Published online before print February 5, 2007, doi: 10.1161/CIRCULATIONAHA.106.649236
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(Circulation. 2007;115:782-791.)
© 2007 American Heart Association, Inc.
Valvular Heart Disease |
Preoperative Posterior Leaflet Angle Accurately Predicts Outcome After Restrictive Mitral Valve Annuloplasty for Ischemic Mitral Regurgitation
From the Quebec Heart Institute, Faculty of Medicine, Laval University, Quebec, Canada.
Correspondence to Dr Mario Sénéchal, Quebec Heart Institute, Department of Cardiology, 2725 Chemin Sainte-Foy, Quebec, Quebec, Canada, G1V 4G5. E-mail mario.senechal{at}crhl.ulaval.ca
Received July 5, 2006; accepted December 11, 2006.
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Abstract |
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Background— Ischemic mitral regurgitation (MR) often persists after restrictive mitral valve annuloplasty, in which case it is associated with worse clinical outcomes. The goal of the present study was to determine whether persistence of MR and/or clinical outcome could be predicted from preoperative analysis of mitral valve configuration.
Methods and Results— In 51 consecutive patients undergoing restrictive annuloplasty for ischemic MR, posterior leaflet (PL) angle, anterior leaflet angle, coaptation distance, and tenting area were quantified by echocardiography before surgery (6±3 days), and MR severity was assessed before and early after surgery (9±4 days). Postoperatively, persistence of mild to moderate MR (vena contracta >3 mm) was observed in 11 (22%) of the patients. The best predictor of postoperative persistence of MR was a PL angle 
45 degrees (sensitivity 100%, specificity 97%, positive predictive value 92%, negative predictive value 100%). Patients with persistent MR had markedly lower 3-year event-free survival (26±20%) compared with those with nonpersistent MR (75±12%, P=0.01). Preoperative presence of a PL angle 45 degrees also was associated with a markedly lower 3-year event-free survival (22±17% versus 76±12%; P<0.001).
Conclusions— In patients undergoing restrictive annuloplasty for ischemic MR, persistence of MR and 3-year event-free survival can accurately be predicted by preoperative analysis of mitral valve configuration. Patients with a PL angle 45 degrees (ie, with high PL restriction) should thus be considered poor candidates for this procedure, and concomitant or alternative procedures should be contemplated.
Key Words: mitral valve • echocardiography • ischemia • regurgitation
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Introduction |
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Ischemic mitral regurgitation (MR) is a serious complication of coronary artery disease and is associated with poor outcomes.1,2 The basic mechanism of ischemic MR is remodeling of the ischemic left ventricle (LV), leading to displacement of the papillary muscles, annular dilatation, and leaflet tethering. These modifications of the LV and mitral valve geometry prevent normal leaflet coaptation.3 Restrictive mitral valve annuloplasty (MVA) combined with coronary artery bypass graft (CABG) is the conventional approach for the surgical management of patients with ischemic MR.4 Recent studies have failed to demonstrate a significant impact of this procedure on long-term survival, however.5–7 This finding may be attributable, at least in part, to the persistence or recurrence of MR in these patients. Indeed, previous studies have demonstrated that MR often persists or recurs after MVA8–10 and can adversely affect a patient’s outcome.11 In a recent study by Zhu et al,10 persistent MR was present in 19% of patients early after operation. The persistence of MR after MVA could be explained by the postoperative persistence of tethering of both leaflets and/or by worsening of posterior leaflet (PL) tethering that is potentially caused by ring prosthesis implantation, which may anteriorly displace the PL and reduce its mobility.10,12–14 McGee et al9 report that 28% of patients have 3+ or 4+ MR and that 25% have 2+ MR 6 months after MVA. Among these patients with
2+ MR at 6 months, approximately 40% already had significant persistent MR early after operation.
Clinical Perspective p 791
The objective of the present study was to determine whether the preoperative echocardiographic indices of mitral valve configuration could be used to accurately predict the persistence of MR and outcomes after MVA in patients with ischemic MR.
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Methods |
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Study Population
The echocardiograms of 70 consecutive patients with ischemic MR who underwent surgery for restrictive MVA with or without CABG at the Quebec Heart Institute between January 2002 and December 2005 were analyzed for the present study. Patients were excluded from the study if they had concomitant organic mitral valve lesions, significant aortic regurgitation, or significant aortic stenosis. The final study group was composed of 51 patients (42 men, 9 women; mean age, 65±8 years). Moreover, 20 healthy subjects with no history of cardiovascular disease and with normal Doppler echocardiographic examination were recruited for the control group. These control subjects had a gender distribution and average body size similar to those of the patients with ischemic MR.
