Methods Population. Echocardiographic assessment

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1 Diastolic dysfunction and left atrial enlargement as contributing factors to functional mitral regurgitation in dilated cardiomyopathy: Data from the Acorn trial Seong-Mi Park, MD, a Seung Woo Park, MD, b Grace Casaclang-Verzosa, MD, c Steve R. Ommen, MD, c Patricia A. Pellikka, MD, c Fletcher A. Miller, Jr., MD, c Maurice E. Sarano, MD, c Spencer H. Kubo, MD, d and Jae K. Oh, MD c Seoul, South Korea; Rochester and St. Paul, MN Background Functional mitral regurgitation (MR) is commonly seen in dilated cardiomyopathy (DCM), which may result from left ventricular (LV) dilatation and alteration in the geometric relationship of mitral valve apparatus. However, not all patients with DCM show significant MR and left atrial (LA) enlargement. The aim of this study was to assess responsible factors for developing mitral valve regurgitation. Methods Of 300 patients enrolled in the Acorn trial, baseline echocardiography studies were available in 288, of whom 144 were excluded because of a variety of reasons. Echocardiographic data were examined for the remaining 144 patients in sinus rhythm with DCM, but without organic mitral valve disease and ischemic heart disease. Mitral regurgitation was assessed by color-flow imaging. All echocardiographic parameters were indexed to body surface area. Results Of 144 patients, 87 had MR grade 2 (group 1) and 57 had MR grade 0 or +1 (group 2). Group 1 had larger tenting area, tenting height, tethering distance, LA volume index, and mitral annular area than group 2 (all P b.001); LV volume index and ejection fraction were similar between groups. The major determinant of MR severity was tenting area (r = 0.49, P b.001), and this was best related to mitral annular area (r = 0.85, P b.001). Mitral annular area was most strongly associated with LA volume (r = 0.56, P b.001). In addition, LA volume index was highly correlated with LV diastolic dysfunction (r = 0.58, P b.001), both in total and in group 2 only. Conclusions For patients with DCM in the Acorn trial, MR severity was associated with LA volume and mitral annular area but not with LV volume. Mitral annular area and LA volume were closely related, even in patients without significant MR. These findings suggest that LA enlargement caused by advanced diastolic dysfunction may contribute to causing significant MR by augmenting mitral annular dilatation in DCM. (Am Heart J 2009;157:762.e3-762.e10.) Functional mitral regurgitation (MR) frequently accompanies advanced dilated cardiomyopathy (DCM) and is associated with a poor prognosis. 1,2 The competent mitral valve needs well-coordinated function of the left atrium (LA), the mitral annulus, the mitral leaflets, subvalvular apparatus, and the left ventricle (LV). 3 Functional MR mostly results from dysfunction of one or more of these components. Mitral regurgitation in DCM has been known to be related to either mitral annular dilatation or changes in the geometry of the papillary muscles resulting from LV dilatation and systolic dysfunction. 4-6 Recent reports From the a Division of Cardiology, Korea University College of Medicine, Seoul, South Korea, b Sungkyunkwan University School of Medicine, Seoul, South Korea, c Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, and d Cardiovascular Center, Acorn Cardiovascular Inc, St. Paul, MN. Submitted July 18, 2008; accepted December 18, Reprint requests: Jae K. Oh, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN oh.jae@mayo.edu /$ - see front matter 2009, Published by Mosby, Inc. doi: /j.ahj indicate that excess valvular tenting due to apical and posterior displacement of papillary muscle may be associated with functional MR in DCM. 7,8 However, the detailed mechanisms of these factors leading to functional MR have yet to be clarified. Moreover, even patients with severe LV dilatation may not have MR or an enlarged LA. Left atrium enlargement may be associated with LV remodeling, diastolic dysfunction, MR, and atrial fibrillation Left atrium enlargement caused by superimposed diastolic dysfunction may contribute to the development of more pronounced MR. Nevertheless, the relationship between the development of functional MR and diastolic function in patients with advanced DCM has not been well investigated. The Acorn trial provides a unique opportunity to evaluate the mechanism of functional MR in DCM because patients with a wide range of MR severity were recruited for the study. This trial is one of the largest prospective studies involving a cardiac support device (Acorn CorCap; Acorn Cardiovascular, St Paul, MN) and mitral valve repair in patients with advanced DCM and heart failure. 12 In the mitral valve repair stratum, patients with heart failure and significant MR requiring mitral valve

