Background
Left atrial (LA) mechanics in patients with severe mitral regurgitation (MR) remain largely unexplored. The aim of the present evaluation was to assess the effect of severe MR on LA function, its potential relation with conventional surgical indications, and long-term postoperative survival.
Methods
Two-dimensional speckle-tracking strain and volumetric indices of LA reservoir, conduit, and contractile function were assessed in 121 patients with severe MR and 70 controls. Patients were divided according to the presence ( n = 46) or absence ( n = 75) of one or more guidelines-based criteria for mitral surgery (symptoms, left ventricular ejection fraction ≤ 60%, left ventricular end-systolic diameter ≥ 40 mm, atrial fibrillation, or systolic pulmonary arterial pressure >50 mm Hg).
Results
In patients with severe MR compared with controls, significant LA reservoir and contractile dysfunction was observed, which was more pronounced in patients with mitral surgery indication ( P < .05 for all strain and volumetric indices). Of all indices of LA function, LA reservoir strain was an independent predictor (odds ratio, 0.88; 95% confidence interval, 0.82–0.94; P < .001) and had the highest accuracy to identify patients with indications for mitral surgery (area under the receiver operating characteristic curve, 0.8; 95% confidence interval, 0.72–0.87). A total of 117 patients underwent mitral valve surgery. Patients with LA reservoir strain ≤24% showed worse survival at a median of 6.4 years (interquartile range, 4.7–8.7 years) after mitral surgery ( P = .02), regardless the symptomatic status before surgery. LA reservoir strain, on top of mitral surgery indications, provided incremental predictive value for postoperative survival.
Conclusions
Impaired LA reservoir strain in patients with severe organic MR relates to long-term survival after mitral valve surgery, independently of and incremental to current guidelines-based indications for mitral surgery.
Severe chronic mitral regurgitation (MR) causes a significant left atrial (LA) volume overload, leading to LA dilatation as a compensatory mechanism to maintain LA pressure homeostasis and prevent pulmonary congestion. Measures of LA remodeling, such as LA diameter and LA volume index, have been shown to predict outcomes in patients with severe organic MR and are helpful for risk stratification and clinical decision making in these patients. However, chronic MR may induce significant LA ultrastructural changes, potentially affecting LA myocardial contractility and relaxation before LA dilatation occurs. Therefore, assessment of LA function, rather than dimension, might be of significant value to guide therapy in patients with severe MR. However, data on the effect of severe MR on LA function are scarce, and the potential incremental value of LA function assessment to predict timing for surgery is unexplored.
Different LA functions can be evaluated, including reservoir (storage of pulmonary venous inflow during ventricular systole), conduit (passive emptying during early diastole), and contractile (active emptying at late diastole) function. These sequential LA functions play a crucial role in cardiac performance by optimizing left ventricular (LV) filling and can be measured using conventional two-dimensional (2D) echocardiography by detecting the phasic changes of LA volume during the cardiac cycle. More recently, 2D speckle-tracking longitudinal deformation (strain and strain rate) imaging has also showed accurate characterization of all phases of LA function.
Therefore, the aims of this study were (1) to characterize LA reservoir, conduit, and contractile function using 2D speckle-tracking deformation imaging in patients with chronic severe organic MR; (2) to determine its clinical relation to the presence of guidelines-based conventional indications for mitral surgery; and (3) to explore its association with long-term survival after mitral valve surgery.
Methods
Patient Population
The patient population consisted of patients presenting with chronic severe organic MR, who were referred to our center within the past decade. Clinical and echocardiographic data were prospectively collected in the department’s cardiology information system (EPD-Vision; Leiden University Medical Center, Leiden, The Netherlands) and retrospectively analyzed.
Clinical assessment included demographics, medications, identification of comorbidities, and symptoms according to the New York Heart Association functional class. Echocardiographic evaluation included conventional measurements and speckle-tracking analysis for LA deformation analysis. Patients with prior cardiac surgery or myocardial infarction, congenital heart disease, concomitant mitral stenosis exceeding mild severity (mean gradient ≥5 mm Hg), or significant aortic valve disease were excluded. In addition, to avoid confounders for increased pulmonary pressure, patients with significant pulmonary disease were excluded.