Surgical Technique
The mitral valve was assessed intraoperatively through a standard left atriotomy. A complete ring annuloplasty was performed in the majority (88%) of patients using a Physio ring (Edwards Lifescience, Irvine, Calif). Ring size was selected by downsizing the measured intertrigonal length by 2 sizes.15 Intraoperatively, the MVA was evaluated by transesophageal echocardiography. In presence of MR >1+, either a smaller-size annuloplasty or a mitral valve replacement was performed. In these cases, the patients were excluded from the retrospective series. Moreover, every vessel that could be grafted was grafted.
Echocardiographic Measurements
Two-dimensional and Doppler transthoracic echocardiography examinations with commercially available echocardiographic systems (Sonos 5500 or 7500, Philips Medical Systems, Amsterdam, the Netherlands) were performed 6±3 days (range, 1 to 19 days) before surgery and 9±4 days (range, 1 to 15 days) after surgery at the time of predischarge examination.
LV Geometry and Function
The LV end-diastolic and end-systolic diameters were measured using M-mode in the parasternal long-axis view. LV end-diastolic and end-systolic volumes and LV ejection fraction were determined by the modified biplane Simpson method. To assess the LV shape, LV end-diastolic and end-systolic sphericity indices were calculated by dividing the LV short-axis dimension by the LV long-axis dimension in the 4-chamber view. The LV outflow tract stroke volume was calculated by multiplying the LV outflow tract area by the LV outflow tract velocity–time integral measured by pulsed-wave Doppler. The closing forces index was evaluated by multiplying the systolic blood pressure by the mitral annulus area.
Mitral Valve Configuration and Left Atrial Geometry
Mitral valve configuration was assessed in midsystole using the parasternal long-axis and 4-chamber views (Figure 1). The mitral valve tenting area was measured as the area enclosed between the annular line and mitral valve leaflets. The coaptation distance was defined as the distance between the annular line and the leaflet’s coaptation point. The PL angle and the anterior leaflet angle were calculated according to the following formulas: equation
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where PLA is the PL angle, CD is the coaptation distance, and PLL is the PL length (ie, the distance between the posterior annulus and the PL tip). In the second formula, ALA is the anterior leaflet angle, BD is the bending distance (ie, the distance between the anterior leaflet bending and annular line), and ALBD is the anterior leaflet bending distance (ie, the distance between anterior annulus and anterior leaflet bending point).
Left atrial (LA) geometry was assessed by LA diameter measured in the parasternal long-axis view using M-mode and LA area measured in 4-chamber view with the use of 2-dimensional planimetry.
MR Assessment
MR was assessed quantitatively using the width of the vena contracta of the regurgitant jet and the ratio of the MR color flow jet area to the LA area. Vena contracta was defined as the narrowest portion of the color jet that occurs at or just downstream from the regurgitant orifice. Vena contracta width was measured in the parasternal long-axis view. The largest diameter during systole was measured in at least 3 cardiac cycles and was then averaged.
Postoperative Outcome
Postoperative cardiac events were defined as rehospitalization for congestive heart failure, mitral valve replacement or repair, heart transplant, or cardiovascular-related death.
Prospective Series
We prospectively analyzed the preoperative and early postoperative echocardiograms (5±2 days after surgery) of 21 consecutive patients with ischemic MR between January 2006 and October 2006. These patients were referred for CABG and MR correction. Among these 21 patients, 4 were excluded because of the presence of concomitant organic lesions. The final prospective subset was composed of 17 patients (11 men, 6 women; 64±8 years).
Statistical Analysis
Interobserver and intraobserver variability for measurement of vena contracta width and mitral valve configuration parameters was determined from the analysis of the Doppler echocardiographic images of 14 randomly selected patients by 2 independent observers. The results were compared with a 1-way analysis of variance, Pearson correlation coefficient, and Bland-Altman method.
