Geometric Changes in Mitral Valve Apparatus during Long-term Cardiac Resynchronization Therapy as Assessed with Cardiac CT

Abstract

Purpose

To assess long-term geometric changes of the mitral valve apparatus using cardiac CT in individuals who underwent cardiac resynchronization therapy (CRT).

Materials and Methods

Participants from a randomized controlled trial with cardiac CT examinations before CRT implantation and at 6 months follow-up (Clinicaltrials.gov identifier NCT01323686) were invited to undergo an additional long-term follow-up cardiac CT examination. The geometry of the mitral valve apparatus, including mitral valve annulus area, A2 leaflet angle, tenting height, and interpapillary muscle distances, were assessed. Geometric changes at the long-term follow-up examination were reported as mean differences (95% CI), and the Pearson correlation test was used to assess correlation between statistically significant geometric changes and left ventricular (LV) volumes and function.

Results

Thirty participants (mean age, 68 years ± 9 [SD]; 25 male participants) underwent cardiac CT imaging after a median long-term follow-up of 9.0 years (IQR, 8.4–9.4). There were reductions in end-systolic A2 leaflet angle (−4° [95% CI: −7, −2]), end-systolic tenting height (−1 mm [95% CI: −2, −1]), and end-systolic and end-diastolic interpapillary muscle distances (−4 mm [95% CI: −6, −2]) compared with pre-CRT implantation values. The mitral valve annulus area remained unchanged. LV end-diastolic and end-systolic volumes decreased (−68 mL [95% CI: −99, −37] and −67 mL [95% CI: −96, −39], respectively), and LV ejection fraction increased (13% [95% CI: 7, 19]) at the long-term follow-up examination. Changes in interpapillary muscle distances showed moderate to strong correlations with LV volumes (r = 0.42–0.72; P < .05), while A2 leaflet angle and tenting height were not correlated to LV volumes or function.

Conclusion

Among the various geometric changes in the mitral valve apparatus after long-term CRT, the reduction in interpapillary muscle distances correlated with LV volumes while the reduced A2 leaflet angle and tenting height did not correlate with LV volumes.

Keywords: Mitral Valve Apparatus, Cardiac Resynchronization Therapy, Cardiac CT

Supplemental material is available for this article.

© RSNA, 2024

Summary

In individuals who underwent cardiac resynchronization therapy, cardiac CT-based analysis identified several geometric changes in the mitral valve apparatus during long-term follow-up.

Key Points

• ■ In this long-term follow-up substudy from a previous randomized controlled trial, geometric changes of the mitral valve apparatus were assessed over a median follow-up of 9.0 years (IQR, 8.4–9.4 years) in 30 participants who underwent cardiac resynchronization therapy.

• ■ When compared with implantation values before cardiac resynchronization therapy, several significant geometric changes were found at long-term follow-up, particularly reduced mean differences in A2 mitral valve leaflet angle of −4° (95% CI: −7, −2), tenting height of −1 mm (95% CI: −2, −1), and interpapillary muscle distances of −4 mm (95% CI: −6, −2).

• ■ Interpapillary muscle distances were moderately to strongly correlated with the temporal left ventricular volume reductions (r = 0.42–0.72; P < .05), while the A2 mitral valve leaflet angle and tenting height were not significantly correlated with left ventricular volumes.

Introduction

Cardiac resynchronization therapy (CRT) is a guideline-directed therapy in patients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF) and prolonged QRS duration who remain symptomatic with optimal medical therapy (1). Functional mitral regurgitation affects around one-third of patients with HF and is associated with adverse clinical outcomes (2). CRT is efficient in reducing functional mitral regurgitation, most likely due to the immediate effects of synchronization of the papillary muscles (3) and the more delayed effects of reverse LV remodeling (4). Improvement of mitral regurgitation severity after CRT implantation has been associated with improved outcomes (5). As some patients undergo left atrial (LA) and LV remodeling (4,6), it may be speculated that the mitral valve apparatus also undergoes some geometric changes. However, the geometric changes of the mitral valve apparatus after long-term CRT have not previously been described.

