Author + information
- Received December 12, 2011
- Revision received February 22, 2012
- Accepted February 23, 2012
- Published online May 1, 2012.
- Kibar Yared, MD⁎,⁎ (, )
- Tamara Garcia-Camarero, MD⁎,
- Leticia Fernandez-Friera, MD⁎,
- Miguel Llano, MD⁎,
- Ronen Durst, MD⁎,
- Anil A. Reddy, MD⁎,
- William W. O'Neill, MD† and
- Michael H. Picard, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Kibar Yared, Division of Cardiology, The Scarborough Hospital, University of Toronto Medical School, 3050 Lawrence Avenue, East Toronto, Ontario M1P 2V5, Canada
Objectives Understanding the severity of aortic regurgitation (AR) after transcatheter aortic valve implantation, its impact on left ventricular (LV) structure and function, and the structural factors associated with worsening AR could lead to improvements in patient selection, implantation technique, and valve design.
Background Initial studies in patients at high risk of surgical aortic valve replacement have reported both central valvular and paravalvular AR after transcatheter aortic valve implantation.
Methods Transthoracic echocardiograms were quantified from 95 patients in the REVIVAL (TRanscatheter EndoVascular Implantation of VALves) trial. Transthoracic echocardiograms were obtained before implantation of the Edwards-Sapien valve (Edwards Lifesciences, Irvine, California) and thereafter at selected intervals. Measurements included LV internal diameters and volumes, ejection fraction, aortic valve area, and the degree of aortic regurgitation. Measures of degree of native leaflet mobility, thickness, and calcification, as well as left ventricular outflow tract, aortic annulus, and aortic root diameters were also made.
Results Eighty-four patients remained after 11 were excluded; 26 (29.8%) died over a period of 3 years. At 24 h post-implantation, 75% had some degree of AR, mostly paravalvular. By 1 year, the mean AR grade increased slightly, but not significantly (1.1 ± 0.8 to 1.3 ± 0.9), and all measures of LV structure and function improved (LV ejection fraction, 50.7 ± 16.1% to 59.4 ± 14.0%). Native aortic leaflet calcification and annulus diameter correlated significantly with the severity of AR at 1 year (p < 0.05).
Conclusions AR after transcatheter aortic valve implantation is frequent but is rarely more than mild. Although AR progresses, it is not associated with a harmful impact on LV structure and function over the first year. Native valve calcification and aortic annulus diameter influence the degree of AR at 6 months.
Aortic stenosis (AS) is the most frequent heart valve disease in Western countries, where its prevalence steadily increases with age (1). Once symptoms develop, the average survival of patients with AS is reduced to <5 years (2–6). Successful aortic valve replacement results in a good long-term prognosis (7,8), but unfortunately, >30% of patients with severe AS are rejected for cardiac surgery due to excessive surgical risk (1).
The REVIVAL (TRanscatheter EndoVascular Implantation of VALves) trial studied the safety and efficacy of the Edwards-Sapien bioprosthetic valve (Edwards Lifesciences, Irvine, California) and its transfemoral and transapical implantation techniques in patients with critical AS at high surgical risk (9). Most studies examining the efficacy of transcatheter aortic valve implantation (TAVI) (10–15) have reported an incidence and degree of aortic regurgitation (AR) (central or paravalvular) after valve implantation. However, the structural and functional sequelae of such regurgitation are infrequently reported.
Through serial transthoracic echocardiograms, we sought to investigate the incidence, location, and severity of AR that develops after TAVI and its impact on left ventricular (LV) structure and function. As well, we sought to identify anatomic or pathological factors associated with more severe AR after valve replacement.
The REVIVAL trial is a prospective, multicenter, safety and feasibility study of percutaneous aortic valve implantation (9). Patients were recruited from medical centers in the United States and included those with severe symptomatic AS, defined as a valve area <1.0 cm2 or <0.5 cm2/m2, a mean gradient >40 mm Hg, and New York Heart Association functional class III/IV. Inclusion and exclusion criteria have already been published (9).
The percutaneous approach was performed retrograde from the femoral artery or antegrade by direct implantation via an LV apical puncture. Valve-in-stent delivery at the site of the calcified aortic valve was guided using fluoroscopy and transesophageal echocardiography (TEE). Aortography and TEE were both used to confirm device placement and patency of both left and right coronary ostia. If excessive paravalvular AR was noted, then repeat in-valve balloon inflation was performed, at the discretion of the interventionalist, to ensure proper apposition of the valve-in-stent along the aortic annulus.