The patients were separated into 2 groups depending on the presence or absence of mild to moderate MR after MVA, defined as an early postoperative vena contracta >3 mm.10 These patients with persistence or early recurrence of significant MR were classified as the persistent MR group. Residual MR with a vena contracta width 
3 mm was considered not clinically significant and was classified as nonpersistent MR. Results are expressed as mean±SD or as percentages unless otherwise specified. Before analysis, normality distribution was tested using the Kolmogorov-Smirnov test. Preoperative and operative data of the patients with persistent MR versus those with no persistent MR were compared for statistical significance using a t test, Mann-Whitney rank-sum test, 
2 test, or Fisher exact test as appropriate. Preoperative Doppler echocardiographic indices of mitral valve configuration were compared among the persistent MR, nonpersistent MR, and control groups, using a 1-way analysis of variance and then a Tukey test. The preoperative and postoperative Doppler echocardiographic data were analyzed using a 2-way analysis of variance for repeated measures to assess the effects of time (postoperative versus preoperative examination) and group (nonpersistent MR and persistent MR). The data of the persistent and nonpersistent MR groups were compared with those of the control group, using a 1-way analysis of variance. This test was applied to the preoperative data as well as the postoperative data.
Sensitivity, specificity, positive predictive value, and negative predictive value for prediction of persistent MR were determined for various cutoff values of the echocardiographic parameters using receiver-operating characteristic curves. Forward and backward multiple stepwise regression analyses were performed to identify preoperative and operative independent predictors of persistent MR. For this multivariate analysis, we used the postoperative vena contracta width as the output variable of the model. The variables tested in this analysis were age, gender, LV ejection fraction, LV end-systolic diameter, tenting area, coaptation distance, anterior leaflet angle, PL angle, mitral annulus diameter, preoperative vena contracta width, and prosthesis ring size.
Probabilities of event-free survival were obtained by Kaplan-Meier estimates for the persistent and nonpersistent groups and for the levels of preoperative echocardiographic parameters. The effect of the preoperative and operative variables on event-free survival was assessed with the use of Cox proportional hazard models in univariate and multivariate analysis.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Patient Characteristics
Of the 51 patients, 11 (22%) had persistent MR (vena contracta >3 mm), 10 (20%) had nonclinically significant MR (vena contracta
3 mm), and 30 (58%) had no detectable MR after surgery. There was no significant difference between the nonpersistent MR group (40 patients, 78%) and the persistent MR group (11 patients, 22%) in term of preoperative demographic and clinical data (Table 1). Myocardial infarction site was inferior in 39 patients (76%) and anterior in 12 patients (24%). Distribution of the myocardial infarct site did not differ between the persistent and nonpersistent groups. There was no significant difference between the 2 groups regarding medication. Operative data as well as ring size and type also were similar in both groups (Table 1).
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Reproducibility of Echocardiographic Measurements
There was an excellent correlation (r0.90) between intraobserver measurements and also between interobserver measurements for all preoperative and postoperative echocardiographic parameters. Intraobserver and interobserver relative differences were <5% for all parameters (range for intraobserver, 0.8% to 4.6%; interobserver, 0.7% to 4.8%). The Bland-Altman method showed excellent agreement between interobserver and intraobserver measurement in both low and high values of echocardiographic parameters.
Echocardiographic Measurements
There were significant differences between the control subjects and the ischemic MR patients regarding the Doppler echocardiographic parameters of LV geometry and function, LA geometry, and mitral valve configuration (Tables 2 and 3
). These differences persisted after operation, except for LV end-diastolic volume and sphericity index in the nonpersistent MR group.
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Compared with nonpersistent MR patients, those with persistent MR had higher preoperative and postoperative LV end-diastolic and end-systolic diameters and higher preoperative LA area (Table 2). There was no significant difference between the 2 groups regarding visual estimation of inferior wall motion before and early after operation. Before operation, there was no significant difference with respect to vena contracta width, vena contracta width indexed to body surface area, or MR area:LA area ratio. After correction for type I error, however, there was only a significant difference between preoperative and postoperative LV end-diastolic diameter in both groups and between preoperative and postoperative LV end-diastolic volume in the nonpersistent MR group. Patients in the persistent MR group had significantly higher preoperative mitral annulus diameter, coaptation distance, tenting area, anterior leaflet angle, and PL angle compared with the nonpersistent MR group (Table 3). There was no difference between the 2 groups regarding preoperative mitral annulus diameter after correction for type I error.
