Introduction
The assessment of left ventricular (LV) function in the setting of
mitral stenosis (MS) has been critically examined for decades. In the
1950s, studies by Harvey1 and
Fleming2 explored mechanistic theories related to the
presentation of depressed LV function in MS. Surgical commissurotomy was
widely considered as an effective therapy to relieve symptoms at that
time, and the ability to distinguish patients with mechanical
obstruction that may benefit from surgery from those with primary
myocardial insufficiency held clinical and prognostic relevance. Several
studies have subsequently reported reduced pump performance in this
setting3-8 and have attributed this to variable
mechanisms that include impaired LV filling secondary to mitral valvular
obstruction9-11, chronic myocardial
inflammation12-14, sub-valvular scarring resulting in
regional abnormalities,3 15 16 elevated systemic
load4 17-19 and right-left
interactions20. (Table 1)
A more focused inspection of LV diastolic function in MS was first
undertaken by Feigenbaum and colleagues, who measured mean compliance
employing the ratio of mean mitral valve flow to temporal change in
chamber pressure employing biventricular
catheterization.21 No differences in LV compliance was
observed between controls and patients in this study. With wide
utilization of invasive hemodynamic and subsequent advancement of
echocardiographic techniques, multiple investigators have explored LV
performance in this setting, paying specific attention to ventricular
distensibility and the measurement of filling pressures.
The accurate identification of diastolic aberrations in MS is important
as these subjects often present with signs and symptoms of heart failure
and pulmonary congestion that cannot be solely explained by the severity
of mechanical obstruction.22 The evaluation of MS
involves a stepwise process not limited to the assessment of mitral
valve orifice area (MVOA), but also left atrial (LA) size, associated
mitral regurgitation, LV dimensions and LV systolic function. LV
diastolic function assessment (Table 2), while routinely done as a part
of a normal echocardiographic evaluation, remains challenging in the
presence of MS and is most often not assessed in routine clinical
practice.
LA pressure in significant MS is elevated owing to the inability of the
stenotic valve to permit
complete passive atrial emptying during LV diastole, hence relying
heavily on atrial kick. Consequently, LV end-diastolic volume is
markedly reduced, which in turn lowers stroke volume. The expansibility
of LV is impaired owing to a rigid, thickened mitral valve apparatus and
its attachment to LV, leading to alterations in diastolic
function.6 Associated clinical conditions such as
hypertension (HTN), diabetes mellitus (DM), coronary artery disease
(CAD) and advancing age may also contribute to impaired diastolic
function, adding to the complexity of assessment.
Etiology
MS is usually a consequence of rheumatic fever in the context of
developing nations, less often due to degenerative disease with annular
calcification in the elderly in developed countries, and as a radiation
therapy induced abnormality in cancer patients. Approximately one-fourth
of all patients who have rheumatic fever develop MS.23Traditionally, it was believed that LV function was spared in patients
with MS. However, LV dysfunction is frequently seen in this setting and
the consequence of this is less known following mitral valve
replacement.24
During the acute phase of the disease, inflammation encompasses the
endocardium, myocardium and pericardium. While valvular scarring and
subsequent deformation are most apparent long-term presentations,
histological studies suggest that fibroid necrosis in the interstitial
tissue of the myocardium, followed by histiocyte and giant cells during
the granulomatous phase, and subsequent presentation of Aschoff nodules
may contribute to myocardial disarray.25Ultrastructural alterations of LV muscle cells have supported the widely
held concept of a myocardial factor as the basic pathogenetic mechanism
behind impaired LV function in MS.26 With increasing
life expectancy, degenerative causes are more common in developed
nations.27 A fraction (6-8%) of subjects with severe
mitral annular calcification (MAC), usually seen in elderly or in those
patients who are dialysis-dependent, develop MS as a result of calcium
encroaching the base of the valve leaflets.28 29 Less
common causes include systemic disorders like mucopolysaccharidosis,
Whipple’s disease and disorders associated with abnormal serotonin
metabolism.
Prevalence
While studies have suggested that the rate of reduced ejection fraction
(EF) in MS may be as high as 33%, 3-5 specific data
concerning the prevalence of diastolic dysfunction in MS is sparse. This
may be partially attributable to the declining occurrence of disease and
inherent challenges related to diastolic function assessment in the
setting of altered ventricular loading due to valvular obstruction.
