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Comparison of Left Atrial Volume Parameters in Detecting Left Ventricular Diastolic Dysfunction Versus Tissue Doppler Recordings

  • Shih-Hung Hsiao
    Correspondence
    Corresponding author: Tel: 886-7-342-2121, ext 2011; fax: 886-7-345-5045
    Affiliations
    Division of Cardiology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China

    School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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  • Ko-Long Lin
    Affiliations
    Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China
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  • Kuan-Rau Chiou
    Affiliations
    Division of Cardiology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China

    School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
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Published:December 07, 2011DOI:https://doi.org/10.1016/j.amjcard.2011.10.040
      Because of diastolic coupling between the left atrium and left ventricle, we hypothesized that left atrial (LA) function mirrors the diastolic function of left ventricle. The aims of this study were to assess whether LA volume parameters can be good indexes of left ventricular diastolic dysfunction. Six hundred fifty-nine patients underwent cardiac catheterization and measurements of left ventricular filling pressure (LVFP). Echocardiographic examinations including tissue Doppler and LA volumes were also assessed. Ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity and LVFP tended to increase after progression of diastolic dysfunction. The inverse phenomenon existed in LA ejection and LA distensibility. LA distensibility was superior to LA ejection fraction and early diastolic mitral inflow velocity/early diastolic mitral annular velocity for identifying LVFP >15 mm Hg (areas under receiver operating characteristic curve 0.868, 0.834, and 0.759, respectively) and for differentiating pseudonormal from normal diastolic filling (areas under receiver operating characteristic curve 0.962, 0.907, and 0.741, respectively). Multivariate logistic regression showed that LA ejection fraction and LA distensibility were associated significantly with the presence of pseudonormal/restrictive ventricular filling. In conclusion, LA volume parameters can identify LVFP >15 mm Hg and differentiate among patterns of ventricular diastolic dysfunction. For assessing diastolic function LA parameters offer better performance than even tissue Doppler.
      Diastolic dysfunction has a major role in producing signs and symptoms in patients presenting with heart failure.
      • Gaasch W.H.
      • Levine H.J.
      • Quinones M.A.
      • Alexander J.K.
      Left ventricular compliance: mechanisms and clinical implications.
      • Grossman W.
      • McLaurin L.P.
      Diastolic properties of the left ventricle.
      • Grossman W.
      • McLaurin L.P.
      • Rolett E.L.
      Alterations in left ventricular relaxation and diastolic compliance in congestive cardiomyopathy.
      The gold standard for diagnosing diastolic dysfunction is the time constant of relaxation obtained by direct invasive measurement. However, this is not feasible in daily clinical practice.
      • Rakowski H.
      • Appleton C.
      • Chan K.L.
      • Dumesnil J.G.
      • Honos G.
      • Jue J.
      • Koilpillai C.
      • Lepage S.
      • Martin R.P.
      • Mercier L.A.
      • O'Kelly B.
      • Prieur T.
      • Sanfilippo A.
      • Sasson Z.
      • Alvarez N.
      • Pruitt R.
      • Thompson C.
      • Tomlinson C.
      Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: from the Investigators of Consensus on Diastolic Dysfunction by Echocardiography.
      There are several noninvasive parameters that can assess different properties of diastolic dysfunction including Doppler mitral inflow velocity-derived variables, pulmonary venous flow velocity, color M-mode flow propagation velocity, and tissue Doppler imaging (TDI).
      • Nishimura R.A.
      • Tajik A.J.
      Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone.
      • Cohen G.I.
      • Pietrolungo J.F.
      • Thomas J.D.
      • Klein A.L.
      A practical guide to assessment of ventricular diastolic function using Doppler echocardiography.
      • Garcia M.J.
      • Thomas J.D.
      • Klein A.L.
      New Doppler echocardiographic applications for the study of diastolic function.
      • Nagueh S.F.
      • Middleton K.J.
      • Kopelen H.A.
      • Zoghbi W.A.
      • Quiñones M.A.
      Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures.
      • Garcia M.J.
      • Smedira N.G.
      • Greenberg N.L.
      • Main M.
      • Firstenberg M.S.
      • Odabashian J.
      • Thomas J.D.
      Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: animal and human validation.
