Background
Percutaneous mitral valve repair (PMVR) is an alternative treatment in patients with significant mitral regurgitation (MR) who are denied surgery. Although in surgical patients, outcomes have been related both to acute hemodynamic favorable results and to positive cardiac remodeling in the midterm, in the case of PMVR the effect on cardiac chamber remodeling has never been extensively studied. The aims of this study were (1) to evaluate the short- and mid-term remodeling induced by PMVR on cardiac chamber volume using two- and three-dimensional (3D) transthoracic echocardiographic (TTE) imaging and (2) to assess changes in left ventricular (LV) shape on the basis of 3D TTE data.
Methods
Patients undergoing PMVR were prospectively enrolled. Two-dimensional and 3D TTE data sets acquired at baseline, and at 30 days and 6 months after PMVR were analyzed to assess LV and right ventricular (RV) volumes and ejection fraction and left atrial and right atrial volumes. Moreover, 3D endocardial surfaces were extracted to compute 3D shape indexes of LV sphericity and conicity at end-diastole and end-systole.
Results
Six of the 64 enrolled patients did not reach follow-up and were excluded. The analysis was feasible in all 58 patients considered (26 with functional MR and 32 [55%] with degenerative MR). PMVR resulted in significant reduction of MR and in favorable remodeling: (1) effective PMVR was mainly associated with decreased LV loading, (2) PMVR-related reverse remodeling was observed in patients with degenerative MR and those with functional MR at 30 days and continued at 6-month follow-up, (3) favorable remodeling in LV shape from abnormally spherical to more normal conical took place in both groups after PMVR, and (4) RV volumes and systolic function were preserved after PMVR.
Conclusions
A comprehensive two-dimensional and 3D TTE analysis allows investigation from a double perspective (volume and morphology) of the entity and modality of changes following PMVR. In high-risk patients undergoing PMVR, postprocedural heart remodeling involves all cardiac chambers, occurs in the short term, and further improves at midterm follow-up.
Highlights
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The authors examined heart chamber remodeling following successful PMVR.
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A volumetric approach was applied on the basis of 3D TTE data sets to search for dimensional changes of all cardiac chambers simultaneously and to serially analyze LV morphologic remodeling.
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Effective valve repair is mainly associated with decreased LV loading, but it involves all cardiac chambers.
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Favorable remodeling in LV shape from an abnormally spherical to a more normal conical shape takes place.
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Three-dimensional echocardiographic analysis allows investigation of the entity and modality of double-perspective (volume and morphologic) changes involved in PMVR outcomes.
Mitral regurgitation (MR) imposes a pure volume overload on the left heart and causes dilation of the left ventricle and left atrium, accommodating the regurgitant volume at a lower pressure. Although the remodeling process can be initially adaptive, it becomes pathologic as, in the presence of chronic severe MR, the long-standing volume overload leads to the impairment of left ventricular (LV) function, an increase in left atrial (LA) pressure, and changes in the pulmonary vasculature resulting in the subsequent remodeling of the right ventricle. This adverse remodeling affects all cardiac chambers and is associated with poor prognosis. In this context, surgical correction of MR is considered the treatment of choice for patients with significant MR who are either symptomatic or have experienced mechanical consequences of MR. Thanks to lower perioperative mortality, improved survival, better preservation of postoperative LV function, and lower long-term morbidity, surgical mitral valve (MV) repair, when feasible, is recommended over MV replacement. The latter is preferred when durable MV repair is unlikely, as in the presence of rheumatic lesions, extensive valve prolapse, leaflet calcification, or extensive annulus calcification. Surgical correction of MR, either repair or replacement, decreases LV volume load and may trigger a reverse-remodeling process. The mechanisms involved are still under debate, even if long-standing LV volume overload is thought to be inversely associated with the likelihood of effective inverse remodeling. Moreover, after surgical MV repair or replacement, the right ventricle plays an important role in the postoperative course and functional recovery, and it has been demonstrated that right ventricular (RV) impairment after MV replacement significantly increases 5-year mortality compared with patients without right heart failure. Other studies have shown that especially during the early postoperative period, there is a pronounced decrease in RV function, with only partial recovery even after long-term follow-up.
