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\begin{document}

\title{Left ventricular diastolic function in mitral stenosis}



\author[1]{Ashwin Venkateshvaran}%
\author[2]{Satish Govind}%
\affil[1]{Karolinska Institute}%
\affil[2]{Narayana Institute of Cardiac Sciences}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\selectlanguage{english}
\begin{abstract}
The assessment of left ventricular (LV) function in the setting of
mitral stenosis (MS) has been critically examined for decades. Accurate
assessment of aberrations in diastolic function 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. Echocardiographic evaluation of diastolic
dysfunction includes an evaluation of reduced LV compliance, diminished
restoring forces and enhanced stiffness, which are challenging in the
setting of MS owing to altered hemodynamic loading. Conventional
echocardiographic and Doppler measures offer limited information. Novel
assessments employing speckle tracking echocardiography are relatively
less studied. A more comprehensive assessment including clinical
evaluation, identification of concomitant disorders and comorbidities is
particularly warranted in older subjects with degenerative MS to suspect
diastolic dysfunction and arrive at optimal medical therapy or
intervention. This review provides an overview of etiological,
pathophysiological, echocardiographic and invasive assessment of
diastolic dysfunction in the setting of MS, with specific focus on
strengths and limitations of available echocardiographic and Doppler
techniques.%
\end{abstract}%



\sloppy


\textbf{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 Harvey\textsuperscript{1} and
Fleming\textsuperscript{2} 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
setting\textsuperscript{3-8} and have attributed this to variable
mechanisms that include impaired LV filling secondary to mitral valvular
obstruction\textsuperscript{9-11}, chronic myocardial
inflammation\textsuperscript{12-14}, sub-valvular scarring resulting in
regional abnormalities,\textsuperscript{3 15 16} elevated systemic
load\textsuperscript{4 17-19} and right-left
interactions\textsuperscript{20}. (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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.

\textbf{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.\textsuperscript{23}Traditionally, 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.\textsuperscript{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.\textsuperscript{25}Ultrastructural 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.\textsuperscript{26} With increasing life expectancy, degenerative
causes are more common in developed nations.\textsuperscript{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.\textsuperscript{28 29} Less common causes
include systemic disorders like mucopolysaccharidosis, Whipple's disease
and disorders associated with abnormal serotonin metabolism.

\textbf{Prevalence}

While studies have suggested that the rate of reduced ejection fraction
(EF) in MS may be as high as 33\%, \textsuperscript{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.\textsuperscript{27}In
another study, close to 1 in 4 subjects with degenerative aortic
stenosis were reported with hemodynamically significant MS secondary to
MAC.\textsuperscript{30} Additionally, comorbidities such as chronic
renal disorders and DM are also associated with MAC\textsuperscript{25
26} Taken together, this data suggests that diastolic aberrations in
this population may not be uncommon.

\textbf{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).\textsuperscript{31} Changes in LA and LV compliance
also impact symptoms and exertion tolerance.\textsuperscript{32 33}While
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.\textsuperscript{21}Tension
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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.

\textbf{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 \selectlanguage{greek}τ \selectlanguage{english}(tau), and passive
chamber stiffness employing pressure-volume loops.\textsuperscript{37}In
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.\textsuperscript{6} Other mechanisms proposed to explain
reduced LV compliance in MS include restriction of regional myocardial
segments\textsuperscript{13} and the influence of a dilated, overloaded
right heart on left-sided distensibility.\textsuperscript{19 38}Negative
diastolic pressures have been demonstrated in MS which characterizes
ventricular early diastolic suction.\textsuperscript{34}With
super-imposed diastolic aberrations, these early filling forces may be
negated.\textsuperscript{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.

\textbf{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.\textsuperscript{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.

\textbf{Transmitral Doppler indices}

Key variables to be considered during echocardiographic evaluation of
diastolic dysfunction include early diastolic transmitral velocity (E),
early diastolic mitral annular velocity by tissue Doppler imaging (TDI)
(e') and their corresponding relationship (E/e'), LA volume index (LAVi)
and peak tricuspid regurgitation velocity.\textsuperscript{40} In the
setting of MS, however, these offer limited value to assess myocardial
disease as they are often related to the degree of valvular stenosis.
E-wave velocity reflects left-sided atrioventricular gradient during
early diastole and is affected by alterations in LV relaxation and LA
pressure. In the setting of significant LV diastolic dysfunction,
transmitral gradient is low despite increased LA pressure owing to
concomitant increase in LV diastolic pressure. Pressure half-time
employing echocardiography, thereby, is decreased due to increase in LV
diastolic pressure caused by increased LV chamber stiffness and hence,
may not provide an accurate estimation of valve area using this
method.\textsuperscript{40} (Figures -- 1, 2). Further, elevated
transmitral velocities secondary to valvular obstruction and lower
myocardial velocities in the setting of reduced output result in
abnormally high E/e' values that may not faithfully represent invasive
filling pressures.\textsuperscript{41} LA volumes are often increased as
an adaptation response to elevated pressures secondary to valvular
obstruction. This is further compounded by the frequent occurrence of
AF, which further distorts LA geometry. In keeping with these
observations, current guidelines have suggested that recommended
echocardiographic measures to identify LV diastolic function may not be
accurate to assess LV filling pressures in the setting of significant
mitral valve disease.\textsuperscript{40}