      However, many diastolic parameters are influenced by physiologic factors, particularly by alternations in preload. TDI has emerged as a new technique that is less affected by loading conditions and provides a strong complementary role in the assessment of diastolic function. Left atrial (LA) volume parameters are potentially useful tools for assessing diastolic dysfunction,
      • Tsang T.S.
      • Barnes M.E.
      • Gersh B.J.
      • Bailey K.R.
      • Seward J.B.
      Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden.
      • Murata M.
      • Iwanaga S.
      • Tamura Y.
      • Kondo M.
      • Kouyama K.
      • Murata M.
      • Ogawa S.
      A real-time three-dimensional echocardiographic quantitative analysis of left atrial function in left ventricular diastolic dysfunction.
      but their roles need further investigation. The objective of the present study was to use LA volume parameters for grading diastolic dysfunction compared to TDI.

      Methods

      From December 2007 through March 2010, 1,128 patients who underwent cardiac catheterization were recruited prospectively. Exclusion criteria were the (1) presence of mitral stenosis, prosthetic mitral valve, or mitral regurgitation with greater than mild severity, (2) any abnormality of the atrial septum (e.g., atrial septal defect or aneurysm), (3) acute coronary syndrome, (4) rhythm other than sinus rhythm, (5) inadequate image quality (particularly the pattern of pulmonary venous flow), and (6) lack of informed consent. In total 659 patients were enrolled for final analysis; reasons for catheterization were peripheral artery obstructive disease (n = 26), survey of congestive heart failure (n = 102), and coronary angiography/management (n = 531). Creatinine clearance was estimated for each participant according to the Cockcroft–Gault equation. Renal dysfunction was defined as an estimated creatinine clearance <60 ml/min at first blood sampling at hospitalization.
      • Dries D.L.
      • Exner D.V.
      • Domanski M.J.
      • Greenberg B.
      • Stevenson L.W.
      The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction.
      The protocol was approved by the institutional review board (VGHKS99-015). After a detailed explanation patients were invited to participate in this study and written informed consents were obtained from all enrolled participants before cardiac catheterization.
      Selective angiography was performed using standard techniques. After catheterization, left ventricular filling pressure (LVFP) measurements were performed using a fluid-filled pigtail catheter placed into the left ventricle. The fourth intercostal space in the midaxillary line was used as the 0 level. LVFP was recorded continuously (50 mm/s) by a 6Fr pigtail catheter placed at the mid LV cavity using fluoroscopic screening. Measured pressure recordings included LV systolic pressure and LV pressure before the A wave, which was defined as pressure at onset of atrial contraction. The average of LV pressure before the A wave over 5 cardiac cycles defined LVFP.
      • Hurrell D.G.
      • Nishimura R.A.
      • Ilstrup D.M.
      • Appleton C.P.
      Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: a simultaneous catheterization and Doppler echocardiographic study.
      LVFP was considered increased at >15 mm Hg.
      Echocardiography (iE33 System, Philips Medical System, Andover, Massachusetts) was performed immediately after LVFP measurements with patients still on the cardiac catheter laboratory table in a slightly left decubitus position. Transmitral flow profiles including peak early diastolic flow velocity (E), late diastolic flow velocity (A), and mitral early deceleration time were assessed. LV ejection fraction was calculated using the Simpson biplane technique. In addition, pulmonary venous flow velocities were obtained. LV mass was calculated by the formula described by Devereux and Reichek.
      • Devereux R.B.
      • Reichek N.
      Echocardiographic determination of left ventricular mass in man Anatomic validation of the method.
      LV mass was indexed to a patient's body surface area. Pulse-wave TDI was performed using spectral pulse-wave Doppler signal filters and minimum optimal gain. In apical views a pulse-wave Doppler sample volume was placed at the level of the mitral annulus over the septal and lateral borders. Pulse-wave TDI results were characterized by a myocardial systolic wave, an early diastolic wave (e′), and an atrial contraction diastolic wave. The pulse-wave TDI tracing was recorded over 5 cardiac cycles at a sweep speed of 100 mm/s and used for off-line calculations. The average e′ of the septal and lateral mitral annuluses was chosen to estimate LVFP by the E/e′ method.