Patients were further dichotomized on the basis of the presence of one or more conventional criteria for mitral surgery indication, according to current guidelines: New York Heart Association class III or IV symptoms, LV ejection fraction (LVEF) ≤ 60%, LV end-systolic diameter ≥ 40 mm, atrial fibrillation, or systolic pulmonary arterial pressure at rest >50 mm Hg. Accordingly, phasic LA functions were evaluated in both patient groups.
In addition, 70 individuals with similar ages, body surface areas, and gender distribution served as a control group. These subjects underwent clinically indicated echocardiography for the evaluation of potential cardiac symptoms, murmurs, or increased cardiovascular risk profiles, but all showed absence of significant structural or functional abnormalities.
A total of 117 patients (97%) underwent mitral valve surgery a mean of 85 ± 19 days after the baseline echocardiographic examination. This practice is in line with current guidelines advocating that early mitral valve surgery may be performed at experienced valve centers with high repair rates for patients presenting with severe organic MR, despite an absence of symptoms or LV dysfunction. All-cause mortality was assessed in all operated patients by reviewing patients’ medical files and by evaluation of the official Dutch National Survival Registry for patients who were followed by the referring center postoperatively.
Echocardiography
Transthoracic 2D echocardiography was performed in the left lateral decubitus position using commercially available ultrasound systems (Vivid-5, Vivid-7, and E9; GE Vingmed Milwaukee, WI) equipped with a 3.5-MHz transducer. Electrocardiographically triggered standard 2D grayscale and color Doppler images were acquired in cine-loop format and transferred to a workstation for offline analysis (EchoPAC 110.0.0; GE Medical Systems, Horten, Norway). Chamber quantification was performed conforming to current recommendations. LA anteroposterior linear diameter was measured in the 2D left parasternal long-axis view. LV and LA volumes were assessed using Simpson’s biplane method and were indexed to body surface area. LVEF was calculated from LV volumes as recommended. In accordance with recent guidelines, a multiparametric integrative approach was used to assess MR severity (additional transesophageal images were used when available). In particular, an effective regurgitant orifice area ≥40 mm 2 or regurgitant volume ≥60 mL, using the proximal isovelocity surface area method, as well as the presence of flail mitral leaflet or ruptured papillary muscle defined severe MR. If none of these factors were present or the proximal isovelocity surface area method was not feasible (because of eccentricity of regurgitant jet), presence of vena contracta width ≥7 mm in combination with one or more qualitative (large central jet, severe coanda effect, large flow convergence radius, dense mitral envelope on continuous-wave Doppler) and/or semiquantitative (pulmonary Doppler systolic venous flow reversal, E-wave dominance ≥1.5 m/sec) variable(s) defined severe MR. MR etiology was categorized as flail (free mitral leaflet edge reversing into the left atrium), prolapse (mitral leaflet coaptation line behind annular plane without edge reversing into the left atrium), or degenerative (degenerative mitral valve abnormalities without flail or prolapse). All Doppler measurements represented the average of three beats (five beats if atrial fibrillation was present). Mitral inflow was analyzed to assess early flow (E wave), deceleration time, and mitral valve pressure gradient. Early diastolic peak velocity (E′) was derived from the lateral wall on the apical four-chamber view color tissue Doppler acquisition. Systolic pulmonary arterial pressure at rest was calculated using the maximal tricuspid regurgitant jet velocity and right atrial pressure estimation, on the basis of diameter and respiratory variation of the inferior caval vein.
LA Function: Volumetric Indices
LA volumes were assessed just before mitral valve opening (maximal LA volume [Vol max ]), at mitral valve closure (minimal LA volume [Vol min ]), and at P-wave onset on electrocardiography just before atrial contraction, if in sinus rhythm (pre-A LA volume [Vol P ]). As previously reported, LA reservoir function was calculated as LA expansion index (Vol max − Vol min /Vol min × 100), LA conduit function as LA passive emptying fraction (Vol max − Vol P /Vol max × 100), and LA contractile function as LA active emptying fraction (Vol P − Vol min /Vol P × 100). In patients with atrial fibrillation, LA contractile function could not be calculated.