Despite a clear surgical indication, approximately half of symptomatic patients with severe MR are denied surgery because of significant comorbidities or other risk factors, including age and LV dysfunction.
Percutaneous MV repair (PMVR) with the MitraClip system (Abbott Vascular, Menlo Park, CA) is currently considered an effective procedure for reducing MR of functional or degenerative origin in patients in whom surgical correction of MR is not suitable. Previous studies demonstrated the feasibility and safety of PMVR in restoring MV competence, alleviating clinical symptoms, and inducing reverse LA and LV remodeling. Few studies, mainly based on two-dimensional (2D) echocardiographic parameters, have explored the impact of PMVR on RV dimensions and performance and on right atrial (RA) dimensions.
However, data on how and to what extent PMVR affects remodeling of all cardiac chambers simultaneously are lacking. Also, the effects of PMVR on LV shape have not been extensively studied. LV shape has been related to exercise capacity and prognosis in patients with idiopathic or dilated cardiomyopathy. In these subjects, a more spherical ventricular shape was related to a lower exercise duration and poorer outcomes.
It has also been demonstrated that patients with asymptomatic severe MR due to MV prolapse exhibited changes in LV shape despite preserved LV function and also that early MV repair can restore near normal LV morphology after surgery. We hypothesized that PMVR, in addition to reducing volume overload, might have a favorable impact on LV morphology and that this hypothesis could be confirmed using three-dimensional (3D) echocardiography.
Accordingly, the aims of this study were (1) to evaluate immediate and short-term volumetric remodeling following PMVR on cardiac chambers using 2D and 3D transthoracic echocardiographic (TTE) imaging and (2) to assess the LV morphologic remodeling on 3D TTE data sets.
Methods
All patients who underwent successful PMVR at Centro Cardiologico Monzino, IRCCS, between 2010 and 2015 were prospectively included in the study. All patients had moderate to severe or severe MR and met class I or IIa indications for MV surgery.
A “heart team” of cardiologists, cardiovascular surgeons, and anesthesiologists referred the patients for MitraClip placement on the basis of current guidelines, MV anatomy, and the presence of high-risk criteria (including logistic European System for Cardiac Operative Risk Evaluation score >20%) or other comorbidities, such as neurologic disorders and respiratory diseases. Clinical exclusion criteria included recent myocardial infarction, any interventional or surgical procedure within 1 month, renal insufficiency, active infections, history of rheumatic heart disease, and prior MV leaflet surgery, consistent with those adopted in the Endovascular Valve Edge-to-Edge Repair Study.
Following the standard protocol of our hospital for PMVR, all patients underwent clinical and echocardiographic evaluation at baseline, after the procedure (before hospital discharge), at 30 days, at 6-month follow-up, and then annually. Patients who did not complete 6-month follow-up were excluded from the analysis.
Clinical and echocardiographic data were digitally stored and analyzed offline. Three-dimensional data sets were used to calculate LV and RV volumes and function and LA volume; RA volume was derived from 2D TTE imaging. The obtained measurements were used to assess changes in cardiac chamber dimensions, morphology, and function during immediate and midterm follow-up after PMVR, separately for patients with functional MR (FMR) and those with degenerative MR (DMR). Reverse LV remodeling was defined as a decrease of 10% in the LV indexed volumes.
The local ethics committee approved the study protocol, and all participants provided written informed consent.
Imaging Protocol
The imaging protocol included complete 2D and 3D TTE examinations performed the day before and at 30-day and 6-month follow-up after PMVR using an iE33 ultrasound system (Philips Medical Systems, Andover, MA).
Comprehensive 2D TTE evaluation (S5 probe), following the standard protocol of our laboratory, allowed the quantification of 2D LV volumes and function using the biplane Simpson method, LA end-systolic area, and systolic pulmonary artery pressure, as well as grading of the severity of MR at baseline according to current recommendations. All patients were assigned MR severity scores of 1 (mild), 2 (mild to moderate), 3 (moderate to severe), or 4 (severe) through the integration of multiple criteria both qualitative (color flow Doppler jet characteristics, pulmonary vein flow pattern) and quantitative (vena contracta width, regurgitant volume, regurgitant fraction, and effective regurgitant orifice area). In agreement with current guidelines, different cutoff values were used for the quantitative grading of MR severity for FMR and DMR.