      • Rivas-Gotz C.
      • Manolios M.
      • Thohan V.
      • Nagueh S.F.
      Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity.
      All LA volume measurements were calculated using the biplane area–length method.
      • Ujino K.
      • Barnes M.E.
      • Cha S.S.
      • Langins A.P.
      • Bailey K.R.
      • Seward J.B.
      • Tsang T.S.
      Two-dimensional echocardiographic methods for assessment of left atrial volume.
      LA volumes were measured at 3 points: (1) immediately before the mitral valve opening (maximal LA volume), (2) at the onset of the P wave on electrocardiogram (preatrial contraction volume), and (3) at the mitral valve closure (minimal LA volume). LA distensibility was calculated as (maximal LA volume minus minimal LA volume) multiplied by 100% divided by minimal LA volume. LA ejection fraction was calculated as (preatrial contraction volume minus minimal LA volume) multiplied by 100% divided by preatrial contraction volume. LA volumes were indexed to body surface area.
      • Hsiao S.H.
      • Huang W.C.
      • Lin K.L.
      • Chiou K.R.
      • Kuo F.Y.
      • Lin S.K.
      • Cheng C.C.
      Left atrial distensibility and left ventricular filling pressure in acute versus chronic severe mitral regurgitation.
      Diastolic dysfunction was classified by mitral inflow pattern.
      • Nishimura R.A.
      • Tajik A.J.
      Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone.
      Presence of mitral E/A <0.75 or deceleration time >240 ms was considered evidence of impaired relaxation. In a more severe stage of diastolic dysfunction with pseudonormal LV filling, transmitral flow characteristics were similar to those in patients with normal diastolic function. In this study pseudonormal and normal LV fillings were defined by the presence of a mitral E/A of 0.75 to 1.50 and a deceleration time of 151 to 240 ms and differentiated by (1) E/e′ >15
      • Ommen S.R.
      • Nishimura R.A.
      • Appleton C.P.
      • Miller F.A.
      • Oh J.K.
      • Redfield M.M.
      • Tajik A.J.
      Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study.
      or (2) E/e′ ≥11 in association with atrial reversal duration of pulmonary venous flow exceeding the mitral A-wave duration by ≥30 ms.
      • Yamamoto K.
      • Nishimura R.A.
      • Burnett J.C.
      • Redfield M.M.
      Assessment of left ventricular end-diastolic pressure by Doppler echocardiography: contribution of duration of pulmonary venous versus mitral flow velocity curves at atrial contraction.
      • Barberato S.H.
      • Pecoits-Filho R.
      Usefulness of left atrial volume for the differentiation of normal from pseudonormal diastolic function pattern in patients on hemodialysis.
      Restrictive diastolic filling was the most severe form of diastolic dysfunction with markedly increased LVFP. Presence of mitral E/A >1.5 or deceleration time ≤150 ms was considered evidence of this abnormality.
      • Nishimura R.A.
      • Tajik A.J.
      Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician's Rosetta Stone.
      In the first 100 enrolled cases maximal LA volume, minimal LA volume, and preatrial contraction volume were measured by 2 independent observers. Interobserver variability was calculated as the difference between values obtained by the 2 observers divided by the mean. Interobserver difference and variability of maximal LA volume were 3.2 ± 5.4 ml and 5.4 ± 8.7%, respectively. Interobserver variabilities and differences were 6.1 ± 8.9% and 2.9 ± 4.1 ml for minimal LA volume and 5.7 ± 7.4% and 2.5 ± 3.4 ml for preatrial contraction volume, respectively. Therefore, interobserver variabilities in LA distensibility and LA ejection fraction measurements were 5.8 ± 7.6% and 3.5 ± 4.2%. Interobserver difference and variability of mitral E velocity were 3.1 ± 5.8 cm/s and 4.2 ± 7.4%. Interobserver variabilities and differences were 2.7 ± 5.2% and 0.2 ± 0.4 cm/s for myocardial systolic wave, 2.2 ± 5.1% and 0.2 ± 0.4 cm/s for e′, and 2.8 ± 5.6% and 0.3 ± 0.5 cm/s for atrial contraction diastolic wave, respectively. Thus, the interobserver variability in E/e′ was 6.3 ± 7.4%.