2 762.e4 Park et al American Heart Journal April 2009 repair were enrolled. In the stratum without mitral valve replacement, patients with heart failure but no significant MR were enrolled. Patients in both strata had similar degrees of LV dysfunction but different amounts of MR. Therefore, we sought to elucidate the differences in echocardiographic parameters between patients who had DCM with or without at least moderate functional MR and to identify structural and functional parameters best correlated with the severity of functional MR. Figure 1 Methods Population Echocardiography Core Laboratory at Mayo Clinic, Rochester, MN, performed comprehensive echocardiographic measurements of all patients enrolled in the Acorn trial at 18 different clinical sites. From the baseline echocardiographic data, we identified eligible patients for this study using the following inclusion criteria: (1) no organic mitral valve disease, (2) no history of ischemic heart disease or myocardial infarction causing ischemic functional MR, and (3) presence of sinus rhythm. Of 300 patients enrolled in the Acorn trial, demographic and echocardiographic data were available for 288 patients. Of them, we excluded 144 patients because of organic mitral valve disease (34 patients), significant arrhythmia or atrial fibrillation (63 patients), ischemic cardiomyopathy (30 patients), and difficult echocardiographic images (17 patients). The remaining 144 patients were divided into 2 groups according to the MR grade: (1) the patients with MR grade +2, +3, and +4 ( 2) as group 1 and (2) the patients with MR grade 0 and +1 (b2) as group 2. Echocardiographic assessment All echocardiographic parameters were measured off-line, and an average of 2 to 3 cardiac cycles was used. Left ventricular enddiastolic volume, end-systolic volume, and ejection fraction were measured by using the biplane Simpson disk method. Left ventricular length and width were measured from the apical 4-chamber view, and LV sphericity index was calculated by the ratio of LV length to width at end diastole. 13 Left atrial volume was measured by the biplane area-length method from apical 2- chamber and 4-chamber views when the LA area was maximal during end systole. All volumetric parameters were indexed by body surface area. Severity of MR was assessed semiquantitatively by Doppler color-flow imaging. Mitral regurgitation severity was graded using the consensus recommendations of the American Society of Echocardiography Task Force. 14 Mitral annular area was calculated by using the mitral annulus diameters measured in apical 4-chamber (d 1 ) and 2-chamber (d 2 ) views at end systole (Figure 1), using an ellipsoid assumption 15 : mitral annular area = d 1 d 2 p=4 The tenting area, tenting height, and tethering distance were measured as shown in Figures 1 and 2 and as studied previously. 7 All parameters were indexed to the body surface area of the patient. Because tissue Doppler imaging for the mitral annulus was not available in the Acorn trial, diastolic function was assessed by Measurement of mitral annular diameters (A and B, d1 and d2) and tenting height (A, dot line). measurement of the early and late mitral inflow velocities, the early to late mitral inflow velocity ratio, and the deceleration time of the early mitral inflow velocity as measured by mitral inflow pulsed-wave Doppler echocardiography. 16 Diastolic