Post-PMVR overall MR severity was assessed through the integration of the same criteria, and the mean transvalvular gradient was also estimated. The presence of significant residual left-to-right shunting across the site of atrial septal puncture was assessed qualitatively using the color Doppler method.
Three-dimensional TTE imaging (X3-1 probe) was performed after the 2D examination in the full-volume mode from the apical window. Two consecutive acquisitions were obtained from the four-chamber apical view optimized for the visualization of the right and left cardiac cavities, respectively. LV and LA volumetric reconstructions were obtained offline from the left cavity–focused data set, while the RV-focused view was analyzed for the RV measures.
Three-Dimensional Measurement Protocol
Left Ventricle
LV endocardial surfaces were obtained semiautomatically from 3D data sets using commercial software (4D-LV Analysis; TomTec, Unterschleissheim, Germany). After manual tracing of the endocardial borders on end-diastolic and end-systolic frames in the two-, three-, and four-chamber views, the software automatically generated the LV surfaces throughout the cardiac cycle. The operator then manually adjusted the detected surfaces before quantification, if needed. From these surfaces, LV volume-versus-time curves were obtained, from which end-diastolic volume (EDV) and end-systolic volume (ESV) were measured, and the LV ejection fraction (LVEF) was computed as 100 × (EDV − ESV)/EDV. Additionally, these surfaces were exported and used as the basis for 3D shape analysis.
Custom software implemented in the MATLAB environment (The MathWorks, Natick, MA) was used to quantify LV morphology by computing 3D shape indexes from LV endocardial surfaces. Briefly, the LV surface was sampled along a helical pattern aligned with the LV long axis from apex to base, obtaining a signal s , that describes the distance of the endocardial surface from the long axis. Global 3D shape indexes were then defined by measuring the degree of similarity between the signal s , computed from the left ventricle, and the signal s ref , obtained using the same procedure from a reference 3D shape (i.e., a sphere and a cone). Spherical and conical 3D shape indexes in dimensionless units were computed as shape index = 1 − A / A max , where A is the area between the two signals s and s ref , normalized to the maximal area A max under the signals. The obtained indexes, called sphericity and conicity, computed throughout the cardiac cycle, were independent of LV dimensions and varied between zero and one, with higher values corresponding to better similarity with the relevant reference shape. More detailed description is available elsewhere.
Right Ventricle
Dedicated RV analysis software (4D RV-Function; TomTec Imaging Systems) was used to analyze the RV 3D TTE volumetric data sets. Briefly, after manual selection of the central reference points of the tricuspid valve and MV annuli and of the LV apex, the software visualized the RV cavity by the coronal, sagittal, and frontal cut planes at end-systole and at end-diastole. After manual tracing of the endocardial borders on each of the three cut planes, the software automatically detects the RV surfaces throughout the cardiac cycle computing RV volumes. RV EDV and RV ESV were obtained as maximum and minimum, respectively. RV ejection fraction (RVEF) was then measured as the percentage change of the volumes.
Left Atrium
Quantification of LA volume was performed using a semiautomatic contour-tracing algorithm (QLAB; Philips Medical Systems), marking five atrial reference points on the mitral annulus and the LA superior wall in the four- and two-chamber views; a preconfigured ellipse was automatically fitted to the endocardial border, and the maximal LA volume was measured in the end-systolic frame just before the MV opening. Manual corrections of the automatic trace were made to exclude LA appendage and pulmonary vein entrance.
Right Atrium
RA volume was derived from 2D TTE imaging. The RA major-axis length was measured from the apical four-chamber view as the maximal distance from the center of the tricuspid annulus to the center of the superior RA wall, parallel to the interatrial septum. For measurement of RA area, the endocardium was traced at the end of ventricular systole from the lateral aspect of the tricuspid annulus to the septal aspect, excluding the superior and inferior cava vein and RA appendage. For the calculation of RA volume, the single-plane area-length method was used, applying the formula 8/3π (area/major-axis length).