      SPSS (SPSS, Inc., Chicago, Illinois) was used for all statistical analyses. All continuous variables were presented as mean ± SD. Analysis of variance and post hoc test for unpaired data were used to estimate group differences. Comparison of clinical characteristics was performed by chi-square analysis for categorical variables. Bivariate analysis, simple correlation, and linear regression were used when appropriate. Area under the receiver operating characteristic curve was used to evaluate the sensitivity and specificity for predicting increased LVFP and differentiating pseudonormal from normal ventricular filling. Accuracy of receiver operating characteristic curve analysis was measured by area under the receiver operating characteristic curve, which indicated which parameters provided superior or inferior performance. Univariate and multivariate logistic regression analyses were performed on potential variables for predictions of increased LVFP and presence of pseudonormal ventricular filling. Variables with a potential association with multivariate modeling were selected by univariate analyses and subsequently selected with entry and retention in the model set at a significance level of 0.05. Multivariate logistic regression analysis was performed to assess the correlation between clinical parameters and advanced diastolic dysfunction (pseudonormal/restrictive filling).

      Results

      Table 1 presents the basic characteristics and echocardiographic parameters according to diastolic function. Seventy-four of 659 patients (11.2%) were classified as having normal filling, 317 (48.1%) as having impaired relaxation, 175 (26.6%) as having pseudonormal filling, and 93 (14.1%) as having restrictive filling. Three hundred seventy-six patients (57.1%) had normal systolic function, defined as LV ejection fraction >50%.
      Table 1Basic characteristics and echocardiographic parameters among all four groups of diastolic function
      VariableNormalImpaired RelaxationPseudonormalRestrictivep Value
      (n = 74)(n = 317)(n = 175)(n = 93)
      Age (years)60 ± 1467 ± 1364 ± 1566 ± 140.082
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Women/men15/6467/31666/17238/94<0.0001
      Diabetes mellitus10 (12.7%)126 (32.9%)90 (37.8%)52 (39.4%)<0.0001
      Hypertension29 (36.7%)259 (67.6%)143 (60.1%)70 (53%)<0.0001
      Current smoker43 (54.4%)199 (52%)122 (51.3%)56 (42.4%)0.003
      Body weight (kg)68 ± 1068 ± 1165 ± 1365 ± 130.008
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Renal dysfunction (creatine clearance <60 ml/min)18 (22.8%)225 (58.7%)135 (56.7%)88 (66.7%)<0.0001
      Left ventricular mass index (g/m2)119 ± 28146 ± 33153 ± 34168 ± 40<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Heart rate (beats/min)70 ± 1273 ± 1279 ± 1582 ± 17<0.0001
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Mitral early diastolic flow velocity (cm/s)83 ± 2164 ± 1888 ± 26103 ± 30<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Mitral late diastolic flow velocity (cm/s)68 ± 1886 ± 1875 ± 2258 ± 25<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Deceleration time (ms)183 ± 25231 ± 57188 ± 33146 ± 41<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Systolic velocity of pulmonary venous flow (cm/s)54 ± 1250 ± 1246 ± 1342 ± 17<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Diastolic velocity of pulmonary venous flow (cm/s)44 ± 1048 ± 1053 ± 1457 ± 17<0.0001
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Atrial reverse velocity of pulmonary venous flow (cm/s)30 ± 631 ± 832 ± 635 ± 70.001
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Left ventricular ejection fraction (%)56 ± 750 ± 945 ± 941 ± 12<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Septal mitral annulus (cm/s)
       Systolic velocity of mitral annulus7.3 ± 1.56.5 ± 1.66.0 ± 1.85.3 ± 1.8<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
       Early diastolic velocity of mitral annulus7.6 ± 1.96.0 ± 1.65.8 ± 2.25.3 ± 2.5<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
       Late diastolic velocity of mitral annulus8.3 ± 1.88.2 ± 1.86.9 ± 1.95.7 ± 2.1<0.0001
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Lateral mitral annulus (cm/s)
       Systolic velocity of mitral annulus9.3 ± 2.48.1 ± 2.37.3 ± 2.46.2 ± 2.5<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
       Early diastolic velocity of mitral annulus9.7 ± 2.77.7 ± 2.37.3 ± 2.87.1 ± 2.1<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
       Late diastolic velocity of mitral annulus9.7 ± 2.29.0 ± 2.38.3 ± 2.66.5 ± 2.6<0.0001