Patients (n=12) with prior anterior myocardial infarction had similar severity of MR, LV and LA dimensions, LV function, and mitral configuration parameters compared with those (n=39) with prior inferior myocardial infarction.
Determinants of Persistent MR
In a group including all patients with detectable MR after operation, vena contracta width correlated well with preoperative coaptation distance (r=0.66, P=0.01), tenting area (r=0.60, P=0.001), anterior leaflet angle (r=0.66, P=0.01), and PL angle (r=0.87, P<0.001) in the 4-chamber view (Figure 2). In the persistent MR group, only PL angle (r=0.89, P<0.001), LV end-diastolic diameter (r=0.75, P=0.01), and LV end-systolic (r=0.63, P=0.04) diameter showed good correlations with postoperative vena contracta width.
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nonpersistent MR group; • persistent MR group.In receiver-operating characteristic curve analysis, the preoperative parameters that were the most accurate in predicting a postoperative vena contracta width >3 mm were PL angle, coaptation distance, and tenting area (area under the curve=0.98, 0.87, and 0.90, respectively). LV end-diastolic and end-systolic diameters were less accurate for the prediction of persistent MR (area under the curve=0.74 for both parameters).
The preoperative presence of a PL angle 45 degrees had the best performance for the prediction of persistent MR: sensitivity, 100%; specificity, 95%; positive predictive value, 85%; negative predictive value, 100% (Figure 3). Tenting area 2.5 cm2 and coaptation distance 1 cm also had a high specificity (90%), but their sensitivity was lower (64% for both parameters). Among the 8 (16%) patients with a PL angle 45 degrees, a tenting area 2.5 cm2, and a coaptation distance 1 cm, 7 had persistent MR at hospital discharge, whereas among the 36 (71%) patients with a PL angle <45 degrees, a tenting area <2.5 cm2, and a coaptation distance <1 cm, none had persistent MR.
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Among the preoperative and operative factors, PL angle (
r2=0.47, P<0.001), coaptation distance (r2=0.08, P=0.003), and prosthesis ring size (r2=0.05, P=0.02) were independently associated with larger postoperative vena contracta width on multivariate analysis.
Postoperative Outcome
Patients with persistent MR had markedly lower 3-year cardiac event-free survival compared with those with nonpersistent MR (26±20% versus 75±12%; P=0.01). Patients with PL angle 45 degrees also had significantly lower 3-year event-free survival (22±17% versus 76±12%; P<0.001; Figure 4). The outcomes for patients with PL angle 45 degrees are presented in Table 4. A PL angle 45 degrees was associated with a 2.5-fold increase in the risk of cardiac event (hazard ratio, 2.5; 95% CI, 1.4 to 4.9; P=0.002). Moreover, after adjusting for age, gender, LV ejection fraction, LV end systolic diameter, and prosthesis ring size, PL angle 45 degrees was associated with a 2.4-fold increase in the risk of cardiac events (95% CI, 1.3 to 5.0; P=0.009).
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Echocardiographic Data and Postoperative Outcome in the Prospective Series
Of the 17 patients studied prospectively, 14 had a preoperative PL angle <45 degrees and underwent MVA and CABG. None of these patients had persistent MR after operation. The 6-month event-free survival in these patients was 94%, which is similar to that observed in the retrospective series. Three (18%) patients had preoperative PL angle 45 degrees. One of these patients underwent MVA and CABG and had persistent MR (vena contracta width=0.41) at predischarge examination (Table 4). Although the 2 other patients with excessive PL tethering were initially scheduled for MVA, the surgeon decided, on the basis of PL angle, to do a crossover to mitral valve replacement. In light of the compelling results of our present retrospective study, some surgeons of our institution started to modify their practice and now consider mitral valve replacement as an alternative option to annuloplasty when there is evidence of excessive PL tethering at the preoperative examination. Our 2 patients who underwent valve replacement had no persistent MR after operation. As opposed to the vast majority of patients with a PL angle 45 degrees who underwent MVA, these patients had no adverse events during follow-up.