Statistical Analysis
Continuous variables were tested for normality of distribution using the Shapiro-Wilk test, and the null hypothesis was rejected at the 5% significance level. Accordingly, data are presented as median (interquartile range [IQR]), and nonparametric statistical analysis was applied. For each cohort, the Friedman test with Bonferroni correction was applied to test for differences of each measurement (chamber volumes and LV shape indexes) evaluated the day before and 30 days and 6 months after PMVR. The Kendall test was applied to test for differences in categorical variables (MR regurgitation and New York Heart Association class) evaluated at the three steps of the analysis.
Reproducibility analysis was performed to assess the effect of observer subjectivity on chambers quantification and shape indexes computation. A subset of 15 patients was randomly selected, and two independent and experienced observers, blind to each other’s measurements, performed the analysis. Intra- and interobserver differences were quantified as the mean and 95% CI of the arithmetic differences between repeated measurements on the same subject, according to Bland and Altman. Also, the coefficient of variability was calculated as the SD of the absolute difference between each pair of repeated measurements divided by the mean value of the considered parameters. Statistical analyses were performed using SPSS version 20 (SPSS, Chicago, IL) and MATLAB.
Results
Sixty-four patients underwent successful PMVR (residual regurgitation no more than grade 2 and absence of hemodynamically significant stenosis) between 2010 and 2015. In 20 patients (31%), a single clip was implanted, while in the others, a second ( n = 40 [62%]) or a third ( n = 4 [6%]) clip was positioned to achieve adequate MV competence. Complete 2D and 3D echocardiographic data were available in 58 patients (five patients died and one patient was lost during follow-up). The FMR group included 26 patients (45%); among these patients, 12 (46%) had ischemic cardiomyopathy, and 14 (54%) had nonischemic cardiomyopathy. DMR was diagnosed in the remaining 32 cases (55%). The clinical baseline characteristics of the overall population, and separately for the two MR etiologies, are presented in Table 1 . Patients with FMR, compared with DMR, were younger and had significantly greater values of LV EDV indexed to body surface area (EDVi) and LV ESV indexed to body surface area (ESVi) and lower values of LVEF and of tricuspid annular plane systolic excursion.
| Characteristic | Overall population ( n = 58) | FMR ( n = 26) | DMR ( n = 32) |
|---|---|---|---|
| Age (y) | 78 (72–84) | 72.5 (65–78) | 83 (79–85) ∗ |
| Men | 33 (56.9%) | 17 (65.4%) | 16 (50.0%) |
| BSA (m 2 ) | 1.77 (1.63–1.89) | 1.78 (1.69–1.90) | 1.77 (1.62–1.88) |
| NYHA class | |||
| I and II | 25 (43%) | 9 (35%) | 16 (50%) ∗ |
| III and IV | 33 (57%) | 17 (65%) | 16 (50%) ∗ |
| LV EDVi (mL/m 2 ) | 84 (65–104) | 100 (84–133) | 69 (64–141) ∗ |
| LV ESVi (mL/m 2 ) | 35 (25–64) | 64 (47–92) | 26 (22–34) ∗ |
| LVEF (%) | 54 (35–62) | 35 (30–42) | 62 (56–68) ∗ |
| LA area (cm 2 ) | 34 (28–38) | 35 (28–37) | 32 (28–38) |
| TAPSE (mm) | 22 (19–26) | 19 (17–22) | 25 (21–27) ∗ |
| sPAP (mmHg) | 43 (35–51) | 46 (35–52) | 42 (36–49) |
∗ P < .05 (Wilcoxon rank sum test for continuous data or Fisher exact test for ordinal or categorical data), FMR vs DMR.
No patient was excluded because of inadequate 2D or 3D TTE image quality at baseline or during follow-up. The time required for 3D image analysis, including surface detection throughout the cardiac cycle, manual adjustments, and the computation of the shape indexes, was <10 min on a standard personal computer. No patient developed iatrogenic mitral stenosis after PMVR. The mean transmitral gradient was 3.7 ± 1.6 mmHg at 30 days and 3.6 ± 1.5 mmHg at 6-month follow-up. No evidence of significant residual left-to-right interatrial shunting was observed.
Figure 1 shows an example of 2D and 3D measurements of cardiac chamber volumes after PMVR.