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Mitral early diastolic flow velocity/early diastolic velocity of septal mitral annulus11.7 ± 4.713.5 ± 5.217.2 ± 7.322.9 ± 9.8<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Mitral early diastolic flow velocity/early diastolic velocity of lateral mitral annulus9.4 ± 4.110.5 ± 4.614.1 ± 6.417.1 ± 7.4<0.0001
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Mitral early diastolic flow velocity/average early diastolic velocity of mitral annulus10.0 ± 3.711.5 ± 4.315.0 ± 5.520.1 ± 7.4<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Maximal indexed left atrial volume (ml/m2)23.9 ± 4.530.7 ± 11.840.1 ± 16.148.0 ± 19.8<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Left atrial volume index before P wave (ml/m2)15.6 ± 9.223.7 ± 10.033.2 ± 13.140.4 ± 18.9<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Minimal indexed left atrial volume (ml/m2)9.1 ± 6.115.7 ± 6.926.0 ± 11.735.0 ± 19.0<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Left atrial ejection fraction (%)39 ± 834 ± 922 ± 914 ± 8<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Left atrial distensibility (%)198 ± 61107 ± 4461 ± 2840 ± 19<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Left ventricular filling pressure (mm Hg)10.4 ± 3.114.3 ± 4.320.8 ± 6.326.1 ± 7.2<0.0001
      Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Analysis of variance was performed in all 4 groups.
      low asterisk Normal group versus impaired relaxation group (p <0.05, post hoc analysis).
      Normal group versus restrictive group (p <0.05, post hoc analysis).
      Impaired relaxation group versus pseudonormal group (p <0.05, post hoc analysis).
      § Normal group versus pseudonormal group (p <0.05, post hoc analysis).
      Impaired relaxation group versus restrictive group (p <0.05, post hoc analysis).
      Pseudonormal group versus restrictive group (p <0.05, post hoc analysis).
      Although LV diastolic function progressively worsened, the downward trend of LA distensibility and LA ejection fraction corresponded with an upward trend of E/e′. These 3 diastolic parameters were applied to differentiate pseudonormal from normal diastolic filling in all patients (249 patients) with the presence of mitral E/A of 0.75 to 1.50 and deceleration time of 151 to 240 ms. In accordance to receiver operating characteristic curve analysis, LA distensibility <93% precisely identified pseudonormal diastolic ventricular filling (area under receiver operating characteristic curve 0.962, sensitivity 92%, and specificity 91%) but the sensitivity/specificity of LA ejection fraction <31.6% and E/e′ >11.2 were only 85%/82% and 69%/67% (Table 2). For differentiating pseudonormal from normal diastolic filling in patients with preserved LV systolic function and normal-like ventricular filling, LA distensibility was also better than LA ejection fraction and E/e′ (areas under receiver operating characteristic curve 0.915, 0.842, and 0.685, respectively; Table 2).
      Table 2Differential diagnosis of pseudonormal ventricular filling and left ventricular filling pressure higher than 15 mm Hg
      AUC95% CICut-Off PointsSensitivitySpecificity
      Predict pseudonormal ventricular filling
       All patients (n = 659)
        Early diastolic flow velocity/average early diastolic velocity of mitral annulus0.7410.680–0.802>11.269%67%
        Left atrial ejection fraction (%)0.9070.873–0.940<31.6%85%82%
        Left atrial distensibility (%)0.9620.943–0.982<94%92%91%
       Normal left ventricular ejection fraction (n = 376)
        Early diastolic flow velocity/average early diastolic velocity of mitral annulus0.6850.595–0.774>9.966%64%
        Left atrial ejection fraction (%)0.8420.777–0.908<31%76%80%
        Left atrial distensibility (%)0.9150.863–0.967<95%84%87%
      Predict left ventricular filling pressure >15 mm Hg
       All patients (n = 659)
        Early diastolic flow velocity/average early diastolic velocity of mitral annulus0.7590.727–0.791>11.770%68%
        Left atrial ejection fraction (%)0.8340.807–0.861<29%78%75%
        Left atrial distensibility (%)0.8680.844–0.892<80%79%78%
       Normal left ventricular ejection fraction (n = 376)
        Early diastolic flow velocity/average early diastolic velocity of mitral annulus0.7190.666–0.772>11.066%64%
        Left atrial ejection fraction (%)0.7790.729–0.829<31%70%69%
        Left atrial distensibility (%)0.8280.785–0.871<87%76%74%
      AUC = area under receiver operating characteristic curve; CI = confidence interval.
