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.