Table 2 summarizes the results of the pre- and post-PMVR measurements separately for FMR and DMR. There were significant decreases in MR degree in both groups. New York Heart Association class improved in a large proportion of patients, independently of MR etiology. During follow-up, the 30-day and 6-month echocardiograms showed significant reductions in the degree of MR compared with baseline in both FMR and DMR.
| FMR | DMR | |||||
|---|---|---|---|---|---|---|
| Pre-PMVR | 30 d | 6 mo | Pre-PMVR | 30 d | 6 mo | |
| MR | 3 (3–4) | 1 (1–2) ‡ | 1 (1–2) ‡ | 4 (4–4) | 2 (1–2) ‡ | 1 (1–2) ‡ |
| NYHA | ||||||
| Classes I and II | 9 (34.6%) | 11 (42.3%) | 15 (53.8%) ‡ | 17 (53.1%) | 24 (75.0%) ‡ | 25 (79.1%) ‡ |
| Classes III and IV | 17 (65.4%) | 15 (57.7%) | 11 (42.3%) ‡ | 15 (46.9%) | 8 (25.0%) ‡ | 7 (21.9%) ‡ |
| Left ventricle | ||||||
| EDVi (mL/m 2 ) | 100 (84–134) | 94 (78–118) ∗ | 85 (86–116) ∗ | 69 (63–85) | 60 (51–71) ∗ | 57 (49–63) ∗ , † |
| ESVi (mL/m 2 ) | 64 (49–93) | 55 (41–80) ∗ | 51 (36–69) ∗ , † | 27 (34–21) | 25 (21–29) ∗ | 24 (16–28) ∗ , † |
| LVEF (%) | 35 (31–41) | 37 (33–45) | 42 (36–48) ∗ , † | 62 (56–68) | 58 (54–63) | 57 (53–66) |
| Right ventricle | ||||||
| EDVi (mL/m 2 ) | 74 (55–81) | 63 (54–78) | 60 (51–70) | 56 (43–65) | 51 (45–63) | 54 (45–61) |
| ESVi (mL/m 2 ) | 36 (24–48) | 31 (24–44) | 28 (23–40) | 24 (19–30) | 22 (18–28) | 24 (20–28) |
| RVEF (%) | 51 (39–59) | 50 (43–57) | 52 (43–55) | 55 (49–58) | 55 (52–63) | 56 (51–59) |
| Left atrium | ||||||
| ESVi (mL/m 2 ) | 61 (43–72) | 55 (44–66) | 55 (43–65) | 62 (47–74) | 55 (42–72) | 54 (41–64) ∗ |
| Right atrium | ||||||
| ESVi (mL/m 2 ) | 39 (30–55) | 40 (27–58) | 34 (25–46) | 37 (30–51) | 36 (26–51) | 37 (27–51) |
∗ P < .05 vs pre-PMVR (Friedman test with Bonferroni correction).
† P < .05 vs 30 days (Friedman test with Bonferroni correction).
‡ P < .05 vs pre-PMVR (Kendall test with Bonferroni correction).
In patients with FMR, LV EDVi and ESVi significantly decreased 30 days and 6 months after PMVR compared with the preprocedural values; as a result of proportional decreases in LV volumes, LVEF increased from 35% (IQR, 31%–41%) to 37% (IQR, 33%–45%) at 30-day follow-up and to 42% (IQR, 36%–48%) at 6-month follow-up. Reverse remodeling, defined as a decrease of 10% in LV EDVi and ESVi, was registered in 46% and 65% of patients with FMR, respectively, at end-diastole and end-systole. No significant changes were observed during follow-up in RV, LA, and RA volumes.
In patients with DMR, LV EDVi and ESVi reduced over time, with significant decreases at 30-day and 6-month follow-up, while LVEF remained stable: 55% at baseline (IQR, 49%–58%), 55% at 30-day follow-up (IQR, 52%–63%), and 56% at 6-month follow-up (interquartile range, 51%–59%). In patients with DMR, reverse remodeling was found in 75% and 56% of patients, respectively, for LV EDVi and ESVi. LA volume slightly but significantly decreased at 6-month follow-up. RV EDVi, RV ESVi, RVEF, and RA volume remained unchanged during follow-up.
Figure 2 depicts the cumulative results of LV shape indexes obtained in patients with FMR at the different time points of the study. After PMVR, decreases in end-diastolic and end-systolic sphericity and increases in end-diastolic and end-systolic conicity were evident at each time point.