3 American Heart Journal Volume 157, Number 4 Park et al 762.e5 Figure 2 dysfunction grading was defined as (1) impaired relaxation (early to late mitral inflow velocity ratio b1.0, with prolongation of the deceleration time [N240 milliseconds]); (2) pseudonormalization (early to late mitral inflow velocity ratio of , with normal deceleration time [ milliseconds]); or (3) restrictive filling (early to late mitral inflow velocity ratio 2, or early to late mitral inflow velocity ratio of 1-2 with a deceleration time 160 milliseconds). 16 Statistical analysis Data were expressed as mean ± SD. Variables were compared between the 2 groups using the Student t test. To assess independent determinants of the severity of functional MR, we conducted univariate and multivariate analysis based on stepwise multiple linear regression. Determinants of the tenting area and the degree of LV diastolic dysfunction were explored by univariate and stepwise multiple linear regression analyses. Left ventricular ejection fraction was not included as a variable for all multivariate analysis to avoid multicollinearity because it is both statistically and pathophysiologically related to LV end-diastolic and end-systolic volume. P values b.05 were considered statistically significant. All analyses were performed with commercially available statistical software (SPSS version 10.0; SPSS, Chicago, IL, and JMP; SAS Institute, Cary, NC). No extramural funding was used to support this work; and the authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. Results Baseline clinical characteristics A total of 144 patients (mean ± SD age 53 ± 13 years, 77 men [53%]) were eligible for this study (Table I). Mean ± SD LV ejection fraction was 26.6% ± 8.2%, and LV end-diastolic volume index was 134 ± 45 ml/m 2. The mean ± SD duration of heart failure was 5.2 ± 4.2 years. The etiology of DCM was idiopathic in 96 (66.7%), viral in 15 (10.4%), alcoholic in 4 (2.8%), hypertensive in 12 (8.3%), and miscellaneous in 17 (11.8%). Eighty-seven patients (60.4%) had MR of grade 2 as group 1, and 57 patients had no or mild MR as group 2. The average history of heart failure of group 1 was 5.1 ± 4.2 years, which was similar to that of group 2 (P =.54). Measurement of tethering distance (A) as the distance between the papillary muscle head and the fixed intervalvular fibrosa (annularpapillary distance) and tenting area (B) as the area enclosed between the annular plane and mitral leaflets. Determinants of severity of MR No significant differences were found between the 2 groups in LV end-diastolic volume index, LV end-systolic volume index, and LV ejection fraction (Table I). However, the LA volume index was significantly larger in group 1 (51.0 ± 18.9 vs 33.1 ± 12.0 ml/m 2, P b.001). The echocardiographic parameters of mitral valve deformity, including tenting area, tenting height, tethering distance, and mitral annular area, were significantly larger in group 1 than group 2 (all P b.001) (Table I); these parameters were well correlated to the severity of MR (Table II). However, the parameters of LV end-diastolic volume, LV end-systolic volume, LV sphericity index, and LV ejection

4 762.e6 Park et al American Heart Journal April 2009 Table I. Baseline and echocardiographic characteristics of patients with DCM Variable All patients (N = 144) Value Group 1 (n = 87) Group 2 (n = 57) P value Age, y 53 ± ± ± Men 77 (53%) 41 (47%) 36 (63%) History of heart 5.2 ± ± ± failure (y) NYHA class II 16 (11%) 12 (14%) 4 (7%) III 122 (85%) 70 (80%) 52 (91%) IV 6 (4%) 5 (6%) 1 (2%) Heart rate, beat/min 77 ± ± 9 75 ± Systolic BP, mm Hg 112 ± ± ± LVEDV index, ml/m ± ± ± LVESV index, ml/m ± ± ± Sphericity index 0.70 ± ± ± LVEF, % 26.6 ± ± ± RV systolic pressure, 39.7 ± ± ± 10.0 b.001 mm Hg LAV index, ml/m ± ± ± 12.0 b.001 MA area, cm 2 /m ± ± ± 1.24 b.001 Tenting area, cm 2 /m ± ± ± 0.29 b.001 Tenting height, cm/m ± ± ± 0.13 b.001 Tethering distance, cm/m ± ± ± 0.13 b.001 NYHA, New York Heart Association; BP, blood pressure; LVEDV, left ventricular enddiastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; RV, right ventricular; LAV, left atrial volume; MA, mitral annular. Values are mean ± SD or number of patients (percentage). For comparisons between group 1 (MR grade 2) and group 2 (MR grade b2). fraction were not important determinants of MR severity by univariate analysis (Table II). The tenting area showed the best correlation with the severity of MR (r = 0.49, P b.001). Multiple regression analysis also showed tenting area to be the strongest determinant of the severity of MR (r 2 = 0.33, P b.001). Determinants of tenting area Left ventricular end-diastolic volume index, LV endsystolic volume index, LV sphericity index, tenting height, tethering distance, and mitral annular area were related to tenting area (Table II). Mitral annular area showed the best correlation with tenting area by univariate analysis (r = 0.85, P