Two-dimensional echocardiography is usually applied to assess the mitral valve apparatus. However, this imaging modality has modest reproducibility (7) and may not be optimal for detailed anatomic and functional evaluation of the mitral valve apparatus (8). Cardiac CT provides highly reproducible three-dimensional isotropic data with a high spatial resolution that can be shown in any two-dimensional imaging plane. Accordingly, cardiac CT can be applied to accurately assess the mitral valve apparatus geometry (9–11).

In this study, we aimed to assess the long-term morphologic and geometric changes of the mitral valve apparatus following CRT using cardiac CT.

Materials and Methods

Study Sample

This study was a long-term follow-up (LFU) substudy of the Empiric Versus Imaging Guided Left Ventricular Lead Placement in Cardiac Resynchronization Therapy (ImagingCRT) trial (Clinicaltrials.gov identifier NCT01323686) (12,13) and was conducted from May 2021 to April 2022. The LFU protocol was approved by the local ethics committee and conforms to the principles outlined in the Declaration of Helsinki. All participants gave written informed consent before enrollment.

In short, ImagingCRT was conducted from April 2011 to April 2014 and comprised 182 participants with the following characteristics: (a) New York Heart Association (NYHA) functional class II–IV despite optimal medical treatment, (b) LV EFs less than or equal to 35%, (c) QRS duration greater than or equal to 120 msec with left bundle branch block morphology or right ventricular paced QRS duration greater than or equal to 180 msec, and (d) over 40 years of age. Participants were randomized 1:1 to either (a) imaging-guided LV lead placement closest to the latest mechanically activated nonscarred myocardial segment as determined by cardiac CT, speckle-tracking echocardiography, and SPECT, or (b) standard care implantation. Atrioventricular and interventricular delay optimization were performed at 1-day, 1-month, and at 6-month follow-up (6MFU). All participants alive in May 2021 were invited to participate in this LFU study (>7 years), including an additional outpatient visit.

Preimplant and Follow-up Assessment

At the preimplant, 6MFU, and LFU assessments, participants underwent NYHA functional class assessment, 6-minute walk test, measurement of N-terminal pro–B-type natriuretic peptide (NT-proBNP), 12-lead electrocardiography, echocardiography, and contrast-enhanced cardiac CT (12,13). For cardiac CT to be performed, an estimated glomerular filtration rate greater than or equal to 30 mL/min/1.73 m² was required. Medical therapy was assessed at preimplant, 6MFU, and LFU assessments. At the LFU assessment, we reviewed participant files for the occurrence of HF hospitalization (patients admitted to the hospital for >24 hours with symptoms of HF and requiring intravenous treatment for HF) since CRT implantation.

Image Acquisition and Analysis

Echocardiography at the preimplant, 6MFU, and LFU assessments was performed at rest using the Vivid E9 or the Vivid E95 systems (GE Medical Systems). Offline analysis was performed using the EchoPac BT11–12 tool (GE Medical Systems). Echocardiographic LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were estimated using Simpson biplane method (14), and mitral regurgitation was quantified according to recommendations by the European Association of Cardiovascular Imaging (15).

Contrast-enhanced cardiac CT acquisition protocols at the preimplant and 6MFU assessments have previously been described in detail (12,13). The LFU cardiac CT acquisition was performed using a dual-source CT scanner (Siemens Force; Siemens Healthcare) with an 80–120-kV tube voltage. During breath hold, a contrast-enhanced retrospective helical electrocardiographically gated scan timed according to optimal contrast material filling of the ventricular cavities was obtained. Tube current modulation was applied with a reduction of the current to 20%, and full pulsing was applied from 60% to 70% of the R-R interval. Scan pitch was 0.2–0.4 depending on heart rate, and images were reconstructed in 5% intervals of the cardiac cycle. During cardiac CT performed at the 6MFU and LFU assessments, the CRT device remained active. The Circle CVI 42 analysis software (version 5.8.0; Circle Cardiovascular Imaging) was used for dimensional and geometric measures of (a) the D-shaped mitral valve annulus (MVA) in end systole and end diastole, yielding MVA area, posterior perimeter, trigone-to-trigone distance, and intercommissural and septal-to-lateral distances (Fig 1A); (b) mitral valve leaflets in end systole (Fig 1B); and (c) minimum papillary muscle distances in end systole and end diastole (Fig 1C–1E) with input of the landmarks of the aortic root, mitral valve, and apex (11,16). The mitral valve sphericity index was calculated as the ratio of the septal-to-lateral to intercommissural distance. 3mensio Structural Heart (version 10.3; Pie Medical Imaging) was used for the assessment of the LA EDV, ESV, and EF, and Qmass Advanced version 2014 (version 2014; Medis) was used for the assessment of LV EDV, ESV, and EF (17).