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Discussion |
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To our knowledge, the present study provides the first demonstration that adverse outcomes after MVA can largely be predicted from the configuration of the mitral valve on the preoperative echocardiogram assessment. Indeed, the preoperative PL angle had a very high sensitivity and specificity to predict persistent MR early after operation. This parameter also was very powerful in predicting longer-term outcomes. Hence, 12 of the 13 patients with this finding developed
3/4 MR and, correspondingly, had New York Heart Association functional class III/IV (Table 4). Three-year event-free survival in these patients also was much lower than in the rest of the cohort (22±17% versus 76±12%, P<0.001). In contrast, perioperative assessment of MR severity by transesophageal echocardiography immediately after the realization of MVA was not helpful in predicting the persistence of MR and/or outcome after operation. These results are consistent with previous studies showing that perioperative transesophageal echocardiography generally underestimates ischemic MR severity and has a relatively low performance to predict early or late recurrence of MR after surgery.16
Mechanism of Persistent Ischemic MR
The results of the present study are in accordance with both fundamental and clinical studies that have examined the potential mechanism(s) of ischemic MR and its persistence after restrictive MVA. Green et al12 have shown, in an ovine model, that MVA considerably reduces the mobility of the PL and transforms the mitral valve in a unicuspid valve, where valve closing is performed only by the anterior leaflet. Similarly, Matsunaga et al13 have reported that annuloplasty does not protect against recurrent MR in patients with severe alteration of mitral valve geometry, such as severe displacement of posterior papillary muscle and important systolic apical traction of the leaflet. Zhu et al10 have proposed that the persistence of significant MR after MVA is attributable to persistent tethering of both leaflets with predominant increases in PL tethering. The results of the study by Kuwahara et al17 also suggest that this mechanism may be implicated not only in the persistence of MR immediately after restrictive annuloplasty but also in the recurrence of MR thereafter.
The fact that the PL angle was superior to other indices of valve geometry in predicting outcomes can likely be explained in light of the aforementioned findings as well as those reported by Agricola et al.18 Indeed, these authors describe 2 patterns of valve leaflet tethering that are essentially determined by the type of LV remodeling. Hence, approximately 59% of patients in their study had asymmetric tethering attributable to local LV remodeling, and these patients were characterized by increased restriction of PL, whereas 41% of patients had symmetric tethering of both leaflets associated with global LV remodeling. Interestingly, the common denominator of these 2 patterns is the presence of PL restriction with anterior leaflet restriction (symmetric tethering) or without anterior leaflet restriction (asymmetric tethering) (Figure 5). Likewise, in the present study, excessive LV dilatation was observed in 8 of the 11 patients with persistent MR; in addition to a PL angle 45 degrees, these patients also had concomitant tenting area 2.5 cm2 and coaptation distance 1.0 cm (Figure 3), consistent with a pattern of symmetric tethering and also consistent with the study of Calafiore et al19 showing that a coaptation distance 1.1 cm is associated with a high risk of MR recurrence after MVA. Nonetheless, the 3 patients who had persistent MR without LV dilatation presented only PL restriction, without concomitant high tenting area or increased coaptation distance consistent with an asymmetric pattern of tethering. Hence, our results suggest that, in the presence of important PL restriction, restrictive annuloplasty may worsen the PL tethering and lead to persistent MR, regardless of the type of LV remodeling and/or leaflet tethering pattern (Figure 5), and the common denominator in all cases is severe tethering of the PL. Nonetheless, anterior leaflet restriction—and, alternatively, as shown in Figure 5, slippage relative to a restricted PL—should not be overlooked in understanding and repairing mitral valve tethering. The consideration of the anterior leaflet angle in combination with the other indices of mitral valve morphology may be useful to guide the operative strategy, especially in patients with global LV remodeling and symmetric tethering.
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Reduced closing forces after annuloplasty also have been proposed to potentially explain persistent MR.20 The results of our present study do not, however, support this hypothesis. Indeed, we observed no significant difference between the persistent and nonpersistent MR groups regarding preoperative or postoperative closing forces index. Also, this parameter did not correlate with postoperative MR severity. We found that a larger mitral prosthesis ring was an independent risk factor for worse postoperative MR severity, but this factor accounted for only 5% of the variance of MR severity (r2=0.05, P=0.02) compared with 55% for the parameters of preoperative mitral valve configuration (r2=0.47, P<0.001 for PL angle; r2=0.08, P=0.003 for coaptation distance).
Clinical Implications
The prevalence of persistent MR observed in the present study (22%) is quite high and is consistent with that reported by Zhu et al10 (19% of mild to moderate MR). More recently, Serri et al11 have reported a prevalence of 11% of persistent MR. The lower prevalence found by these investigators may be attributable to the fact that they used a semiquantitative visual estimation method to assess MR severity (whereas we used a quantitative method [ie, vena contracta width]) or to a difference in the baseline characteristics of patients.
