The impact of the specific etiology of mitral regurgitation (MR) on outcomes in the transcatheter aortic valve replacement (TAVR) population is unknown. This study aimed to evaluate the longitudinal changes in functional versus organic MR after TAVR in addition to their impact on survival. Consecutive patients who underwent TAVR from May 2007 to May 2015 who had baseline significant (moderate or greater) MR were included. Transthoracic echocardiography was used to evaluate the cohort at baseline, post-procedure, 30-day, 6-month, and 1-year follow-up. The primary outcomes included mortality at 30 days and 1 year. Longitudinal, mixed-model regression analyses were performed to assess the differences in the magnitude of longitudinal changes of MR, left ventricular (LV) ejection fraction, and New York Heart Association functional class. Seventy patients (44% men, mean 83 years) with moderate or greater MR at baseline (30 functional vs 40 organic) were included, with the functional group having a statistically significant mean younger age and higher rates of previous coronary artery bypass grafting. Kaplan-Meier cumulative mortality rates were similar: 30 days (10% vs 17.5%, unadjusted log-ranked p = 0.413) and 1 year (29.4% vs 23.2%, unadjusted log-ranked p = 0.746) in the functional versus organic MR groups, respectively. There were greater degrees of short- and long-term improvement in MR severity (slope difference p = 0.0008), LV ejection fraction (slope difference p = 0.0009), and New York Heart Association class (slope difference p = 0.0054) in the functional versus organic group. In conclusion, patients with significant functional versus organic MR who underwent TAVR have similar short- and long-term survival; nevertheless, those with a functional origin are more likely to have significant improvements in MR severity, LV-positive remodeling, and functional class. These findings may help strategize therapies for MR in patients with combined aortic and mitral valve disease who are undergoing TAVR.
The current clinical practice regarding transcatheter aortic valve replacement (TAVR) is focused on ameliorating the impact of associated co-morbid conditions to improve overall clinical outcomes. The reported prevalence of concomitant mitral regurgitation (MR) in patients who underwent TAVR ranges from 2% to 33%, and in this setting, the MR is often left untreated. Previous studies have demonstrated conflicting evidence on the impact of significant MR on mortality outcomes after TAVR. Some studies have demonstrated an association between moderate or greater MR and long-term mortality. In contrast, large trials and registry data have demonstrated no difference in mortality outcomes after adjustment between moderate or greater MR and less than moderate MR at long-term follow-up. However, there is scant data available on the differentiated cause of MR (functional vs organic) and its impact on outcomes. Data from the surgical literature indicate that in functional MR, reverse remodeling leading to changes in left ventricular (LV) geometry may contribute to a greater improvement of MR severity because of reduction in LV filling pressures and mitral tethering forces. The available data, in this regard, in the TAVR population are sparse and incomplete. The aim of this study was to assess the impact of significant functional versus organic MR in patients who underwent TAVR, comprehensively assess MR severity and the mitral valve (MV) apparatus, and to evaluate the longitudinal changes of MR according to the specific etiology.
Methods
This study consisted of a total of 70 consecutive patients with concomitant baseline severe symptomatic calcific aortic stenosis (AS) and moderate or greater MR, who were deemed by our multidisciplinary heart team to be either high or prohibitive risk candidates for conventional surgical aortic valve replacement and were subsequently treated with TAVR from May 2007 to May 2015. Only clinically significant MR, deemed moderate or greater in severity, at baseline, was included. All data were prospectively collected and entered into our institution’s database. The screening process included a baseline comprehensive medical history, physical examination, surgical risk assessment, frailty index testing, and multiple diagnostic noninvasive, and invasive tests deemed necessary for a standard, pre-TAVR evaluation. In addition, a computed tomography of the cardiac structures and peripheral vasculature for annular and iliofemoral sizing, respectively, were also completed. Exclusion criteria included patients with initial treatment assignment to balloon aortic valvuloplasty, history of MV surgery or valvuloplasty, and post-TAVR percutaneous MV therapy. The internal institutional review board approved this study. The study cohort (total n = 70) was categorized into 2 groups based on the etiology of baseline MR: functional (n = 30) and organic (n = 40). All patients had either monitored anesthesia care or general anesthesia during the TAVR selected on a case-by-case basis as previously described. Clinical safety end points have all been prospectively adjudicated, and all comply with the Valve Academic Research Consortium (VARC)-2 consensus report definitions.