Figure 1:

Contrast-enhanced cardiac CT images in a 73-year-old female participant included in the long-term follow-up substudy. (A) The short-axis segmentation of the D-shaped mitral valve annulus (MVA; red and yellow line) yielded measures of the posterior perimeter (P.Pe.), trigone-to-trigone (TT) distance, intercommissural (IC) distance, septal-to-lateral (SL) distance, and MVA area. (B) The mitral valve geometry was assessed in a long-axis view by measuring the A2 and P2 leaflet angles, as well as the tenting height from MVA to the coaptation of the leaflet angles. Papillary muscle geometry was assessed in the long-axis view as the minimum anteromedial papillary muscle (APM)–to–MVA distance (C), the minimum posterolateral papillary muscle (PPM)–to–MVA distance (D), and the minimum APM-to-PPM distance (E). All measures were measured in both end systole and end diastole, except leaflet angles and tenting height, which were only measured in end systole.

D.B.F. (cardiology fellow with cardiac CT experience of >1 year) manually performed all cardiac CT analyses with supervision by K.K., J.D. (engineers with cardiac CT experience of >2 and >3 years, respectively), and P.B. (radiologist and cardiac CT expert with experience of >10 years), who adjudicated all cases before they were included in the dataset.

Statistical Analysis

Continuous variables are presented as means ± SDs or medians with IQRs in parentheses, as appropriate. Categorical variables are presented as frequencies and percentages. The χ² test, paired t test, and one-way analysis of variance with repeated measures were used to assess differences between groups with Bonferroni correction of all pairwise tests. The mean differences with 95% intervals were reported with 95% Bonferroni corrected CIs. Significant geometric changes of the mitral valve apparatus from the preimplant to LFU assessment were correlated to changes in LA and LV volumes and function, MVA area, and remaining significant geometric changes of the mitral valve during the LFU assessment as assessed with cardiac CT using Pearson correlation test. A correlation of less than 0.40 was considered weak, 0.40–0.69 as moderate, and greater than or equal to 0.70 as strong (18). Geometric changes from the preimplant to LFU assessment that reached statistical significance were compared among different participant groups (NYHA functional class improved ≥1 vs NYHA functional class nonimproved, mitral regurgitation severity improved ≥1 grade vs mitral regurgitation severity nonimproved, and LV EF improvement ≥15% vs LV EF improvement <15%) using an unpaired t test. Intraobserver agreement of cardiac CT measures was evaluated in 20 participants using κ statistics, with coefficients greater than 0.90 considered excellent. A two-tailed P value less than .05 was considered statistically significant. All statistical analyses were performed using Stata version 16 (StataCorp).

Results

Study Sample

Among the 182 participants enrolled in the ImagingCRT study between 2011 and 2014, 153 (84%) underwent preimplant cardiac CT and were included for cardiac CT analyses (Fig 2). Among the 182 participants, 90 (49%) were alive in May 2021 and invited for the LFU substudy. Of these, 30 participants (33%) accepted the LFU study invitation and had analyzable cardiac CT, while the remaining were excluded due to unavailable or unanalyzable cardiac CT acquisitions, declining of the study invitation, or loss to follow-up (Fig 2). The median time to the follow-up examination was 9.0 years (IQR, 8.4–9.4). The mean age of participants (five female [17%] and 25 [83%] male participants) at the preimplant assessment was 68 years ± 9. Twenty participants (67%) had ischemic cardiomyopathy, and the mean LV EF was 25% ± 6 as assessed with echocardiography. The distribution of participants from the initial randomization was 15 participants (50%) from the imaging-guided group and 15 participants (50%) from the standard care group. Preimplant characteristics of the included and nonincluded patients and between randomization groups are presented in Tables S1 and S2. The mean cumulated estimated radiation dose was 13.7 mSv ± 7.4 for the preimplant and 6MFU cardiac CT investigations, while the mean radiation dose for the LFU cardiac CT investigation was 13.0 mSv ± 8.6. Intraobserver agreement for all parameters assessed with cardiac CT was excellent, with κ values greater than 0.90.

