Left Atrial Distensibility to Predict Left Ventricular Filling Pressure and Prognosis in Patients With Severe Mitral Regurgitation
Left Atrial Distensibility to Predict Left Ventricular Filling Pressure and Prognosis in Patients With Severe Mitral Regurgitation
A large left atrial (LA) volume, which represents chronic diastolic dysfunction, is
 associated with a poor outcome, regardless of systolic function. Thus, the LA volume provides
 a long-term view of whether the patient has diastolic dysfunction, regardless of the loading
 conditions present at the examination, such as hemoglobin A1c in diabetes mellitus. To date,
 the relation between the LA volume and left ventricular (LV) filling pressure has not been
 confirmed directly by simultaneous echocardiographic catheterization. The present study,
 therefore, assessed the correlation between the LA volume and LV filling pressure in patients
 with severe mitral regurgitation (MR). Because the LA pressure increases to maintain adequate
 LV diastolic filling, increased atrial wall tension tends to dilate the chamber and stretch
 the atrial myocardium. Therefore, the lower the ability of the left atrium to stretch, the
 greater the pressure in the left atrium. The study is designed to assess 1) the relationship
 between LV filling pressure and LA distensibility, and 2) the power of left atrial
 distensibility to predict the prognosis, including operation mortality, the rate of
 post-operation atrial fibrillation, and late heart failure event in patients with severe
 mitral regurgitation.
Introduction LA volume provides the significantly prognostic information in the general
 population and patients with heart disease, including acute myocardial infarction, left
 ventricular dysfunction, mitral regurgitation, cardiomyopathy and atrial fibrillation. Large
 LA volume, which represents chronic diastolic dysfunction, is associated with poor outcome,
 regardless of systolic function. Thereby, LA volume provides a long-term view of whether or
 not the patient has the disease of diastolic dysfunction, regardless of whatever loading
 conditions are present at the time of the examination, as the hemoglobin A1C in diabetes
 mellitus. Until now, the relation between LA volume and LV filling pressure confirmed
 directly by simultaneous echocardiography-catheterization is sparse. This study therefore
 assessed the correlation between LA volume and LV filling pressure in patients with severe
 mitral regurgitation (MR). As LA pressure rises to maintain adequate LV diastolic filling,
 increased atrial wall tension tends to dilate the chamber and stretch the atrial myocardium.
 Therefore, the smaller LA stretchability, the more pressure LA faces. The study is designed
 to assess 1) the relationship between LV filling pressure and LA distensibility, and 2) the
 power of left atrial distensibility to predict the prognosis, including operation mortality,
 the rate of post-operation atrial fibrillation, and late heart failure event in patients with
 severe mitral regurgitation.

 Methods Study population: Between August 2010 and July 2012, this study will enroll 100
 severe MR patients who will receive cardiac catheterization for pre-operation evaluation.
 Exclusion criteria are the following: 1) presence of mitral stenosis, 2) more than mild
 severity of aortic valvular problem, 3) any abnormality of atrial septum (e.g., atrial septal
 defect or aneurysm), and 4) rhythm other than sinus rhythm. MR are categorized by mapping jet
 expansion in the LA in 4- and 2-chamber views at end systole from three separate cardiac
 cycles. MR is considered severe when regurgitant jet area occupies more than 40% of the LA
 area. The grade of MR is increased by one degree (moderate to severe) in cases of eccentric
 MR jet based on evidence of reduced color-flow jet areas due to loss of momentum in jets
 adjacent to chamber walls. Significant coronary lesion is defined as diameter stenosis > 70%
 in at least one major coronary artery. The control group consisted of 50 other comorbid
 disease-, age- and gender-matched patients with negative results of coronary angiography,
 despite positive result of screen test for coronary artery disease (treadmill, Thallium scan,
 stress echocardiography, or 64-slides CT angiography), and they are selected after confirming
 no evidence of valvular heart disease by echocardiography. All patients and controls will
 give written informed consent to participate in the study, and the study is approved by the
 institutional review board.

 Cardiac catheterization: Coronary angiography will be performed to evaluate hemodynamic
 condition and to test for coronary artery disease. The LV filling pressure is continuously
 recorded (50 mm/s) by a 6-F pigtail catheter placed at the apex of the left ventricle and is
 taken from 3 to 5 end-respiratory cycles if patients can tolerate breath holding. The LV
 filling pressure value is calculated as the mean of at least 3 consecutive cardiac cycles. An
 LV filling pressure > 15 mmHg is considered elevated.