Transthoracic echocardiograms were obtained before implantation of the Edwards-Sapien valve (baseline), and thereafter at 24 h, 7 and 30 days, and 3, 6, and 12 months post-implantation as well as annually thereafter. These transthoracic echocardiograms were analyzed at a core echocardiography laboratory blinded to the details of the patients and procedure. Parameters from the transthoracic echocardiograms of up to 3 years of follow-up were analyzed. Measurements included pre- and post-implantation left ventricular end-diastolic and end-systolic internal diameters, and left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) (using the biplane method of disks). In addition, pre- and post-implantation aortic valve area (by the continuity equation), aortic peak velocity, and Doppler-derived peak and mean gradients across the aortic valve were measured. Functional measurements included left ventricular ejection fraction (LVEF), calculated from the LV volume, and cardiac output, calculated from the product of heart rate and Doppler-derived stroke volume. Central AR was quantified by incorporating the vena contracta width and jet height based on the most recent American College of Cardiology/American Heart Association valvular guidelines (2). Trace AR was designated as 1+, mild as 2+, moderate as 3+, and severe as 4+. Paravalvular AR was distinguished from central, valvular AR (Fig. 1). Paravalvular AR was graded based on the extent of the circumference of the stent involved: trace, <5% of valvular circumference; mild, <10%; moderate, <20%; and severe, ≥20% (16). Native valvular structural parameters evaluated on the baseline transthoracic echocardiogram included qualitative measures of degree of leaflet mobility, thickness as well as left ventricular outflow tract (LVOT), aortic annulus, and aortic root diameters. Calcification of the native leaflets was scored based on the degree of reflectivity (brightness) and percentage of the leaflets involved (0, <25%; 1, 25% to 50%; 2, 50% to 75%; 3, >75%). Similar data were also collected on successive transthoracic echocardiograms.
Statistical analyses were conducted with SPSS version 13.0 (SPSS Inc., Chicago, Illinois). Measurements are presented as mean ± SD, unless otherwise specified. The Wilcoxon matched-pairs signed-rank test with Bonferroni correction was used to assess the significance of differences among continuous variables. An adjusted p value <0.01 was considered statistically significant. Categorical variables were compared using chi-square analysis. Correlations between linear measurements were conducted by univariate linear regression analysis, whereas correlations between the degree of AR and certain specific measurements were performed using Spearman's correlation. Interobserver variability was also assessed using Spearman's correlation.
From 2006 to 2008, the transthoracic echocardiograms of 95 patients were available. Eleven patients were excluded from this analysis because they did not receive a percutaneous valve. Forty-nine patients (58.3%) underwent a transfemoral approach, and the remaining 35 (41.7%) underwent a transapical approach. Of the 84 patients who received a percutaneous valve and formed the final analysis group, 53 (63.1%) had a 26-mm valve implanted and 31 patients (36.9%) received a 23-mm valve. By 6 months, data on 61 patients were available. In addition, data on 49, 21, and 14 patients were available at 1, 2, and 3 years, respectively.
At baseline, before valve implantation, the median degree of native AR was 2.0 (interquartile range [IQR] [25% to 75%]: 1.0 to 2.0). At 24 h post-implantation, 75% of patients had some degree of AR detected by transthoracic echocardiography (TTE). At 6 months, 89% (54 of 61) of patients had some degree of AR. At 1 year, that proportion decreased slightly to 81% (39 of 48) but remained stable at 2 years (81%; 17 of 21) and 3 years (85%; 11 of 13). The number of patients in each category of AR at each follow-up interval is shown in Figure 2. The median AR grade increased slightly but significantly from 1.0 (IQR: 0.75 to 2.0) at 24 h to 1.0 (IQR: 1.0 to 2.0) at 6 months post-implantation (p < 0.05 for comparison of means). At 1 year (median 1.0; IQR: 1.0 to 2.0) of follow-up, the difference in AR grade was no longer statistically significant. Similarly, the amount of AR at 2 (2.0; IQR: 1.0 to 2.0) and 3 (2.0; IQR: 1.0 to 2.0) years of follow-up was no different statistically than that measured 24 h after valve implantation.
At 24 h post-implantation, 39 of 60 patients (65%) with any AR had paravalvular AR, 6 (10%) had central AR, and 15 (25%) had evidence of both. Figure 3 highlights the location of AR at each follow-up period.