LA Function: Deformation Indices
LA longitudinal strain and strain rate was assessed using 2D speckle-tracking analysis with QRS onset as the reference point, applying a commercially available LV strain software package to the left atrium (EchoPAC version 110.0.0). In summary, the region of interest was adjusted to include the LA myocardium in both the four-chamber and two-chamber apical views that included both the left atrium and left ventricle. Manual correction was performed to optimize tracking results if needed. The values of LA strain and strain rate were calculated as the average value of the four-chamber and two-chamber views, as described in Figure 1 . As previously reported, LA reservoir function was calculated as peak systolic LA strain (LA reservoir strain), while LA contractile function was measured as the LA strain value at P-wave onset on electrocardiography, if in sinus rhythm (LA contractile strain). Finally, LA conduit function was assessed as the difference between LA reservoir and contractile strain (LA conduit strain). In addition, LA reservoir strain rate was measured as peak systolic positive value, LA conduit strain rate as the early diastolic negative peak, and LA contractile strain rate as the late diastolic negative peak (if in sinus rhythm) ( Figure 1 ). In patients with atrial fibrillation, LA contractile strain (rate) could not be calculated.
Fifteen subjects were randomly selected to perform a blinded interobserver and intraobserver (1 week after the first observation) agreement test for LA strain measurements.
For simplicity, absolute deformation values are reported as positive numbers.
Statistical Analysis
Continuous variables were compared using independent Student’s t tests and Mann-Whitney U or Kruskal-Wallis tests if not normally distributed and are expressed as mean ± SD. Categorical values were compared using χ 2 tests and are expressed as percentages. Multiple-group comparisons were performed using one-way analyses of variance with post hoc Bonferroni correction. Receiver operating characteristic curve analysis was performed to assess the accuracy of various deformation and volumetric indices of LA function to predict the presence of conventional indications for mitral surgery. The optimal cutoff value was obtained by maximizing the sum of sensitivity and specificity. Subsequently, multiple logistic regression analysis identified independent predictors of the presence of mitral surgery indications. Covariates with P values < .05 at the univariate level were included in the multivariate logistic regression analysis, which was performed using a backward elimination approach. In addition, Cox regression analysis including conventional guidelines-based criteria for mitral surgery and LA reservoir strain was performed to identify the independent determinants of long-term mortality after mitral surgery. To maximize the possibility to detect any relationship of this clinical model with postoperative mortality, covariates with univariate significance of P < .10 were included in the multivariate analysis. Kaplan-Meier curves were constructed to explore differences in long-term survival after mitral valve surgery in different patient subgroups stratified according to LA reservoir strain, using the previously mentioned receiver operating characteristic curve–based cutoff value and compared using the log-rank test. The incremental value of successive conventional guidelines-based criteria for mitral surgery and LA reservoir strain to predict postoperative mortality was assessed using the likelihood ratio test: the model containing the covariate of interest was tested against the nested model not containing the covariate. Finally, linear regression analysis was performed to explore the correlation between LA reservoir strain, LA diameter, and LA volume indexed to body surface area (LAVI), respectively. Statistical analysis was performed using SPSS version 17.0. (SPSS, Inc., Chicago, IL) and Stata version 12.1 (StataCorp LP, College Station, TX). All tests were two sided, and P values < .05 were considered statistically significant.
Results
Patient Population
A total of 160 patients with chronic severe organic MR who underwent complete clinical and echocardiographic examinations were included. Thirty-nine patients (24%) with poor acoustic windows were excluded. The mean frame rate for echocardiographic examinations performed within the first half of the past decade did not significantly differ from those performed during the most recent half (56.4 vs 59.4 frames/sec, respectively, P = .31). Clinical and echocardiographic characteristics of the remaining 121 patients (mean age, 63 ± 13 years; 77% men) are summarized in Table 1 . Overall, preserved LV systolic function was observed, with mild LV dilatation and severe LA dilatation. Severe MR was documented, with a mean mitral vena contracta width of 8 ± 0.9 mm, mean E wave of 1.3 ± 0.2 m/sec, and mean proximal isovelocity surface area radius of 11 ± 2 mm. Forty-six patients did not meet any conventional criteria for mitral surgery, whereas 75 patients met one or more criteria. In particular, symptoms were present in 34 patients (28%), LVEF ≤ 60% in 19 (16%), LV end-systolic diameter ≥ 40 mm in 27 (22%), atrial fibrillation in 26 (21%), and systolic pulmonary arterial pressure at rest >50 mm Hg in 29 (24%). Of note, no patients presented with LVEFs ≤ 30%. By definition, the presence of atrial fibrillation, New York Heart Association class III or IV symptoms, LV end-systolic diameter, LVEF, and pulmonary arterial pressure significantly differed between patients with conventional criteria for mitral surgery and those without ( Table 1 ). In addition, age, use of β-blockers, use of diuretics, LAVI, MR vena contracta width, E wave, and deceleration time were significantly different between the groups ( P < .05 for all).