The transthoracic echocardiographic (TTE) studies were rigorously evaluated on a de novo basis for this study, in regard to the LV function and dimensions, MR etiology, severity, and MV apparatus at multiple longitudinal intervals, including baseline, post-procedure, 30-day, 6-month, and 1-year follow-up. A comprehensive evaluation with 2-dimensional and Doppler TTE was performed at baseline for all the patients. The severity of MR and LV function and dimensions were assessed on all the follow-up TTE studies. MR has been defined with the conventional degree of severity: none or trace (grade 0), mild or mild-to-moderate (grade 1+), moderate (grade 2+), moderate-to-severe (grade 3+), and severe (grade 4+). The general severity of MR was defined according to the widely accepted guidelines. The baseline TTE included de novo assessments of the following parameters: regurgitant volume; effective regurgitant orifice area by proximal isovelocity surface area; vena contracta; pulmonary venous systolic flow reversal; mitral inflow E-wave velocity; MV anteroposterior and transverse diameters; presence of inferior wall-motion abnormality; posterior leaflet tethering; leaflet calcification (deemed ≥50% of leaflet width); significant leaflet restriction because of calcification; presence of a flail or prolapsed MV, ruptured chordae, cleft MV, previous endocarditis, rheumatic MV disease; tenting area, tenting height, and coaptation length; and eccentricity of the MR jet. Mitral leaflet tenting parameters were measured in the mid-systolic, parasternal long-axis view for all patients.
Functional MR (also known as secondary MR) was defined as MR related to LV dysfunction, wall motion abnormality, or dilation with resultant papillary muscle displacement and, therefore, tethering and non-coaptation of 1 or both leaflets, with or without mitral annular dilation. The MV apparatus is usually normal in the functional group, although the leaflet coaptation point is usually apically displaced causing apical tenting of the leaflets. Organic MR (also known as primary MR) was defined as a pathology of ≥1 components of the MV apparatus itself, including the leaflets (including significant leaflet calcification of ≥50% width of the leaflets), chordae tendinae, the papillary muscles, or the mitral annulus (excluding dilated annulus).
Statistical analyses were completed using SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina). Continuous variables are presented as mean ± SD. Categorical variables are expressed as percentages. Student’s t test was used to compare continuous variables, whereas the chi-square or Fisher’s exact test were used to compare categorical variables. All probabilities are 2 sided, and statistically significant differences were defined as p <0.05. Kaplan-Meier curves were generated for the unadjusted mortality probability of functional versus organic MR at 30-day and 1-year follow-up post-TAVR procedure as primary end points. In addition, longitudinal, mixed-model regression analyses were performed to assess the differences in the outcome of the degree of longitudinal changes of the severity of MR, left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) functional class up to 1 year of sequential follow-up. Given the limitation in the quantity of follow-up patients, regression analyses for predictors of MR improvement were not attempted.
Results