      Maximal LA volume, minimal LA volume, and LA ejection fraction were associated linearly with LVFP (F368.4, r
      • Grossman W.
      • McLaurin L.P.
      Diastolic properties of the left ventricle.
      = 0.301; F497.6, r
      • Grossman W.
      • McLaurin L.P.
      Diastolic properties of the left ventricle.
      = 0.392; F748.2, r
      • Grossman W.
      • McLaurin L.P.
      Diastolic properties of the left ventricle.
      = 0.476, respectively, p <0.0001 for all comparisons). LA distensibility correlated logarithmically to LVFP (LVFP = 54.1 to 8.4 × ln[LA distensibility]; F1,105.4, r
      • Grossman W.
      • McLaurin L.P.
      Diastolic properties of the left ventricle.
      = 0.571, p <0.0001; Figure 1) . Figure 2 demonstrates the distribution of diastolic parameters according to LVFP and diastolic dysfunction classification. Receiver operating characteristic curve analysis showed than LA distensibility better identified LVFP >15 mm Hg than LA ejection fraction and E/e′ (areas under receiver operating characteristic curve 0.868, 0.834, and 0.759, respectively; Table 2, Figure 3) . In patients in subgroups with normal systolic function, receiver operating characteristic curve analysis showed that LA distensibility was also superior to LA ejection fraction and E/e′ (areas under receiver operating characteristic curve 0.828, 0.779, and 0.719, respectively; Table 2, Figure 3). Figure 4 shows the incidence of each grade of diastolic dysfunction according to LA distensibility. LA distensibility <50% indicated pseudonormal or restrictive diastolic dysfunction with little possibility of normal or impaired relaxation ventricular filling. Conversely, those with LA distensibility >100% were almost classified as having normal or impaired relaxation.
      Figure thumbnail gr1
      Figure 1Logarithmic relation between left ventricular filling pressure and left atrial distensibility.
      Figure thumbnail gr2
      Figure 2Distribution of diastolic parameters according to (A) left ventricular filling pressure and (B) conventional diastolic grading system. LAEF = left atrial ejection fraction.
      Figure thumbnail gr3
      Figure 3Receiver operating characteristic curve analyses for (A) identifying pseudonormal from normal-like mitral inflow pattern, (B) identifying pseudonormal from normal-like mitral inflow pattern in patients with preserved left ventricular systolic function, (C) predicting left ventricular filling pressure >15 mm Hg, and (D) predicting left ventricular filling pressure >15 mm Hg in patients with preserved left ventricular systolic function. AUC = area under receiver operator characteristic curve. Other abbreviation as in .
      Figure thumbnail gr4
      Figure 4Incidence of each grade of diastolic dysfunction according to left atrial distensibility.
      Univariate and multivariate analyses to assess correlations between pseudonormal/restrictive ventricular filling and covariables (clinical and echocardiographic parameters) are presented in Table 3. LV ejection fraction and LVFP were related to severe diastolic dysfunction with borderline influences (p = 0.052 and 0.043, respectively). However, remarkable correlations existed between severe diastolic dysfunction and LA volume parameters including inverse correlations among LA ejection fraction, LA distensibility, and pseudonormal/restrictive filling and a positive correlation between indexed maximal LA volume and pseudonormal/restrictive filling.