| Variable | Controls ( n = 70) | All patients ( n = 121) | No surgical indication ( n = 46) | Surgical indication ( n = 75) | P ∗ |
|---|---|---|---|---|---|
| Clinical characteristics | |||||
| Age (y) | 63 ± 12 | 63 ± 13 | 59 ± 14 | 66 ± 11 | .008 |
| Men | 47 (67%) | 77 (64%) | 32 (70%) | 45 (60%) | .30 |
| BSA (kg/m 2 ) | 1.9 ± 0.21 | 1.9 ± 0.20 | 1.9 ± 0.21 | 1.9 ± 0.20 | .80 |
| AF | 0 (0%) | 26 (21%) | 0 (0%) | 26 (35%) | <.001 |
| NYHA class | <.001 | ||||
| I | 70 (100%) | 38 (32%) | 20 (43%) | 18 (24%) | |
| II | 0 (0%) | 49 (40%) | 26 (57%) | 23 (31%) | |
| III | 0 (0%) | 30 (25%) | 0 (0%) | 30 (40%) | |
| IV | 0 (0%) | 4 (3%) | 0 (0%) | 4 (5%) | |
| Hypertension | 31 (45%) | 11 (10%) | 4 (10%) | 7 (11%) | 1.00 |
| Hypercholesterolemia | 20 (29%) | 11 (10%) | 4 (10%) | 7 (11%) | 1.00 |
| Diabetes | 9 (13%) | 4 (3%) | 0 (0%) | 4 (5%) | .30 |
| Smoking history | 25 (43%) | 21 (21%) | 7 (18%) | 14 (23%) | .20 |
| Medication use | |||||
| β-blockers | 8 (12%) | 41 (34%) | 8 (17%) | 33 (44%) | .003 |
| Diuretics | 9 (13%) | 36 (30%) | 7 (15%) | 29 (39%) | .006 |
| ACE inhibitors/ARBs | 22 (32%) | 54 (45%) | 17 (37%) | 37 (49%) | .20 |
| Statins | 21 (31%) | 20 (17%) | 5 (11%) | 15 (20%) | .20 |
| MR etiology | .13 | ||||
| Degenerative | — | 7 (6%) | 1 (2%) | 6 (8%) | |
| Flail | — | 40 (33%) | 12 (26%) | 28 (37%) | |
| Prolapse | — | 74 (61%) | 33 (72%) | 41 (55%) | |
| Echocardiographic data | |||||
| LVESD (mm) | 25.2 ± 4.1 | 34.8 ± 6.4 | 31.9 ± 4.5 | 36.6 ± 6.7 | <.001 |
| LVEDVI (mL/m 2 ) | 55 ± 11 | 85 ± 21 | 84 ± 18 | 87 ± 23 | .70 |
| LVESVI (mL/m 2 ) | 20 ± 6 | 28 ± 11 | 25 ± 7 | 30 ± 13 | .20 |
| LVEF (%) | 64 ± 6 | 68 ± 8 | 70 ± 5 | 66 ± 9 | .047 |
| LA diameter (mm) | 35 ± 4 | 49 ± 8 | 46 ± 6 | 50 ± 8 | .001 |
| LAVI (mL/m 2 ) | 31 ± 8 | 76 ± 33 | 64 ± 23 | 83 ± 36 | .002 |
| Vena contracta (mm) | 1.7 ± 1.25 | 8.0 ± 0.92 | 7.6 ± 0.81 | 8.2 ± 0.91 | <.001 |
| E wave (m/sec) | 0.6 ± 0.2 | 1.3 ± 0.2 | 1.2 ± 0.2 | 1.4 ± 0.2 | <.001 |
| E′ | 7.3 ± 2.0 | 8.5 ± 2.1 | 8.5 ± 1.6 | 8.6 ± 2.4 | .9 |
| DT (msec) | 218 ± 49 | 180 ± 43 | 189 ± 34 | 174 ± 47 | .01 |
| Systolic PAP at rest (mm Hg) | 26 ± 5 | 43 ± 16 | 32 ± 8 | 49 ± 17 | <.001 |
∗ For comparison between patient groups with and without mitral surgery indication.