\textbf{Pulmonary vein velocities}

Pulmonary S-wave velocity (which includes S\textsubscript{1} and
S\textsubscript{2} waves) is impacted by alterations in LA pressure, in
addition to LA and LV contractility. D-wave velocity is influenced by
early diastolic LV filling and maintains a strong relationship with
mitral E velocity.\textsuperscript{42} The resultant ratio (S/D) is
related to changes in compliance of the LA but may have limited accuracy
in mitral valve disease.\textsuperscript{40} In addition, pulmonary vein
flow is influenced by obstruction imposed by the
valve\textsuperscript{43} and is less likely to represent changes in LV
compliance.

\textbf{Mitral velocity propagation}

Mitral flow propagation velocity (V\textsubscript{p}) has been proposed
as an indicator of LV relaxation and correlates with invasive time
constants of relaxation.\textsuperscript{44} Additionally, E/Vp ratio
has been shown to correlate with LA pressure,\textsuperscript{45} but
may not be accurate in patients with normal
EF.\textsuperscript{40}Further, transmitral E wave velocity is governed
by the severity of mitral obstruction, making this measurement
unreliable in the setting of MS.

\selectlanguage{ngerman}\textbf{IVRT/T \textsubscript{E-e´} ratio}

Time intervals are less prone to hemodynamic alterations and hold
relevance in the load-altered MS milieu. Early clinical and auscultatory
study suggest that IVRT, the time interval between aortic valve closure
and mitral valve opening, is altered in MS.\textsuperscript{46 47} More
recent echocardiographic data suggests that IVRT demonstrates
significant relationship with invasive filling pressures in the setting
of mitral stenosis\textsuperscript{41} and in degenerative mitral
annular calcification.\textsuperscript{48} Further, shorter IVRT and
higher mitral A-wave velocity suggest elevated early diastolic LA
pressures. However, IVRT is not routinely measured in clinical practice
and is affected by heart rate and arterial
pressure.\textsuperscript{40}The time interval between E and e'
(T\textsubscript{E-e'}) has demonstrated good relation to \selectlanguage{greek}τ \selectlanguage{english}in animal
and human studies and is relatively load-independent.\textsuperscript{49
50} Using pulse wave doppler, the E wave is recorded and the time
interval between the onset of QRS complex and the E wave is taken note
of. Similarly, using TDI, the time interval between the onset of QRS
wave on the ECG and the e' wave is noted. The difference between the two
is depicted as the T\textsubscript{E-e'} time interval. IVRT is then
divided by this value. The normal value is \textless{}2. In normal LV
diastolic function, E and e' occur at the same time or e' may precede
it. With elevated LA pressure, the mitral E wave occurs earlier and
annular e' velocity is delayed, lengthening T\textsubscript{E-e'.} In
keeping with these findings, Diwan et al. demonstrated that
time-adjusted IVRT (IVRT/ T\textsubscript{E-e'}) displayed the strongest
correlation with capillary wedge pressure in MS and could track changes
in capillary wedge pressure after valve surgery.\textsuperscript{41} A
value of \textless{} 4.2 indicates increased LV diastolic pressures in
MS with reasonable accuracy. However, in the presence of atrial
fibrillation, these values may be hard to ascertain.