Moreover, persistent MR, even if mild to moderate at the outset, was associated with much worse clinical outcomes (Table 4). This finding is also consistent with recent studies.9,11 A probable explanation for the poorer outcomes is that persistent MR, even if mild, likely contributes to further deterioration of LV geometry, thus entailing more severe MR and creating a vicious circle, whereby more severe MR begets worse geometry, and vice versa.14
The clinical implications of the present study are important because they suggest that the patients with the worst outcomes after MVA for ischemic MR can prospectively be identified on the basis of preoperative echocardiograms. Hence, our results show that the procedure is most likely to fail in patients with a PL angle 45 degrees; in such patients, concomitant or alternative procedures should be contemplated. In this regard, there are presently many research efforts to find procedures that can improve LV geometry and, thus, enable the treatment of ischemic MR on the basis of its causal mechanism.21–24 Meanwhile, a better case scenario in patients with a PL angle 45 degrees would probably be mitral valve replacement with chordal sparing. In this respect, the patients with PL angle 45 degrees who underwent mitral valve replacement in our prospective series had no events and returned in functional New York Heart Association class II during follow-up (Table 4). On the other hand, a more restrictive annuloplasty with downsizing of more than 2 sizes in these patients would likely have worsened PL angulation and been unable to restore adequate leaflet coaptation (Figure 5).
Limitations
The main limitation of the present study is its retrospective design. It is possible that unidentified factors might have influenced the results. Nonetheless, our results show that the persistence of MR could have been predicted before operation in the vast majority of patients from the echocardiographic assessment of mitral valve configuration.
Another limitation is that MR severity was quantitatively evaluated only with the use of vena contracta width and not by proximal isovelocity surface area or volumetric methods. A previous study, however, had demonstrated that vena contracta width is a simple, accurate method to assess regurgitation severity.25 In this regard, Lesniak-Sobelga et al26 have shown excellent correlations between vena contracta width and effective regurgitant orifice area (r=0.85), regurgitant volume (r=0.85), regurgitant fraction (r=0.84), and angiographic grade (r=0.85). Moreover, the fact that the persistence of MR defined on the basis of vena contracta width was associated with markedly worse clinical outcomes further corroborates the validity of this method for the assessment of MR severity.
Clinical experience shows that reliance on a single quantitative echocardiographic parameter often entails potential pitfalls and limitations. Hence, we caution that measurement of PL angle requires good-quality tracings and may be subject to a certain learning curve. The consideration of other indices such as coaptation distance, tenting area, and anterior leaflet angle may be useful to obtain a more comprehensive evaluation of mitral valve morphology. Moreover, 3-dimensional echocardiography could contribute to improve the feasibility and accuracy of the measurement of these indices and, particularly, of PL angle.
Conclusion
The results of the present study show that the postoperative persistence of MR can be predicted from the preoperative analysis of the mitral valve configuration by transthoracic echocardiography. Patients with a preoperative PL angle 45 degrees are at very high risk for MR persistence and worse outcomes when treated by restrictive annuloplasty and CABG. In these patients, alternative or concomitant procedures should be considered. Procedures aimed at restoring ventricular geometry seem promising, but they require further investigation. In the meantime, mitral valve replacement with chordal sparing may be the preferred approach in these patients.
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Acknowledgments |
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We thank Paul Cartier, MD (deceased), Daniel Doyle, MD, Richard Baillot, MD, Eric Charbonneau, MD, Denis Desaulniers, MD, Patrick Mathieu, MD, Jacques Métras, MD, Jean Perron, MD, and Pierre Voisine, MD for implanting ring annuloplasty and for their participation in the present study. We also thank Paul Poirier, MD, PhD, and Michelle Dubois, BSc, for their contribution in the preparation of the manuscript and Brigitte Dionne, Stéphanie Dionne, and Dominique Labrèche for their technical assistance.
Sources of Funding
This work was supported by a grant from the Quebec Heart Institute, Quebec, Canada (Dr Sénéchal) and also from the Canadian Institutes of Health Research (MOP 67123), Ottawa, Canada. Dr Pibarot holds the Canada Research Chair in Valvular Heart Diseases, Canadian Institutes of Health Research, Ottawa, Ontario, Canada.
Disclosures
None.
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