b.001). Multiple regression analysis identified increased mitral annular area to be an independent contributor to tenting area (r 2 = 0.72, P b.001). Patients with greater mitral annular area had significantly increased tenting area (r = 0.85, P b.001) (Figure 3, A). Relation of mitral annulus to LV and LA volume Mitral annular area was more closely associated with LA volume index than with LV volume index for all patients (Table II). A similar relationship was found even within group 2 patients with bgrade 2 MR (LA volume index, r = Table II. Correlations of the severity of functional MR and mitral deformation with echocardiographic parameters (N = 144) Correlation measured Variable r P value Severity of functional MR LVEDV index LVESV index Sphericity index LVEF Tenting area 0.49 b.001 Tenting height 0.43 b.001 Tethering distance 0.38 b.001 MA area 0.44 b.001 Tenting area LVEDV index LVESV index Sphericity index Tenting height Tethering distance 0.43 b.001 MA area 0.85 b.001 MA area LVEDV index LVESV index Sphericity index LAV index 0.56 b , P b.001; LV end-systolic volume index, r = 0.33, P =.03; LV end-diastolic volume index, r =0.30,P =.05). Relationship of LV parameters to diastolic dysfunction The early to late mitral inflow velocity ratio and deceleration time were related more closely to LA volume index and MR severity than to other echocardiographic parameters (Table III). Left atrial volume index was independently related to the early to late mitral inflow velocity ratio by multiple regression analysis (r 2 = 0.51, P b.001). A larger LA volume was related to an increase in the early to late mitral inflow velocity ratio (Figure 3, B). These findings were present in both groups, even in patients with no MR (n = 31, early to late mitral inflow velocity ratio, r = 0.67, P b.001). The degree of diastolic dysfunction was associated with LV volume index, LV ejection fraction, LA volume index, and severity of MR (Table III). Left atrial volume index showed the greatest correlation with the degree of diastolic dysfunction by multiple regression analysis (r 2 = 0.41, P b.001). Discussion Occurrence of functional MR in patients with LV systolic dysfunction is associated with poor prognosis. Hemodynamically significant MR may cause worsening of symptoms and prognosis. Indeed, in previous studies, MR was associated with increased cardiovascular mortality in unselected patients with systolic dysfunction. 1,2 Patients with DCM who have similar LV size and volume frequently have varying degrees of MR, whereas a correlation between LV size and severity of MR is expected if functional MR is caused primarily by LV remodeling. Our findings demonstrated no significant

5 American Heart Journal Volume 157, Number 4 Park et al 762.e7 Figure 3 Scatter plot showing correlation between tenting area and mitral annular area (A, r = 0.85, P b.001) and correlation between the early to late peak mitral inflow velocity (E/A) ratio and left atrial volume index (B, r = 0.63, P b.001). MA, Mitral annular; LAV, left atrial volume. difference in LV size and volume between patients who had DCM with and without MR of at least moderate degree who were enrolled in the Acorn trial. The severity of functional MR in this patient cohort was correlated most significantly with the mitral valvular tenting area, which was in turn more closely related to mitral annular size and diastolic dysfunction severity than to LV volume. Diastolic dysfunction, therefore, appears to be an important contributing factor for development of MR in patients with DCM, probably by causing enlarging of the LA volume and the mitral annulus and subsequent augmenting of the tenting area. Diastolic function is affected by multiple factors, including MR. Therefore, it is impossible to measure how much diastolic dysfunction is related to MR or other factors in this patient population. However, patients who have varying degrees of diastolic dysfunction can have similar LV volumes and LV ejection fractions, which indicates that other important conditions influence diastolic function. Preceding or superimposed diastolic dysfunction may have an important role in functional MR. Dilatation of the mitral annulus alone in patients with atrial fibrillation is not sufficient to cause, 17 and our data show that LV dilatation alone also is not sufficient. A combination of LV dilatation and mitral annulus enlargement