By 1 year, in those patients who started with no AR within 24 h of valve implantation, significantly more AR developed (to trace, p < 0.001), whereas those with trace or mild AR did not change significantly (Fig. 4). Although few in number, those patients with moderate AR trended down to trace (p = NS). A similar trend is seen after a follow-up of 3 years. Only 1 patient, starting with moderate AR, survived to 3 years still demonstrating moderate AR.
Interobserver variability for the grading of AR was assessed between the 2 readers. The correlation between the 2 readers was strong and highly significant (r = 0.816; p < 0.0001).
Structural and functional changes
Before percutaneous valve implantation, the mean aortic valve area was 0.6 ± 0.2 cm2, the aortic valve peak velocity was 4.1 ± 0.7 m/s, and the aortic valve peak and mean gradients were 70.2 ± 23.3 mm Hg and 43.4 ± 15.1 mm Hg, respectively. As expected, these parameters all improved significantly immediately after valve implantation (p < 0.0001). Measurements remained similar for up to 3 years post-implantation (Table 1).
Compared with pre-implantation measurements, the mean aortic root diameter, LVESD, and LVEDD did not change significantly up to 3 years. On the other hand, the LVEDV and LVESV decreased significantly up to 1 year. Although decreased from baseline, volume measurements were not significantly different thereafter. Both cardiac output and LVEF increased significantly at 6 months and remained so at 3 years (Table 1). LV volumes (at 1 year vs. baseline) of patients in whom at least moderate AR developed by 1 year (n = 3) were compared with those with no or trace AR. In the latter group, LV volumes decreased significantly (LVEDV 83.6 ± 43.3 ml vs. 104.3 ± 42.8 ml, p < 0.01; LVESV 38.1 ± 31.6 ml vs. 55.0 ± 37.4 ml, p < 0.01), whereas the difference in volumes in the moderate AR group was not statistically significant (LVEDV 158.0 ± 58.6 ml vs. 129.7 ± 47.8 ml, p = NS; LVESV 74.7 ± 61.0 ml vs. 77.3 ± 75.2 ml, p = NS). In addition, both mean LVEDV and mean LVESV at 1 year were greater in the moderate AR group compared with those with no or trace AR (p < 0.001). However, it must be noted that the baseline end-diastolic and end-systolic volumes of those patients with at least moderate AR at 1 year were much greater than those with trace or no AR at 1 year.
Survival data were available up to 3.3 years after valve implantation. Seventeen patients (19.5%) had died within 6 months of valve implantation, 21 patients within 1 year, and a total of 27 patients were dead by 3.3 years. Mean survival at 3.3 years was not significantly different among the groups of no, trace, and mild AR (Fig. 5). Only 2 patients had moderate AR at 24 h post-implantation; 1 died 3 months post-implantation, and the other died after 3 years.
Predictors of AR
The differences between the diameter of the aortic annulus and the implanted prosthetic valve were calculated. The implanted valve was almost always greater than the measured annulus (median difference of −4.4 mm; IQR: −3.1 to −6.0 mm). No correlation was found between these differences and the total amount of AR at 1 year.
Measurements of the severity of AR at 1 year were split into 2 groups according to implanted valve size. Of those who received a 23-mm valve and were alive at 1 year, 12 of 18 (66.7%) had some degree of AR, most of which was paravalvular (7 of 12). In the 26-mm valve group, 27 of 30 (90.0%) had some degree of AR, most of which was again paravalvular (16 of 27). Both 6-month and 1-year data are presented in Table 2. The size of the implanted valve did not correlate significantly with the severity of AR nor did it influence the location of AR at 6 months. More patients with a 23-mm valve had central mild to moderate AR compared with those with a 26-mm valve. However, more patients with a 26-mm valve had a combination of central and paravalvular, mild to moderate AR. The method of implantation (transfemoral or transapical) had no bearing on the degree or location of AR at 1 year.
Native LVOT, aortic annulus, root and leaflet dimensions, and pathology were evaluated to elucidate whether they determined the severity of AR at 1 year. At baseline, the mean native LVOT diameter was 19.7 ± 1.7 mm. As expected, the amount of leaflet calcification, mobility, and thickening was significantly less in the bioprosthetic valve at 1 year compared with the baseline native valve. The aortic annulus diameter decreased significantly at 1 year (18.2 ± 2.1 mm vs. 20.5 ± 2.6 mm). Baseline LVOT and aortic root dimensions did not correlate with the severity of AR both at 6 months and 1 year. The amount of native leaflet calcification (mean score 2.4 ± 0.6) correlated significantly with the severity of AR at 6 months (r = 0.25; p < 0.05) as did the pre-implantation aortic annulus diameter, albeit weakly (r = 0.28, p < 0.05), this latter correlation being driven by the worsening of central AR (r = 0.31, p < 0.01). No aortic leaflets were found to be flail at 6 months.