Figure 2:

Flow diagram of participant selection. eGFR = estimated glomerular filtration rate, LFU = long-term follow-up, 6MFU = 6-month follow-up.

Clinical and Echocardiographic Long-term Changes

During the LFU assessment, two (7%) participants were hospitalized for HF after 5 and 6 years, respectively. Compared with preimplant values, NT-proBNP and QRS duration were significantly reduced at the LFU visit (Table 1). Data on medical therapy during the follow-up period are presented in Table 1.

Table 1:

Clinical and Echocardiographic Parameters of Study Participants

In total, LV EF improved by greater than or equal to 5% in 25 participants (83%) and greater than or equal to 15% in 12 patients (40%) at the 6MFU assessment compared with the preimplant assessment. At the LFU assessment, LV EF improved by greater than or equal to 5% in 26 participants (87%) and greater than or equal to 15% absolute in 15 participants (50%) as compared with preimplant values (Table 1). The overall mitral regurgitation severity grading reduced throughout the follow-up period (Table 1).

Changes in LA and LV Volumes and Function Assessed with Cardiac CT

There was no evidence of differences in LA volumes (mean differences of LA EDV, −3 mL [95% CI: −12, 7] and LA ESV, −9 mL [95% CI: −22, 3]) and LA EF (mean difference, −4% [95% CI: −10, 2]) during the follow-up period (Table 2). LV volumes decreased (mean differences of LV EDV, −68 mL [95% CI: −99, −37] and LV ESV, −67 mL [95% CI: −96, −39]), while LV EF increased (mean difference, 13% [95% CI: 7, 19]) over time (Table 2).

Table 2:

Cardiac CT-derived Temporal Changes of the Left-sided Chambers Following Cardiac Resynchronization Therapy

MVA Dimensions and Mitral Valve Leaflet Geometry

The MVA area did not change throughout the follow-up period, nor did the posterior perimeter, trigone-to-trigone distance, intercommissural distance, septal-to-lateral distance, or the mitral valve sphericity index (Table 3).

Table 3:

Cardiac CT-derived Geometric Changes of the Mitral Valve Apparatus Following Cardiac Resynchronization Therapy

Temporal differences in mitral valve leaflet geometry are detailed in Table 3. Compared with preimplant values, the end-systolic A2 leaflet angle at the LFU assessment was significantly reduced, with a mean difference of −4° (95% CI: −7, −2) (Figs 3,4). No significant reduction was observed for the end-systolic P2 leaflet angle (mean difference, −4° [95% CI: −9, 1]). A reduction from the preimplant to LFU assessment was also found for the tenting height, with a mean difference of −1 mm (95% CI: −2, −1) (Figs 3, 4). Changes from the preimplant to LFU assessment in end-systolic A2 leaflet angle did not correlate with changes in LA volumes and EF (r = −0.03 to 0.17 and r = 0.38, respectively; all P > .05; Table S3) or LV volumes and EF (r = −0.13 to −0.09 and r = −0.01, respectively; all P > .05; Table S3) but were moderately correlated with the end-systolic tenting height (r = 0.64; P < .001; Table S3). Changes from the preimplant to LFU assessment end-systolic tenting height were not significantly correlated with LA volumes and EF (r = 0.04–0.13 and r = 0.12, respectively; all P > .05; Table S3) or LV volumes and EF (r = 0.24–0.32 and r = −0.30, respectively; all P > .05; Table S3). During the LFU assessment, no mean differences in end-systolic A2 leaflet angle or tenting height relative to NYHA functional class, mitral regurgitation severity, LV EF, or initial randomization group reached statistical significance (Tables S4–S7).