synergistically causes a larger mitral valve tenting area and more severe MR. Structural determinants of functional MR Previous reports have identified several factors that cause functional MR independently, including LV dilatation, LV sphericity, apical and posterior displacement of papillary muscle, LV dysfunction, and mitral annular dilatation. However, the precise mechanism of functional MR is better clarified by incorporating the following contributing factors: (1) abnormally increased tension on the leaflets caused by displacement of the papillary muscles, or mitral annular dilatation, which restricts leaflet motion toward closure, and (2) decreased global LV systolic function, which decreases the transmitral pressure that closes the mitral leaflets. 21 Yiuetal 7 reported that the degree of mitral valve tenting directly determines the effective orifice area of functional MR. Tenting is characterized by insufficient systolic leaflet body displacement toward the mitral annulus, with coaptation limited to the leaflet tips, 3 which results in MR. Alterations of the mitral annulus have an adjunct role. Considerable annular dilatation would be required to result in inadequate mitral coaptation because the ratio of leaflets to the annular surface area is N2. 3 Our results also showed that the severity of functional MR increased with increasing mitral valve tenting area and that functional MR was more closely related to local rather than to global LV remodeling, as described previously. 7 However, local remodeling is more common in ischemic cardiomyopathy, whereas remodeling is more global in nonischemic DCM. The shape of the mitral annulus is also different in patients with ischemic cardiomyopathy compared with that in patients with DCM. 22,23 In patients with ischemic cardiomyopathy who have more regional remodeling, the mechanism of increased tenting area may be somewhat different from that in patients with nonischemic DCM. The study population in the Acorn trial consisted mostly of patients with more advanced DCM who had severe LV dysfunction; our study included patients with nonischemic cardiomyopathy only. In this population, no significant

6 762.e8 Park et al American Heart Journal April 2009 Table III. Correlation of transmitral Doppler parameters and diastolic dysfunction with echocardiographic parameters (N = 144) LAV index MR severity LVEDV index LVESV index LVEF Variable r P r P r P r P r P E 0.42 b b A E/A 0.63 b b DT 0.35 b Diastolic dysfunction E, Early mitral inflow velocity; A, late mitral inflow velocity; E/A, early to late mitral inflow velocity ratio; DT, deceleration time of E. correlation between the degree of LV dilatation and the severity of MR was found. Role of diastolic dysfunction in functional MR In patients with chronic heart failure, high LV filling pressure is associated with poor prognosis, serious symptoms, and low exercise tolerance. 24,25 Normalization or improvement of LV filling pressure achieved by appropriate unloading treatment may decrease congestive symptoms and improve quality of life. Patients with a decreased LV ejection fraction had an increased risk proportional to the increase in the size of the LA, which was independent of LV ejection fraction, age, or symptomatic status. A main determinant of LA volume is ventricular diastolic function. It has recently been suggested that enlarged LA volume may be the morphophysiologic expression of chronic diastolic dysfunction. 26 In fact, the LA is exposed directly to LV diastolic pressure through the open mitral valve; and it tends to dilate with increasing pressure because of its thin wall structure. Other important determinants of LA volume are the degree of ventricular remodeling, MR, and the presence of atrial fibrillation. Previous studies have also shown a strong relationship between LA volume and diastolic markers in patients with heart failure. 