Indirect evidence, however, can be obtained from the Euro Heart Survey,
where MS accounted for 12% of subjects and the prevalence of
degenerative MS increased dramatically with aging.27In another study, close to 1 in 4 subjects with degenerative aortic
stenosis were reported with hemodynamically significant MS secondary to
MAC.30 Additionally, comorbidities such as chronic
renal disorders and DM are also associated with MAC25
26 Taken together, this data suggests that diastolic aberrations in
this population may not be uncommon.
Pathophysiology
Pathophysiological consequences of MS are primarily due to an increased
transmitral pressure gradient across a stenosed valve, which in turn
leads to both a reduction in forward flow across the valve and increased
LA pressure that is retro-transmitted to elevate pulmonary pressures.
Both myocardial and mechanical factors contribute to the pathogenesis of
functional deterioration. Symptoms correlate with elevations in LA mean
pressure and are often precipitated by tachycardia and onset of atrial
fibrillation (AF).31 Changes in LA and LV compliance
also impact symptoms and exertion tolerance.32 33While reduced cardiac output in patients with MS is often attributed to
mechanical obstruction across the mitral orifice, this frequently does
not increase following mitral commissurotomy.21Tension created by a fibrosed mitral valve apparatus, altered RV-LV
interaction, passive elastic changes due to the chronic decrease in
preload and myocardial fibrosis might be responsible for LV systolic and
diastolic dysfunction.
In patients with LV diastolic dysfunction, symptoms of dyspnea exceed
severity of MS and such patients may have persistent symptoms even after
mitral valvotomy or valve replacement. Normally, negative LV
intraventricular pressure generated in early diastole (diastolic
suction) leads to lower reliance on LA filling during the cardiac cycle.
Sabbah and colleagues observed that this mechanism was lost in MS
patients having diastolic dysfunction.34 Studies have
suggested that over 30% of subjects with MS demonstrate elevated LVEDP
based on invasive criteria. Recurrent symptoms and repeat intervention
were more common in the group with elevated LVEDP as compared with those
that did not present with marked diastolic
dysfunction.35
Frequency of CAD in MS has also been studied. In 96 patients,
angiographically significant coronary artery stenosis was found in 28%
among patients above 40 years age and prognosis of these patients was
compromised due to this added complication.36 LV
systolic and diastolic dysfunction can occur among MS patients
irrespective of their basic rhythm. Systolic function is more affected
in patients with AF and diastolic function is more affected in patients
with sinus rhythm. Tissue doppler imaging and 2D speckle strain imaging
are tools that are available to assess subclinical LV dysfunction in MS
patients.
Invasive Evaluation
Direct estimation of LV diastolic performance can be obtained employing
multiple invasive approaches, which include measuring LVEDP, rate of
pressure decline during isovolumic relaxation or τ (tau), and passive
chamber stiffness employing pressure-volume loops.37In an elegant study employing micromanometer techniques with concomitant
transient occlusion of the inferior vena cava, Liu and colleagues
demonstrated reduced diastolic compliance in MS and attributed this to
tethering of an immobile mitral apparatus. In this study, increased LV
chamber stiffness normalized after balloon
intervention.6 Other mechanisms proposed to explain
reduced LV compliance in MS include restriction of regional myocardial
segments13 and the influence of a dilated, overloaded
right heart on left-sided distensibility.19 38Negative diastolic pressures have been demonstrated in MS which
characterizes ventricular early diastolic suction.34With super-imposed diastolic aberrations, these early filling forces may
be negated.39
In contrast, patients with normal LV diastolic function have low or
normal LV diastolic pressures. To confirm whether LV diastolic
dysfunction truly contributes to raised LA pressures, vasodilators can
be used to reduce afterload and demonstrate significant decrease in
diastolic pressures. In patients without diastolic dysfunction, the
reduction in LA pressure is likely to be marginal.
Echocardiographic Evaluation
LV diastolic dysfunction is a consequence of dampened LV relaxation in
the presence or absence of reduced restoring forces and elevated levels
of ventricular stiffness, leading to elevated filling
pressures.40 Echocardiographic evaluation of diastolic
dysfunction includes an evaluation of reduced LV compliance, diminished
restoring forces and enhanced stiffness. An assessment of these three
ventricular properties are particularly challenging in MS, where a
significantly narrowed mitral valve obstructs flow into the LV,
resulting in reduced filling and thereby, altered hemodynamic loading.