Figure 3:

Central tendencies of the mitral valve apparatus at preimplant and long-term follow-up illustrated with contrast-enhanced cardiac CT images in long-axis view in an 85-year-old male participant. During a median follow-up of 9.0 years (IQR, 8.4–9.4), the end-systolic A2 leaflet angle and tenting height, as well as end-systolic and end-diastolic anterolateral papillary muscle (APM)–to–posteromedial papillary muscle (PPM) distances became significantly reduced as compared with preimplant values. Values are means ± SDs or medians with IQRs in parentheses.

Figure 4:

Graphs show the long-term geometric changes of mitral valve apparatus. The values are pairwise Bonferroni-corrected absolute mean differences (MD) with 95% CIs in parentheses. APM = anterolateral papillary muscle, LFU = long-term follow-up, PPM = posteromedial papillary muscle, 6MFU = 6-month follow-up.

The preimplant cardiac CT measures of MVA dimensions and mitral valve leaflet geometry were similar between participants and nonparticipants as well as between participant subgroups according to improvement in NYHA functional class, mitral regurgitation severity, and LV EF (Tables S8, S9).

Papillary Muscle Geometry

The posteromedial papillary muscle (PPM) head was located further apically relative to the MVA as compared with the anterolateral papillary muscle (APM) head in both end systole and end diastole at the preimplant, 6MFU, and LFU assessments (mean PPM-to-MVA distance of 26.3 mm ± 5 to 28.1 ± 6 mm and mean APM-to-MVA distance of 22.6 mm ± 4 to 24.1 mm ± 4, Table 3). However, the end-systolic and end-diastolic PPM-to-MVA and APM-to-MVA distances did not change significantly at follow-up (analysis of variance P = .15–.94, Table 3). Compared with the preimplant visit, there was a significant reduction in the interpapillary muscle distance as assessed by the APM-to-PPM distance at the LFU assessment, with a mean difference of −4 mm (95% CI: −6, −2) in both end systole and end diastole (Table 3, Figs 3, 4). The changes in end-diastolic and end-systolic APM-to-PPM distances were moderately to strongly correlated with changes in LV volumes (r = 0.42–0.72; all P < .05), but not LV EF (r = −0.25, −0.18; all P > .05, Table S3). Change in end-systolic APM-to-PPM distance was moderately correlated with change in end-systolic tenting height (r = 0.59; P = .01). No other statistically significant correlations were found (Table S3). During LFU, there was no evidence of differences in end-systolic and end-diastolic APM-to-PPM distances between participant subgroups according to improvement in NYHA functional class, mitral regurgitation severity, LV EF, and initial randomization group (Tables S4–S7).

The preimplant cardiac CT measures of the papillary muscle geometry were comparable between participants and nonparticipants, as well as between participant subgroups according to improvement in NYHA functional class, mitral regurgitation severity, and LV EF (Tables S8, S9).

Discussion

In individuals who underwent CRT and were assessed with cardiac CT at the LFU assessment, the A2 leaflet angle, tenting height, and interpapillary muscle distances were smaller compared with preimplant values. Interpapillary muscle distances were found to correlate with the temporal LV volume reduction, while the A2 mitral valve leaflet angle and tenting height were not significantly correlated.

Despite the relatively small sample size, this cohort is unique in providing detailed high-quality cardiac CT data from three separate time points up to nearly 10 years after CRT implantation. Only two participants were hospitalized due to HF during the follow-up period, and the proportion of participants with greater than or equal to 5% LV EF improvement was 87%. We even observed an improvement of greater than or equal to 15% LV EF, which is often described as a “super response” (19), for half of the study participants. Individuals in this study may therefore reflect those with the most favorable clinical and echocardiographic response to CRT.