      Table 3Univariate and multivariate logistic regression to assess the correlations between pseudonormal/restrictive ventricular filling and covariables
      CharacteristicUnivariate AnalysisMultivariate Analysis
      HR (95% CI)p ValueHR (95% CI)p Value
      Renal dysfunction (creatine clearance <60 ml/min)1.088 (1.003–1.180)0.0431.024 (0.927–1.747)0.462
      Diabetes0.872 (0.501–1.763)0.117
      Hypertension1.22 (0.923–1.613)0.163
      Deceleration time (ms)0.983 (0.980–0.986)<0.00010.987 (0.982–1.061)0.119
      Age (per 1 year)0.999 (0.993–1.006)0.802
      Body weight (per 1-kg increase)0.980 (0.969–0.992)0.0010.984 (0.964–1.005)0.135
      Body mass index (per 1-kg/m2 increase)0.920 (0.878–0.964)<0.00010.940 (0.905–1.997)0.221
      Left ventricular mass index (per 1-g/m2 increase)1.013 (1.008–1.017)<0.00011.003 (0.995–1.081)0.091
      Mitral early diastolic flow velocity (cm/s)1.048 (1.040–1.056)<0.00011.04 (1.024–1.056)<0.0001
      Mitral late diastolic flow velocity (cm/s)0.971 (0.964–0.977)<0.00010.954 (0.941–0.968)<0.0001
      Left ventricular ejection fraction (%)0.922 (0.907–0.937)<0.00010.972 (0.944–1.000)0.052
      Left ventricular filling pressure (per 1-mm Hg increase)1.308 (1.261–1.356)<0.00011.050 (1.001–1.116)0.043
      Early diastolic flow velocity/average early diastolic velocity of mitral annulus (per 1-U increase)1.198 (1.160–1.237)<0.00011.034 (0.970–1.102)0.303
      Maximal indexed left atrial volume (per 1-ml/m2 increase)1.072 (1.058–1.086)<0.00011.024 (1.003–1.047)0.026
      Left atrial ejection fraction (per 1% increase)0.844 (0.825–0.864)<0.00010.959 (0.925–0.993)0.02
      Left atrial distensibility (per 1% increase)0.945 (0.937–0.952)<0.00010.971 (0.961–0.981)<0.0001
      HR = hazard ratio. Other abbreviation as in Table 2.

      Discussion

      In the compliant left atrium and left ventricle, which indicate low and normal LVFP, LA stretchability is a good indicator because collagen fiber of the LA wall in proceeding from minimal to maximal LA maximal volume still has not reached an inextensible level. Generally speaking, if LA compliance is good, there is a larger reservoir capacity for blood flow from the pulmonary veins and less increase in LA pressure. Thus, the cyclic change of LA volume does not result in a conspicuous change of intra-atrial pressure. Conversely, the poorly compliant and dilated left atrium reaches its maximal volume and further elongation is halted. A higher and higher pressure is needed to produce further dilation of the left atrium. In this study LVFP and LA volume change ratio from minimal to maximal LA volume (LA distensibility) had a logarithmic correlation (Figure 1). Early in the course of a high LVFP causing an unfolded left atrium, there is a large increase in LA pressure. With a sustained increase in LA pressure and LVFP the atrium dilates so that remodeling of the left atrium after increasing maximal LA volume results in a further decrease of cyclic LA volume change. Therefore, LA distensibility can reflect instantaneous LVFP, whereas maximal indexed LA volume mirrors the persistence of impaired diastolic function.
      TDI parameters, particularly E/e′, have been reportedly associated with an increase of LVFP and are useful for predicting the late outcome of many cardiovascular diseases.
      • Nagueh S.F.
      • Middleton K.J.
      • Kopelen H.A.
      • Zoghbi W.A.
      • Quiñones M.A.
      Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures.
      • Hillis G.S.
      • Moller J.E.
      • Pellikka P.A.
      • Gersh B.J.
      • Wright R.S.
      • Ommen S.R.
      • Reeder G.S.
      • Oh J.K.
      Noninvasive estimation of left ventricular filling pressure by e/e is a powerful predictor of survival after acute myocardial infarction.