LA Function in Severe MR
Patients with severe organic MR showed significantly impaired LA reservoir function compared with control subjects, assessed both by volumetric expansion index or strain and strain rate ( P < .001 for all), as indicated in Table 2 . LA conduit function assessed with volumetric passive emptying fraction ( P = .20) or LA strain rate ( P = .57) did not differ significantly between patients with severe organic MR and controls, whereas LA conduit strain was significantly impaired in patients with severe organic MR ( P = .01). In 95 patients (79%) who were in sinus rhythm during echocardiography, LA contractile function was reduced when measured by volumetric active emptying function, LA strain, and strain rate ( P < .001 for all).
| LA function variable | Controls ( n = 70) | All patients ( n = 121) | No surgical indication ( n = 46) | Surgical indication ( n = 75) | P ∗ |
|---|---|---|---|---|---|
| Reservoir function | |||||
| Strain (%) † | 31 ± 6.1 | 22 ± 8.4 † | 27 ± 6.6 † | 19 ± 7.7 † | <.001 |
| Strain rate (sec −1 ) | 1.25 ± 0.28 | 0.95 ± 0.32 † | 1.12 ± 0.27 | 0.85 ± 0.31 † | <.001 |
| Expansion index (%) † | 191 ± 61 | 111 ± 64 † | 150 ± 70 † | 87 ± 46 † | <.001 |
| Conduit function | |||||
| Strain (%) † | 17 ± 5.1 | 15 ± 5.0 † | 17 ± 4.7 | 13 ± 4.7 † | <.001 |
| Strain rate (sec −1 ) | 1.08 ± 0.38 | 1.0 ± 0.32 | 1.14 ± 0.34 | 0.98 ± 0.32 † | .04 |
| Passive emptying fraction (%) † | 35 ± 9.9 | 34 ± 9.6 | 37 ± 9.9 | 33 ± 9.1 † | <.001 |
| Contractile function ‡ | |||||
| Strain (%) † | 14 ± 3.0 | 9.2 ± 3.5 † | 10 ± 3.5 † | 8 ± 3.4 † | .03 |
| Strain rate (sec −1 ) | 1.65 ± 0.55 | 1.04 ± 0.39 † | 1.15 ± 0.4 † | 0.94 ± 0.35 † | .06 |
| Active emptying fraction (%) † | 44 ± 9.4 | 28 ± 11 † | 32 ± 12 † | 24 ± 10 † | .001 |
∗ For comparison between patient groups without and with mitral surgery indication.
† P < .05 for comparison with controls.
LA Function to Predict Surgical Indication
As summarized in Table 2 , LA dysfunction was more pronounced in patients with mitral surgery indications versus patients without, and all phases of LA function (reservoir, conduit, and contractile) were affected, assessed by either volumetric or deformation parameters. Patients without mitral surgery indications showed impairment of LA reservoir and contractile function but preserved conduit function.
Subsequently, receiver operating characteristic curve analysis was performed to determine the value of all different deformation and volumetric indices of phasic LA function to predict the presence of guidelines-based mitral surgery indications ( Table 3 ). This analysis showed that LA reservoir strain had the highest predictive value among all indices of LA function, evidenced by an area under the curve of 0.80 (95% confidence interval [CI], 0.72–0.87; Figure 2 A). In particular, a value of LA reservoir strain ≤24% predicted the presence of mitral surgery indications with sensitivity and specificity of 76% and 72%, respectively ( Figure 2 B).