Functional mitral regurgitation can be divided into two phenotypes: (a) ventricular functional mitral regurgitation, which is usually observed in relation to LV dilatation and reduced LV EF (20), and (b) atrial functional mitral regurgitation, which is usually observed in relation to LA dilatation and preserved LV EF (21). Our cohort of participants with severe HF and reduced LV EF are therefore expected primarily to have ventricular functional mitral regurgitation. A recent study by Reid et al (16) described the geometry of the mitral valve apparatus between patients with ventricular functional mitral regurgitation (n = 165), atrial functional mitral regurgitation (n = 18), and no mitral regurgitation (ie, control group; n = 25). The authors used cardiac CT and the same analysis platform as in the present study and reported a systolic MVA area of 12 cm² in patients with ventricular functional mitral regurgitation, which approximates to the 10 cm² at preimplant assessment in the present study. It has been shown that MVA dimensions are larger in patients with versus without mitral regurgitation (22). Our data suggest that the MVA area does not change over time despite reduced mitral regurgitation during LFU, which is not surprising given the fact that MVA is a fibrotic structure (11).

In agreement with the study by Reid et al (16), we found a larger P2 leaflet angle with higher variability than the A2 leaflet angle. It may be speculated that the more central location of the anterior leaflet and, hence, potentially higher exposure to mechanical forces and pressure gradients during ventricular contraction may lead to a lower A2 leaflet angle as compared with the P2 leaflet angle. Consequently, the temporal reduction in the A2 leaflet angle at least partially may be due to the increase in mechanical forces and pressure gradients following mechanical resynchronization. Moreover, we observed a moderate correlation between changes in A2 leaflet angle and tenting height. This finding may be explained by the orientation of the leaflet relative to the MVA, meaning that a reduced A2 leaflet angle will lower the horizontal leaflet position and thereby reduce the tenting height and thus reduce MR severity (23). In a previous study of patients with dilated cardiomyopathy and functional mitral regurgitation, the interpapillary muscle distance assessed with two-dimensional echocardiography was found to be a strong determinant of the mitral valve tenting (24). The changes in interpapillary muscle distance may influence the tension and forces applied to the mitral valve leaflets, which in turn also may affect the tenting height. However, one would also expect the A2 leaflet angle to be correlated with the interpapillary muscle distances. Hence, further investigations of the potential mechanisms of the present findings are needed.

Our study had several limitations. Individuals with HF included in this study were all long-term survivors who had undergone CRT and had significantly improved echocardiographic parameters 9 years following implant. Compared with nonparticipants, the included participants were younger, had lower NYHA functional class, longer 6-minute walk test distance, lower NT-proBNP values, smaller echocardiographic LV volumes, and a higher LV EF at the preimplant visit. Notably, most study participants had no or mild mitral regurgitation. Thus, whether the present findings can be replicated or if more remarkable changes would have been observed if participants had more severe mitral regurgitation requires further investigation in future studies. Therefore, caution should be taken when extrapolating the findings from this study to an unselected CRT population. Larger studies with a comparison between patients with different degrees of functional mitral regurgitation are needed to investigate the mechanisms behind the geometric changes during long-term CRT and their clinical impact. Although all measures of mitral valve geometry were carefully supervised, they were conducted by a single observer, leaving estimates on interobserver agreement unknown. The different implant strategies employed in the two treatment arms in the original randomized controlled trial may potentially have had impact on the geometric changes observed in the current analysis. However, we observed no evidence of differences in preimplant characteristics or in the geometric changes observed between these two groups. The anatomic measures of the mitral valve apparatus were not assessed with echocardiography and, therefore, not compared with the anatomic measures assessed with cardiac CT. Thus, we cannot at this point confirm whether cardiac CT versus echocardiography may be more optimal for this purpose.

In conclusion, various geometric changes in the mitral valve apparatus were found at the LFU assessment in individuals who underwent CRT, particularly reduced A2 leaflet angle, tenting height, and interpapillary muscle distances. The reduction in interpapillary muscle distances was correlated with LV volumes, while the mechanism for the reduced A2 leaflet angle and tenting height requires further investigation. The former may at least partially be secondary to temporal reverse LV remodeling. Our results may offer insights with potential clinical implications. While speculative, certain preimplant measures may predict the long-term CRT response. Additionally, the observed geometrical changes in the mitral valve apparatus may potentially serve as markers for risk stratification and long-term monitoring of individuals undergoing CRT. Understanding the relationship between CRT-induced mitral valve geometry changes and patient outcomes requires further research.