\textbf{Quantitative echocardiography}

TDI as a quantitative tool is based on principles of lower velocity
Doppler frequency shifts and has been extensively used to characterize
both systolic and diastolic function. More specifically, mitral annular
early diastolic recoil velocity (e') has been shown to be associated
with invasively measured time constant of LV relaxation (\selectlanguage{greek}τ\selectlanguage{english}), and has
been validated in both animal models\textsuperscript{51 52} and human
studies.\textsuperscript{53-55} Further, e' has been shown to be less
load-dependent than conventional doppler-derived parameters. With this
background, Ozdemir and colleagues first demonstrated reduced systolic
and diastolic myocardial velocities in MS subjects with normal ejection
fraction (EF). While systolic myocardial velocities demonstrated a
positive correlation with mitral orifice area, no association was
observed with e', suggesting that reduced LV performance in MS could be
attributed to both myocardial and functional
factors.\textsuperscript{56} Sengupta and colleagues also demonstrated
decreased myocardial velocities in MS and subsequent elevation after
balloon commissurotomy. In that study, increase in e' was associated
with MVA. Serial measurements during follow-up showed progressive
improvement in the annular velocities, prompting the authors to suggest
that tissue velocity imaging can be used to monitor changes in LV
function after PTMC.\textsuperscript{57}

2D Speckle tracking echocardiography is another powerful parametric
imaging tool now being increasingly employed in clinical practice. There
is limited data studying diastolic function in MS employing speckle
tracking echocardiography. Sengupta and colleagues showed decreased
strain in patients with severe MS, with rapid improvement in LV
deformation after PTMC, which correlated well with improved diastolic
loading. The findings suggested that impaired LV mechanical function in
MS can be attributed to decreased LV filling, instead of structural
myocardial abnormalities.\textsuperscript{58}

\textbf{Balloon Mitral Commissurotomy}

Percutaneous transvenous mitral commissurotomy (PTMC) is the treatment
of choice for patients with symptomatic MS. Soon after PTMC, an improved
LV filling and increased LV end diastolic volume is observed, with
slight increase in LVEDP and subsequent normalization.\textsuperscript{6
38} In the absence of LV diastolic dysfunction, no significant changes
are seen in LV diastolic pressure, although a fall in LA pressure is
observed. Limited data exists on the impact of PTMC on LV compliance and
the effect of elevated baseline LVEDP on outcomes. Eleid et al reported
LV diastolic dysfunction and elevated invasive LVEDP in one in three
subjects undergoing PTMC and suggested that diastolic aberrations
contribute to existing LA pressure and are associated with greater risk
of failure to improve symptoms. In their study, both body mass index and
DM were associated with diastolic dysfunction. While no significant
differences in severity of pulmonary hypertension or post-interventional
improvement in hemodynamic status was observed when comparing the group
with elevated LV stiffness (LVEDP\textgreater{}15mmHg) with normal
compliance (LVEDP[?]15mmHg), the group with elevated LVEDP had a higher
risk of combined end-point, which included recurrent severe symptoms,
repeat procedure or death (1-year estimate, 42\% vs 81\%; hazard ratio,
2.83; 95\% CI, 1.62-4.96; P\textless{}.001).
\textsuperscript{35}Additionally, lower LVEDP has been proposed as an
independent predictor for intermediate and long-term risk-free survival
in multiple studies.\textsuperscript{59 60}

\textbf{Conclusion}

The assessment of LV diastolic dysfunction in patients with MS is
challenging. Identification of concomitant diastolic disorders is
imperative in the management of older subjects with co-existent systemic
disease, co-morbidities and mismatch between symptom class and MVOA, and
to identify subgroups that may not benefit from balloon intervention.
Such subjects may benefit from optimal medical therapy to decrease blood
pressure, lower heart rate, improve LV diastolic filling and with
diuretics to lower PH. Conventional echocardiographic methods are of
limited value to assess LV diastolic dysfunction in MS.
IVRT/T\selectlanguage{ngerman}\textsubscript{E-e´} ratio is the recommended method to identify
the presence of raised LV filling pressure. Newer diagnostic methods
like speckle tracking echocardiography show promise, but widespread
utility is currently limited owing to insufficient data.

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\textbf{Table 1.} Pathophysiology of left ventricular dysfunction in
mitral stenosis\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
Proposed pathophysiology of left ventricular (LV) dysfunction in mitral
stenosis include\textsuperscript{4} Chronic inflammation leading to
myocardial fibrosis Scarring of the sub valvular apparatus leading to
wall motion abnormality Reduced LV compliance Increased afterload
leading to LV remodelling Abnormal right-left septal interaction due to
significant pulmonary hypertension Concomitant disease such as
hypertension and coronary artery disease Reduced filling of
LV\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} Methods to assess left ventricular diastolic
dysfunction\selectlanguage{english}
\begin{longtable}[]{@{}l@{}}
\toprule
Invasive evaluation Echocardiographic evaluation Transmitral Doppler
Pulmonary vein Doppler Flow propagation velocity Tissue Doppler Speckle
tracking echocardiography\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2/Fig-2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