A total of 70 patients (44% men, mean 83 years) with moderate or greater MR at baseline, including 30 (43%) functional versus 40 (57%) organic MR who had undergone TAVR from May 2007 to May 2015, were consecutively included in this study. This study cohort was selected from a total of 860 TAVR procedures completed at our center through May 2015. Baseline clinical characteristics and baseline echocardiographic and cardiac CTA parameters, according to MR etiology, are included in Tables 1 and 2 , respectively. In addition, Table 3 includes the results of the comprehensive assessment of the MV apparatus in both groups. The 2 groups had a couple of significant baseline differences, including a mean younger age and higher rates of previous CABG surgery in the functional group compared with the organic group ( Table 1 ). In regard to the baseline TTE parameters, there were significant differences between the 2 study groups including a lower mean LVEF, larger baseline left ventricular end-systolic dimension (LVESD) and left ventricular end-diastolic dimension (LVEDD), larger aortic valve area, and a lower mean aortic valve pressure gradient in the functional group compared with the organic group ( Table 2 ). In addition, the functional group had more patients in the moderate-to-severe category. The organic group, as expected, had higher rates of moderate-to-severe mitral annular calcification (MAC) and severe MAC ( Table 2 ). Furthermore, in regard to the comprehensive evaluation of the MV apparatus ( Table 3 ), there were significant baseline differences including a higher mean mitral inflow E-wave velocity in the organic group. The functional group included all the patients with inferior wall motion abnormality and posterior leaflet tethering with compromised leaflet coaptation and, therefore, significantly larger tenting area and tenting height ( Table 3 ). The organic group included more patients with significant leaflet calcification and resultant restriction of the leaflet because of the calcification. The organic group, as expected, included numerically more patients with flail or prolapsed MV, ruptured chordae, cleft MV, and previous healed endocarditis. The procedural and inhospital outcomes are arranged between the 2 groups in Table 4 . It is important to note that there were no significant differences in the intraprocedural parameters, sizes of valves used, or in the inhospital VARC-2 safety outcomes, except for stage 1 or 2 acute kidney injury, which occurred at a higher rate in the functional group, and may be explained on the basis of the baseline reduced LV function in this group. There were no differences in the length of hospital or ICU stays between the 2 groups. The primary outcome of mortality based on the Kaplan-Meier cumulative estimates was similar at 30 days (10% vs 17.5%, unadjusted log-ranged p = 0.413) and 1 year (29.4% vs 23.2%, unadjusted log-ranked p = 0.746) in the functional versus organic MR groups, respectively ( Figures 1 and 2 , respectively). Additional important findings demonstrated statistically significant differences in the sequential longitudinal changes between the 2 groups including statistically greater degrees of improvement in MR severity (slope difference p = 0.0008), LVEF (slope difference p = 0.0009), and NYHA class (slope difference p = 0.0054) in the functional versus the organic MR group, respectively, at up to 1-year follow-up ( Figure 3 ). Of note that, at 1-year follow-up, the relative degree of improvement in LVESD, LVEDD, and pulmonary artery systolic pressure (PASP) measurements, compared with those at baseline, were significantly greater in the functional versus the organic MR group, respectively ( Table 3 ).
| Variable | Mitral Regurgitation | p-value | |
|---|---|---|---|
| Functional (n=30) | Organic (n=40) | ||
| Men | 53.3% (16/30) | 37.5% (15/40) | 0.187 |
| Age (years +/- SD) | 79.8+/- 8.3 | 84.8+/-7.8 | 0.012 |
| Body mass index (kg/m 2 +/- SD) | 25.1+/-3.5 | 25.7+/-5.6 | 0.635 |
| Body surface area (m 2 ) | 1.83+/- 0.2 | 1.76+/- 0.2 | 0.247 |
| Hypertension | 93.1% (27/29) | 97.2% (35/36) | 0.582 |
| Diabetes mellitus | 32.1% (9/28) | 25.0% (9/36) | 0.528 |