27,28 Our findings indicate that LA volume is strongly related to the degree of diastolic dysfunction and the severity of MR. The increased LA size caused by MR and diastolic dysfunction is associated with mitral annular dilatation, which is related to more severe MR. Once functional MR has developed, it is associated with numerous deleterious hemodynamics; and this may lead to deterioration of patients with congestive heart failure, resulting in a poor outcome (eg, volume overload, worsening diastolic dysfunction, more enlarged LA, and increased pulmonary pressure). Deterioration of diastolic dysfunction and LA enlargement and development of functional MR may affect each other; it is difficult to determine which one may occur first and may have a key role in patients with DCM and severe functional MR. However, our patients had similar degrees of LV dilatation but different LA sizes, depending on whether they had clinically significant MR or no MR. Left atrial size is closely related to the degree of diastolic dysfunction in patients with or without significant MR and even in patients with grade 0 MR. The mitral annular area, which was a main determinant of tenting area, was strongly associated with LA volume. Therefore, we propose that increased LA volume as a result of more advanced diastolic dysfunction may be a one of the major contributors to the development of clinically significant functional MR in patients with DCM because it augments mitral annular dilatation in these patients. Limitations The Acorn trial was a multicenter clinical study, with echocardiography performed at multiple clinical sites. Although a manual of echocardiography was distributed to each clinical center to facilitate standardization of the echocardiographic examination, numerous examiners were involved in the acquisition of the echocardiographic studies. However, all the echocardiographic measurements in this trial were performed in 1 location. Although tissue Doppler imaging has been shown to better predict LV filling pressure, tissue Doppler imaging for the mitral annulus was not available in the Acorn trial; and assessment of diastolic function was based mainly on mitral inflow velocities. Because MR affects measurements of transmitral inflow velocities, independent of the true changes of LV diastolic function, 29,30 mitral inflow diastolic indices are less reliable for prediction of LV filling pressure in the presence of MR and may lead to misinterpretation in patients with MR, resulting frequently in a pseudonormalization pattern. 31 However, we observed good correlation between LA volume and the early to late mitral inflow velocity ratio and deceleration time of early mitral inflow velocity, and between LA volume and the mitral annular area in patients without significant MR; and these relationships can explain the development of functional MR in our patient population. Clinical implications For patients who have DCM, those with at least moderate functional MR and diastolic dysfunction have a less favorable prognosis and lower survival than those

7 American Heart Journal Volume 157, Number 4 Park et al 762.e9 without them. Our findings indicate that LA enlargement caused by advanced diastolic dysfunction, in addition to LV dilatation and systolic dysfunction, has an important role in the development of functional MR. Therefore, our findings highlight the importance of identifying and treating diastolic dysfunction and its hemodynamic sequelae to minimize their contributions to the development of MR and to the worsening of congestive heart failure. Conclusions In the Acorn trial of patients with advanced DCM, 60% had MR of grade 2 or greater. The 2 groups of patients categorized by the severity of MR (grade 0 and +1 or grade 2) had significant differences in LA volume index and mitral annular size but not in LV volume index. Mitral annular size and LA volume index were closely related even in patients without significant MR. These findings suggest that increased LA volume index caused by more advanced diastolic dysfunction may be a one of the major contributors to the development of significant MR by its augmentation of mitral annular dilatation in advanced DCM. References 1. Koelling TM, Aaronson KD, Cody RJ, et al. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144: Junker A, Thayssen P, Nielsen B, et al. The hemodynamic and prognostic significance of echo-doppler proven mitral regurgitation in patients with dilated cardiomyopathy. Cardiology 1993;83: Perloff JK, Roberts WC. The mitral apparatus: functional anatomy of mitral regurgitation. Circulation 1972;46: Tanimoto M, Pai RG. Effect of isolated left atrial enlargement on mitral annular size and valve competence. Am J Cardiol 1996;77: Oki T, Fukuda N, Iuchi A, et al. Possible mechanisms of mitral regurgitation in dilated hearts: a study using transesophageal echocardiography. Clin Cardiol 1996;19: Otsuji Y, Handschumacher MD, Schwammenthal E, et al. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 1997;96: Yiu SF, Enriquez-Sarano M, Tribouilloy C, et al. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;102: Aikawa K, Sheehan FH, Otto CM, et al. The severity of functional mitral regurgitation depends on the shape of the mitral apparatus: a three-dimensional echo analysis. J Heart Valve Dis 2002;11: Appleton CP, Galloway JM, Gonzalez MS, et al. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease: additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22: Rossi A, Golia G, Gasparini G, et al. Left atrial filling volume can be used to reliably estimate the regurgitant volume in mitral regurgitation. J Am Coll Cardiol 1999;33: Sanfilippo AJ, Abascal VM, Sheehan M, et al. Atrial enlargement as a consequence of atrial fibrillation: a prospective echocardiographic study. Circulation 1990;82: Mann DL, Acker MA, Jessup M. Rationale, design and methods for a pivotal randomized clinical trial for the assessment of a cardiac support device in patients with New York Heart Association class III-IV heart failure. J Card Fail 2004;10: D'Cruz IA, Schroff SG, Janicki JS, et al. Differences in the shape of normal, cardiomyopathic, and volume overloaded human left ventricle. J Am Soc Echocardiogr 1989;2: Gardin JM, Adams DB, Douglas PS, et al. Recommendations for a standardized report for adult transthoracic echocardiography: a report from the American Society of Echocardiography's Nomenclature and Standards Committee and Task Force for a Standardized Echocardiography Report. J Am Soc Echocardiogr 2002;15: Vijayaraghavan G, Boltwood CM, Tei C, et al. Simplified echocardiographic measurement of the mitral anulus. Am Heart J 1986;112: Oh JK, Appleton CP, Hatle LK, et al. The noninvasive assessment of left ventricular diastolic function with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 1997;10: Otsuji Y, Kumanohoso T, Yoshifuku S, et al. Isolated annular dilation does not usually cause important functional mitral regurgitation: comparison between patients with lone atrial fibrillation and those with idiopathic or ischemic cardiomyopathy. J Am Coll Cardiol 2002; 39: Godley RW, Wann LS, Rogers EW, et al. Incomplete mitral leaflet closure in patients with papillary muscle dysfunction. Circulation 1981;63: Sabbah HN, Kono T, Rosman H, et al. Left ventricular shape: a factor in the etiology of functional mitral regurgitation in heart failure. Am Heart J 1992;123: Kono T, Sabbah HN, Rosman H, et al. Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure. J Am Coll Cardiol 1992;20: Kaul S, Spotnitz WD, Glasheen WP, et al. Mechanism of ischemic mitral regurgitation: an experimental evaluation. Circulation 1991; 84: Nagasaki M, Nishimura S, Ohtaki E, et al. The echocardiographic determinants of functional mitral regurgitation differ in ischemic and non-ischemic cardiomyopathy. Int J Cardiol 2006; 108: Kwan J, Shiota T, Agler DA, et al. Real-time three-dimensional echocardiography study. Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation. Circulation 2003;107: Keogh AM, Baron DW, Hickie JB. Prognostic guides in patients with idiopathic or ischemic dilated cardiomyopathy assessed for cardiac transplantation. Am J Cardiol 1990;65: Franciosa JA, Baker BJ, Seth L. Pulmonary versus systemic hemodynamics in determining exercise capacity of patients with chronic left ventricular failure. Am Heart J 1985;110: Simek CL, Feldman MD, Haber HL, et al. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8: Rossi A, Cicoira M, Zanolla L, et al. Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 2002;40:

8 762.e10 Park et al American Heart Journal April Patel JB, Borgeson DD, Barnes ME, et al. Mitral regurgitation in patients with advanced systolic heart failure. J Card Fail 2004;10: Rossi A, Cicoira M, Golia G, et al. Mitral regurgitation and left ventricular diastolic dysfunction similarly affect mitral and pulmonary vein flow Doppler parameters: the advantage of enddiastolic markers. J Am Soc Echocardiogr 2001;14: Appleton CP, Hatle LK, Popp RL. Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study. J Am Coll Cardiol 1988;12: Fuchs RM, Heuser RR, Yin FC, et al. Limitations of pulmonary wedge V waves in diagnosing mitral regurgitation. Am J Cardiol 1982;49:

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