, survival data obtained in the 1980s and published in
1994 indicate that patients with an EF of 50% to 60% exhibit
a similar postoperative survival as those with MR and an EF
exceeding 60%.20 In asymptomatic patients without coronary
disease, the 5-year survival rate was 90% and 93% in these 2
groups, respectively. A more recent analysis of surgical
outcomes indicates that survival trends had continued to
improve by 1992 to 1995.35 Most of the patients in that report
were symptomatic, most had significant LV enlargement, and
many had an EF ⬍60%. Despite these risk factors and other
comorbidities, postoperative survival of the patients was not
significantly different from expected survival. Thus, it ap-
pears that the continued improvement in surgical techniques
and a better understanding of LV function in MR allow safe
and effective surgery in patients with evidence of borderline
or mild LV systolic dysfunction (ie, transitional stage of MR).
As suggested more than 25 years ago, an EF limit of 55%
might well be appropriate in the current era.36
Management
Having identified a patient with what appears to be hemody-
namically significant MR, the physician must consider at
least 3 issues. Management decisions should be based on
quantitative assessments and should not be based on any
single measurement or observation. First, the severity of the
regurgitation should be established. Corrective surgery is
indicated only if the regurgitation is severe. Given the
difficulties in quantifying severity, it is prudent to question
the diagnosis of severe chronic MR when little or no LV or
left atrial enlargement is found. Second, the patient’s symp-
toms should be assessed and evaluated. In the absence of
cardiac symptoms, many, if not most, physicians hesitate to
recommend surgery unless clear and reliable evidence of LV
dysfunction exists, or some other factor (eg, the development
of atrial fibrillation, patient’s wishes and expectations) must
be considered. By contrast, surgery is indicated in symptom-
atic patients regardless of whether LV function is normal or
abnormal (with the exception of those with the most severe
LV dysfunction; vide supra). Third, the functional state of the
LV must be evaluated. Corrective surgery should be consid-
ered in an asymptomatic patient when the EF enters the
transitional stage (EF 50% to 60%) and is strongly recom-
mended before the decompensated stage (EF ⬍50%).
Disclosures
None.
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KEY WORDS: contractility 䡲 hemodynamics 䡲 remodeling 䡲 ventricular
function, left 䡲 regurgitation 䡲