In this study, we aimed to review the incidence of any type of AR after TAVI with the Edwards-Sapien valve and examine its effects on LV structure and function. This was accomplished by evaluating the trial-mandated transthoracic echocardiograms at a core laboratory. In addition, we sought specific anatomic features of the native valve and aortic root that would be associated with more severe AR.
We found that AR after deployment of the Edwards-Sapien valve occurs frequently; 75% of patients had some form of AR, detected by TTE, within 24 h of implantation. However, typically, the AR was of trace or mild severity. Trace central AR is a physiological finding for this bioprosthesis. Detection of paravalvular AR was more common than central AR regardless of the method of implantation or the size of the valve. Although the fully expanded valve-in-stent is round, the aortic annulus, in particular, a heavily calcified one, is not a perfect circle and the presence of paravalvular AR immediately after implantation would not be unexpected. AR progressed somewhat over the course of 1 year, although, in most cases, it remained mild or less. Although this increase in severity was statistically significant, it was not associated with signs of clinical significance such as increased LV volumes or decreased LVEF.
Interestingly, patients with no AR immediately post-implantation progressed, whereas those with trace or mild AR did not progress. It is not entirely clear why those with no AR progress; however, this may be related to remodeling of the LVOT, aortic annulus, and sinuses of Valsalva after implantation of the valve that does not allow complete apposition of the valve-in-stent to the surrounding annulus. On the other hand, those with moderate AR trended toward trace AR at 6 months, which then increased to moderate at 3 years, although this comparison lacked statistical significance, mostly due to the small number of patients. As mentioned previously, very few patients are left with moderate or more AR immediately after valve implantation because redilation of the valve is often performed if this amount of AR is noted. Redilation of a valve-in-stent is not without consequence because this technique may damage the cusps, resulting in worsened AR. However, this type of injury to the cusps was not noted in any patient in our study.
The degree of AR appears to stabilize over 3 years. Additionally, it is not associated with a harmful impact on LV structure and function. The improved structural and functional changes most likely reflect the effect of the relief of aortic stenosis. It is encouraging however, that, overall, the amount of AR did not adversely affect LV structure or function. The REVIVAL trial mandated that TAVI be used in an elderly cohort of patients with calcific AS who were at very high surgical risk. Therefore, most interest is in a shorter term natural history. The most important finding is that even though some severity of AR is introduced into the already pressure-overloaded, hypertrophied left ventricle of long-standing AS, it is well tolerated.
When evaluated separately, LV volumes in those with moderate AR at 1 year were not significantly different from those at baseline compared with the significant reductions in volumes seen in those with no or trace AR. Unfortunately, given the small number of patients, it is difficult to draw definitive conclusions. However, the lack of significant change in LV volumes may signal an important effect on LV structure over the long term. Although we present data up to 3 years of follow-up, a larger number of patients in the moderate AR group are necessary for a more accurate evaluation.
The diameter of the aortic annulus and the degree of native valve calcification on TTE before valve replacement predicted the degree of AR 12 months after replacement. A larger aortic annulus led to more central AR. This may be explained by the fact that a larger annulus, in addition to requiring the largest valve-in-stent available, would require the most amount of post-dilation and thus potentially result in mild, central leaflet separation. On the other hand, more heavily calcified valves led to relatively more paravalvular AR, which may reflect the incomplete apposition of the stent valve against a markedly calcified boundary, thereby creating potential “channels” of paravalvular AR.
The size of the implanted valve had no bearing on the type or severity of AR that developed over the period of observation. A larger valve is usually chosen to minimize the resultant paravalvular leak or risk of migration of an undersized valve. It is possible that our TTE measurements underestimate the annular size due to beam spread artifact from the highly reflective annular calcification. For this reason, some centers are now favoring the use of computed tomography for aortic annulus measurement (17). Furthermore, the actual diameter of the valve did not correlate with the severity of AR at 6 and 12 months. In aggregate, it seems that in most instances, the correct valve size was chosen, and this subsequently had no bearing on the development or worsening of AR. This finding is in contrast with a recent study suggesting that the lack of congruence between prosthesis and annulus size measured by TTE, as assessed by the ratio of one to the other, is a strong determinant of paravalvular AR (18). In addition to annulus diameter, the geometry and shape of the annulus, the angle between the axis of the LVOT and that of the ascending aorta, and the amount and location of native leaflet calcification have all been examined and should serve as important considerations (19–21) in the selection of the most appropriate valve.