| Hyperlipidemia | 79.3% (23/29) | 72.2% (26/36) | 0.510 |
| Prior cerebrovascular accident or transient ischemic attack | 11.1% (3/27) | 11.8% (4/34) | 1.000 |
| Chronic obstructive pulmonary disease | 41.4% (12/29) | 36.1% (13/36) | 0.664 |
| Forced expiratory volume in 1 second (% predicted +/- SD) | 45.3+/-22.2 | 40.8+/-15.8 | 0.732 |
| Current or prior smoking | 42.3% (11/26) | 28.1% (9/32) | 0.258 |
| Atrial fibrillation/flutter | 55.2% (16/29) | 61.1% (22/36) | 0.629 |
| Chronic kidney disease (GFR <60 mL/kg/min or on hemodialysis) | 51.7% (15/29) | 54.3% (19/35) | 0.838 |
| Carotid artery disease | 9.5% (2/21) | 10.3% (3/29) | 1.000 |
| Prior balloon aortic valvuloplasty | 47.8% (11/23) | 28.1% (9/32) | 0.134 |
| Peripheral vascular disease | 32.1% (9/28) | 23.5% (8/34) | 0.449 |
| Prior coronary artery bypass grafting | 50.0% (14/28) | 22.2% (8/36) | 0.020 |
| Prior percutaneous coronary intervention | 35.7% (10/28) | 22.2% (8/36) | 0.234 |
| Prior myocardial infarction | 33.3% (9/27) | 16.7% (6/36) | 0.124 |
| Coronary artery disease | 82.6% (19/23) | 74.1% (20/27) | 0.468 |
| Heart failure (NYHA Class I) | 0% (0/30) | 0% (0/40) | 1.000 |
| Heart failure (NYHA Class II) | 10% (3/30) | 5% (2/40) | 0.645 |
| Heart failure (NYHA Class III) | 50% (15/30) | 62.5% (25/40) | 0.336 |
| Heart failure (NYHA Class IV) | 40% (12/30) | 32.5% (13/40) | 0.616 |
| Prior Cancer | 27.3% (6/22) | 25.0% (7/28) | 0.856 |
| STS score (mean +/- SD) | 9.9+/-4.8 | 10.4+/-4.5 | 0.629 |
| “Porcelain” aorta | 6.9% (2/29) | 13.9% (5/36) | 0.447 |
| Variable | Mitral Regurgitation | p-value | |
|---|---|---|---|
| Functional (n=30) | Organic (n=40) | ||
| Left ventricular ejection fraction (% mean +/- standard deviation) | 37.7+/-12.4 | 58.9+/-10.5 | <0.001 |
| Left ventricular ejection fraction (<40%) | 66.7% (20/30) | 10% (4/40) | <0.001 |
| Left ventricular ejection fraction (<30%) | 43.3% (13/30) | 2.5% (1/40) | <0.001 |
| Left ventricular end-systolic dimension (cm) | 4.05+/-0.97 | 2.9+/-0.5 | <0.001 |
| Left ventricular end-diastolic dimension (cm) | 5.2+/-0.9 | 4.4+/-0.6 | <0.001 |
| Left atrial diameter (cm) | 4.7+/-0.9 | 4.85+/-0.6 | 0.780 |
| Pulmonary artery systolic pressure (mmHg) | 54.2+/-16.8 | 54.2+/-14.7 | 0.994 |
| Left ventricular outflow tract diameter (cm) | 1.97+/-0.2 | 1.9+/-0.2 | 0.431 |
| Aortic valve area (cm 2 ) | 0.71+/-0.1 | 0.62+/-0.2 | 0.015 |
| Aortic valve max velocity (m/s) | 4.1+/-0.5 | 4.4+/-0.5 | 0.007 |
| Aortic valve max pressure gradient (mmHg) | 67.1+/-14.7 | 72.8+/-15.6 | 0.145 |
| Aortic valve mean pressure gradient (mmHg) | 42.1+/-10.5 | 50.3+/-13.1 | 0.013 |
| Moderate aortic regurgitation (2+/4+) | 4.0% (1/25) | 6.5% (2/31) | 1.000 |
| Moderate-to-severe aortic regurgitation (3+/4+) | 0.0% (0/25) | 0.0% (0/31) | 1.000 |
| Severe aortic regurgitation (4+/4+) | 0.0% (0/31) | 0.0% (0/31) | 1.000 |
| Moderate mitral regurgitation (2+/4+) | 56.7% (17/30) | 77.5% (31/40) | 0.074 |
| Moderate-to-severe mitral regurgitation (3+/4+) | 40% (12/30) | 15% (6/40) | 0.027 |
| Severe mitral regurgitation (4+/4+) | 3.3% (1/30) | 7.5% (3/40) | 0.630 |
| Moderate-to-severe mitral annular calcium | 62.5% (15/24) | 82.9% (29/35) | 0.078 |
| Severe mitral annular calcium | 25.0% (6/24) | 60.0% (21/35) | 0.008 |
| Moderate-to-severe right ventricular dilation | 6.9% (2/29) | 5.4% (2/37) | 0.748 |
| Severe right ventricular dilation | 0.0% (0/29) | 0.0% (0/37) | 1.000 |
| Variable | Mitral Regurgitation | p-value | |
|---|---|---|---|
| Functional (n=30) | Organic (n=40) | ||
| Mitral regurgitation severity grade ≥ 2 | 100% (30/30) | 100% (40/40) | 1.000 |
| Regurgitant volume (mL/beat) | 49+/-12.1 | 44.1+/-14.2 | 0.484 |
| Effective regurgitant orifice area (by proximal isovelocity surface area) (cm 2 ) | 0.34+/-0.1 | 0.3+/-0.1 | 0.587 |