      Nevertheless, TDI offers information on only regional systolic and diastolic functions. When E/e′ is used to assess some disease entities with only regional myocardial impairment such as coronary artery disease, it infers that regional parameters obtained by TDI may not reflect global LV function precisely. In the present study 374 of 659 patients (56.8%) had coronary artery disease defined as stenosis >70% in ≥1 main coronary artery by angiography. Because the application of E/e′ for assessing diastolic function has potential disadvantages in this group, E/e′ to assess increased LVFP is inferior to LA ejection fraction and LA distensibility, although a significant linear correlation existed between E/e′ and LVFP. Our previous study, which investigated the correlation between diastolic parameters and LVFP and studied the prognostic effect of diastolic parameters in patients with acute myocardial infarction, demonstrated that LA parameters are better than E/e′ for predicting LVFP and the short-term and long-term prognoses regardless of ventricular systolic function, vascular status, and Killip classification.
      • Hsiao S.H.
      • Chiou K.R.
      • Porter T.R.
      • Huang W.C.
      • Lin S.K.
      • Kuo F.Y.
      • Cheng C.C.
      • Lin K.L.
      • Lin S.L.
      Left atrial parameters in the estimation of left ventricular filling pressure and prognosis in patients with acute coronary syndrome.
      Clearly, for ischemic heart disease, global parameters as LA distensibility offer better clinical utility.
      Restrictive filling pattern of mitral inflow is relatively easy to identify and is associated significantly with an adverse outcome.
      • Nijland F.
      • Kamp O.
      • Karreman A.J.
      • van Eenige M.J.
      • Visser C.A.
      Prognostic implications of restrictive left ventricular filling in acute myocardial infarction: a serial Doppler echocardiographic study.
      A pseudonormal filling pattern is more difficult to classify according to conventional mitral inflow. However, the outcome of pseudonormal filling is similar to that of restrictive filling including progressive LV dilation, heart failure, readmission, and mortality rate.
      • Møller J.E.
      • Søndergaard E.
      • Poulsen S.H.
      • Egstrup K.
      Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode Doppler echocardiographic study.
      • Whalley G.A.
      • Doughty R.N.
      • Gamble G.D.
      • Wright S.P.
      • Walsh H.J.
      • Muncaster S.A.
      • Sharpe N.
      Pseudonormal mitral filling pattern predicts hospital re-admission in patients with congestive heart failure.
      Because it is essential that patients with advanced diastolic dysfunction be identified early for therapeutic interventions, reliable methods of differentiating a pseudonormal pattern from a normal filling pattern are indicated. Otherwise, a high LVFP is also associated significantly with poor outcome.
      • Møller J.E.
      • Pellikka P.A.
      • Hillis G.S.
      • Oh J.K.
      Prognostic importance of diastolic function and filling pressure in patients with acute myocardial infarction.
      Identification and early treatment of advanced diastolic dysfunction and increased LVFP are crucial to manage patients with heart failure. In this study LA distensibility and LA ejection fraction enabled the discrimination between pseudonormal and normal and the identification of LVFP >15 mm Hg with even better sensitivity/specificity than TDI. This result also can apply to patients with pure diastolic dysfunction (Table 2).
      This study has some limitations. First, this was a single-center study that enrolled only patients indicated for catheterization. Second, tachycardia, particularly a heart rate >120 beats/min, brought about the merging of the E and A waves in mitral inflow, e′ and atrial contraction diastolic wave, and T and P waves on electrocardiogram. Peak velocities of merging E and A waves were used as mitral E in 21 cases and peak velocities of merging e′ and atrial contraction diastolic wave were used as e′ in 16 cases. According to the report of Nagueh et al
      • Nagueh S.F.
      • Mikati I.
      • Kopelen H.A.
      • Middleton K.J.
      • Quiñones M.A.
      • Zoghbi W.A.
      Doppler estimation of left ventricular filling pressure in sinus tachycardia A new application of tissue Doppler imaging.
      it is an acceptable alternative to assess LVFP by the E/e′ method. However, merging of T and P waves on electrocardiogram made measurements of LA ejection fraction impossible, leading to missing data for 13 patients. Third, LVFP was obtained using fluid-filled pigtail catheters. Although micromanometer-tipped catheters would have been ideal, our method used to measure LVFP is standard in the clinical setting and well validated. Fourth, the study cohort included some patients (42.9%) with systolic dysfunction. Although systolic dysfunction increases LVFP and possibly confounds the interpretation of diastolic function, this population reflects the real situation in daily practice. Otherwise, the present study also demonstrated that LA volume parameters are good diastolic parameters even in patients with systolic dysfunction (Table 2).

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