Cribier et al. (11,22) reported the results of the initial 36 percutaneous transcatheter aortic valve replacements performed as part of 2 single-center registries. In both series, AR was paravalvular in all cases and at least moderate in severity in 17 of 27 patients (63%). The amount of paravalvular leak was unchanged in most patients at 4-week follow-up. It is important to note that Cribier et al. (11,22) used 23-mm valves exclusively because this was the only size available for implantation at that time. This valve size may have been undersized in a number of patients and perhaps contributed to the high prevalence of paravalvular AR.
The initial observations by the groups of Cribier et al. (10,11) and Webb et al. (12,13) led to technical refinements including the introduction of a 26-mm valve to help reduce paravalvular regurgitation. Using these refinements, Webb et al. (13) reported, in their series of 50 high-risk patients that central valvular AR was no more than mild and that patients had some degree of paravalvular AR. The 3 patients with moderate paravalvular AR remained stable at 12-month follow-up.
More recently, clinical results from the PARTNER (Placement of Aortic Transcatheter Valves) trial demonstrate mostly mild AR at 30 days and 1 year post-implantation of Edwards-Sapien valves (although moderate or severe AR was present in 11.8% and 10.5% at 30 days and 1 year, respectively) (15). In that cohort, the amount of AR remained stable during the 1-year follow-up period.
In our study, the structural and functional impact of up to mild AR on the LV is limited to the duration of follow-up. In addition, the number of patients with moderate AR after valve implantation was too small to include in robust statistical analyses.
The REVIVAL trial used TTE to assess valve dynamics and area, with a limited assessment of AR. The evaluation of AR post-TAVI can be very challenging, especially when it involves more than one part of the circumference around the valved stent. Serious attempts were made to evaluate the degree of AR in the most quantitative manner. However, a fully quantitative analysis of AR in this study is limited.
Understanding the position of the device or its orientation in relation to surrounding structures is difficult by 2-dimensional TTE unless one relates it to the transducer position. This type of assessment should ideally be performed by TEE during valve implantation. Reassessment of the precise valve position during follow-up may be better performed using 3-dimensional TTE, TEE, or other noninvasive imaging modalities. This was not part of the study protocol and may be the objective of future work in this area.
In summary, central and paravalvular AR is common after percutaneous aortic valve replacement at 1 year follow-up, but the amount of regurgitation is small and does not result in harmful effects on LV structure and function. Paravalvular AR does seem to progress over the course of 12 months, but remains no more than mild in the overwhelming majority of cases. Native aortic leaflet calcification and aortic annulus diameter influence the severity of paravalvular and central AR, respectively. This study provides a motivation for larger imaging trials with longer follow-up to quantify and evaluate the clinical significance of both forms of residual AR.
The authors thank the following principal investigators for each of the participating sites in the REVIVAL trial: William O'Neill, MD, and George Hanzel, MD (William Beaumont Hospital, Royal Oak, Michigan); Jeffrey Moses, MD (Columbia University Medical Center, New York, New York); Murat Tuzcu, MD (Cleveland Clinic Foundation, Cleveland, Ohio); and Todd Dewey, MD (Medical City Dallas, Dallas, Texas). In addition, the authors thank the following individuals responsible for the echocardiography portion of the trial: Michael Gallagher MD (William Beaumont Hospital, Royal Oak, Michigan); Rebecca Hahn, MD (Columbia University Medical Center, New York, New York); William Stewart, MD (Cleveland Clinic Foundation, Cleveland, Ohio); and Jeffrey Horswell, MD (Medical City Dallas, Dallas, Texas).
Dr. O'Neill is a consultant for Medtronic. Dr. Picard directs the REVIVAL Trial echocardiography core laboratory, which is supported by Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- aortic regurgitation
- aortic stenosis
- left ventricular
- left ventricular end-diastolic volume
- left ventricular end-systolic volume
- left ventricular outflow tract
- transcatheter aortic valve implantation
- transesophageal echocardiography
- transthoracic echocardiography
- Received December 12, 2011.
- Revision received February 22, 2012.
- Accepted February 23, 2012.
- American College of Cardiology Foundation
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