| Vena contracta (cm) | 0.55+/-0.1 | 0.6+/-0.1 | 0.725 |
| Pulmonary vein systolic flow reversal | 17% (5/30) | 20% (8/40) | 0.723 |
| Mitral inflow E-wave velocity (m/s) | 1.1+/-0.3 | 1.3+/-0.3 | 0.019 |
| Mitral valve annulus (antero-posterior) (mm) | 3.3+/-0.7 | 3.0+/-0.5 | 0.126 |
| Mitral valve annulus (transverse) (mm) | 3.5+/-0.6 | 3.3+/-0.5 | 0.108 |
| Inferior wall-motion abnormality | 87% (26/30) | 0.0% (0/40) | <0.001 |
| Posterior leaflet tethering | 90% (27/30) | 0.0% (0/40) | <0.001 |
| Significant leaflet restriction due to calcification | 0.0% (0/30) | 75% (30/40) | <0.001 |
| Leaflet calcium (≥50% of leaflet width) | 10% (3/30) | 85% (34/40) | <0.001 |
| Flail or prolapsed mitral valve | 0.0% (0/30) | 7.5% (3/40) | 0.255 |
| Ruptured chordae | 0.0% (0/30) | 7.5% (3/40) | 0.255 |
| Cleft mitral valve | 0.0% (0/30) | 5.0% (2/40) | 0.503 |
| Prior infective endocarditis | 0.0% (0/30) | 2.5% (1/40) | 1.000 |
| Rheumatic valve | 0.0% (0/30) | 0.0% (0/40) | 1.000 |
| Tenting area (cm2) | 2.0+/-0.3 | 1.4+/-0.4 | <0.001 |
| Tenting height (cm) | 1.1+/-0.3 | 0.9+/-0.3 | 0.006 |
| Coaptation length (cm) | 0.5+/-0.3 | 0.5+/-0.2 | 0.549 |
| Eccentric mitral regurgitation jet | 27% (8/30) | 30% (12/40) | 0.760 |
| At 1-year follow-up echocardiography | |||
| Left ventricular ejection fraction (% mean +/- SD) | 50+/-13 | 60+/-7 | 0.027 |
| Δ (follow-up – baseline) left ventricular ejection fraction (%) | +12% | +1% | |
| Left ventricular end-systolic dimension (cm) | 3.3+/-1 | 2.9+/-0.8 | 0.259 |
| Δ (follow-up – baseline) left ventricular end-systolic dimension (cm) | -0.75 cm | 0.0 cm | |
| Left ventricular end-diastolic dimension (cm) | 4.7+/-0.8 | 4.1+/-0.8 | 0.066 |
| Δ (follow-up – baseline) left ventricular end-diastolic dimension (cm) | -0.5 cm | -0.3 cm | |
| Left atrial diameter (cm) | 4.7+/-0.7 | 4.9+/-0.8 | 0.637 |
| Pulmonary artery systolic pressure (mmHg) | 41+/-17 | 52+/-15 | 0.113 |
| Variable | Mitral Regurgitation | p-value | |
|---|---|---|---|
| Functional (n=30) | Organic (n=40) | ||
| Transfemoral approach | 63.3% (19/30) | 85.0% (34/40) | 0.036 |
| Transapical approach | 36.7% (11/30) | 7.5% (3/40) | 0.003 |
| Medtronic CoreValve | 25.0% (8/30) | 37.5% (15/40) | 0.258 |
| Edwards SAPIEN or SAPIEN XT Valve | 73.3% (22/30) | 62.5% (25/40) | 0.443 |
| Conscious sedation | 53.3% (16/30) | 72.5% (29/40) | 0.098 |
| General anesthesia | 46.7% (14/30) | 27.5% (11/40) | 0.098 |
| In-hospital outcomes | |||
| In-hospital mortality | 10.0% (3/30) | 12.5% (5/40) | 1.000 |
| VARC-2 major vascular complications | 13.8% (4/29) | 12.8% (5/39) | 1.000 |
| VARC-2 minor vascular complications | 3.4% (1/29) | 17.9% (7/39) | 0.125 |
| VARC-2 stroke | 3.3% (1/30) | 2.5% (1/40) | 1.000 |
| VARC-2 transient ischemic attack | 0.0% (0/30) | 0.0% (0/40) | 1.000 |
| VARC-2 life-threatening bleeding | 6.9% (2/29) | 12.5% (5/40) | 0.690 |
| VARC-2 major bleeding | 6.9% (2/29) | 0.0% (0/40) | 0.173 |
| VARC-2 minor bleeding | 3.4% (1/29) | 5.0% (2/40) | 1.000 |
| VARC-2 stage 1 acute kidney injury | 22.2% (6/27) | 3.1% (1/32) | 0.040 |
| VARC-2 stage 2 acute kidney injury | 25.9% (7/27) | 3.1% (1/32) | 0.019 |
| VARC-2 stage 3 acute kidney injury | 11.1% (3/27) | 9.4% (3/32) | 1.000 |
| Pacemaker implantation (in-hospital) | 10.0% (3/30) | 7.5% (3/40) | 1.000 |
| Post-procedure hospital stay (days) | 7.2+/-4.9 | 6.9+/-5.1 | 0.807 |
| Post-procedure intensive care unit stay (days) | 4.7+/-4.8 | 4.2+/-4.2 | 0.628 |
| Outcome at 30 days and 1 year | |||
| All-cause mortality at 30-days follow-up ∗ | 10.0% (3/30) | 17.5% (7/40) | 0.498 |
| All-cause mortality at 1-year follow-up † | 32.0% (8/25) | 25.7% (9/35) | 0.772 |
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