 Conventional echocardiographic and myocardial tissue Doppler measurement: Echocardiography
 will be performed immediately after LV filling pressure measurements. LV ejection fraction is
 calculated using Simpson's method for biplane images. Mitral inflow is assessed by
 pulsed-wave Doppler echocardiography form the apical 4-chamber view. From the mitral inflow
 profile, the E-wave velocity, A-wave velocity, and E-deceleration time are measured.
 Pulsed-wave tissue Doppler imaging (TDI) is performed using spectral pulsed Doppler signal
 filters, by adjusting the Nyquist limit to 15 - 20 cm/s and using the minimum optimal gain.
 In the apical 4-chamber view, a 3-mm, a pulsed-wave Doppler sample volume is placed at the
 level of the mitral annulus over the septal border. Pulsed-wave TDI results are characterized
 by a myocardial systolic wave (S') and 2 diastolic waves: early (E') and atrial contraction
 (A'). The pulsed-wave TDI tracing is recorded over 5 cardiac cycles at a sweep speed of 100
 mm/s and is used for offline calculations.

 Measurements of LA volume: All LA volume measurements will be calculated from apical 4- and
 2-chamber views using the biplane area-length method (15). The LA volumes are measured at 3
 points: 1) immediately before the mitral valve opening (maximal LV volume or Volmax); 2) at
 onset of the P-wave on electrocardiography (pre-atrial contraction volume or Volp); and 3) at
 mitral valve closure (minimal LV volume or Volmin). The LA distensibility was calculated as
 (Volmax - Volmin) / Volmin. The LA ejection fraction is calculated as (Volp - Volmin) / Volp.
 In all patients, LA volumes are indexed to body surface area (BSA).

 Measurement of regurgitation volume: The apical window is used to record the pulsed-wave
 velocities at the LV outflow tract and at the mitral annulus and to measure the diameter of
 the mitral annulus. The time-velocity integral is assessed. The stroke volumes of mitral
 annulus and LV outflow tract are obtained by multiplying the cross-sectional area by the
 respective time-velocity integral. The MR regurgitation volume is calculated as Regurgitation
 volume = (stroke volume of mitral annulus) - (stroke volume of LV outflow tract).

 Follow up: All patients will receive mitral valve replacement later. The prevalence of
 operation mortality and post-OP atrial fibrillation will be assessed. Otherwise, patient will
 receive regular follow-up at our outpatient clinic for at least 1 year and any heart failure
 event necessary for hospitalization will be assessed by telephone interview, chart review or
 personal visit interview if needed. Those events, including operation mortality, post-OP
 atrial fibrillation and post-OP hospitalization for heart failure, will account for patients'
 prognosis.

 Interobserver variability: In the first 50 enrolled cases, Volmax, Volmin, and Volp will be
 measured by 2 independent observers. Interobserver variability is calculated as the
 difference between the values obtained by the 2 observers divided by the mean. Interobserver
 difference and variability of Volmax, Volmin, and Volp will be assessed.

 Statistical analysis: The SPSS software (version 12) will be used for all statistical
 analyses. All continuous variables are presented as means ± standard deviation. Analysis of
 variance and post hoc test (Scheffe F-test) for unpaired data are used to evaluate the
 significance of differences between groups. A p vale of < 0.05 is considered statistically
 significant. Comparison of clinical characteristics is performed by chi-square analysis for
 categorical variables. Bivariate analysis, simple correlation and linear regression are used
 as appropriate. The relation curve between LA distensibility and LV filling pressure are
 estimated using SPSS software. ROC curve analysis is also performed to assess the sensitivity
 and specificity of the cut-off points of echocardiographic parameters when predicting
 elevated LV filling pressure (> 15 mmHg), and the presence of the above-mentioned events. If
 LA distensibility is useful for predicting elevated LV filling pressure and major events,
 Kaplan-Meier curve will be performed to assess the cumulative event-free rate according to
 the cut-off point of LA distensibility estimated by ROC curve. The hazards ratios of clinical
 and echocardiographic parameters, including LA distensibility will be assessed by
 multivariate logistic analysis.
Inclusion Criteria:

 -  Patients with severe mitral regurgitation are admitted for surgical intervention and
 are willing to participate in this study.

 Exclusion Criteria:

 -  Presence of mitral stenosis

 -  More than mild severity of aortic valvular problem

 -  Any abnormality of atrial septum (e.g., atrial septal defect or aneurysm)

 -  Rhythm other than sinus rhythm

 -  Inadequate image quality

 -  Lack of informed consent