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Abstract
Objective Intraoperative predictors of functional mitral valve (MV) stenosis after surgical repair of mitral regurgitation (MR) caused by prolapse remain poorly characterised. This study evaluated the effect of annuloplasty size on postoperative MV haemodynamics during exercise and evaluated predictors of MV hemodynamics.
Methods 104 patients were randomly assigned to leaflet resection or preservation for surgical repair of MR in the Canadian Mitral Research Alliance CardioLink-2 study. In this post hoc analysis, we compared MV haemodynamics between the two surgical groups and examined the relationship between annuloplasty size and MV haemodynamics 1 year after repair in the combined groups. Echocardiograms were performed at baseline and intraoperatively. Exercise transthoracic echocardiography was performed 1 year postoperatively. Multivariable linear regression analysis was used to identify predictors of exercise MV gradients at follow-up.
Results Mean age of participants was 65±10 years, and 83% were male. Median annuloplasty size was 34 (IQR 32–36). Dividing by the median, 48 (46%) had annuloplasty size of <34 mm and 56 (54%) had ≥34 mm. Mean and peak exercise gradients at 1 year were 11±5 mm Hg and 22±9 mm Hg in <34, and 6±3 mm Hg and 14±5 mm Hg in ≥34 (p<0.001). Rate of residual MR was similar in both groups. In multivariable analyses, annuloplasty size of ≥34 mm was associated with lower mean and peak exercise gradients at 12 months, after adjustment for repair type, age, sex, heart rate and body surface area (β −4.1, 95% CI −6 to –3, p<0.001, and β −7 95% CI −10 to –4, p<0.001, respectively). Intraoperative mean and peak MV gradients by transesophageal echocardiography independently predicted mean and peak resting and exercise gradients at follow-up (p<0.001). Similar results were obtained in both leaflet resection and preservation.
Conclusion Annuloplasty size of ≥34 mm is associated with a 4 and 7 mm Hg reduction in mean and peak exercise MV gradients, respectively, 1 year post MV repair regardless of the repair strategy used. Intraoperative TEE MV gradients predict exercise MV gradients 1 year post repair.
Trial registration number NCT02552771.
- mitral valve insufficiency
- heart valve diseases
- echocardiography
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Development of functional mitral stenosis with physiological stress after surgical repair of mitral regurgitation (MR) caused by prolapse is associated with functional limitations, increased rates of atrial fibrillation and heart failure.
Leaflet resection and leaflet preservation strategies for mitral valve (MV) repair confer similar rest and exercise MV haemodynamics and exercise capacity at 1 year post repair.
Intraoperative predictors of mid-to-late MV haemodynamics after surgical repair of MR remain poorly characterised.
WHAT THIS STUDY ADDS
Annuloplasty prosthesis size of 34 mm or greater is independently associated with lower MV gradients both at rest and during peak exercise up to 1 year post MV repair, irrespective of whether a leaflet resection or preservation strategy is used.
Intraoperative MV gradients immediately post MV repair as assessed by transesophageal echocardiography can be used to identify patients at risk of elevated MV gradients within the first year after repair.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The findings from this study may be used to guide surgeons in the choice of annuloplasty prosthesis size in patients undergoing MV repair for severe MR caused and prevent functional MV stenosis in the first year post repair.
Introduction
Mitral valve (MV) repair, either through leaflet resection or leaflet preservation using artificial neochordae, has been shown to restore life expectancy and improve symptoms of severe mitral regurgitation (MR) secondary to degenerative disease.1–3 Mitral annuloplasty using prosthetic rings or bands is the key procedure used to restore adequate coaptation and reinforce repair durability. Functional mitral stenosis (FMS), defined as a reduction of the MV effective orifice area and elevation of transmitral pressure gradients, has emerged as a clinically relevant endpoint for patients undergoing MV repair.4–11 The aetiology of MS post repair has been attributed in part to the anatomic alterations that occur after MV repair, particularly when leaflet resection is employed.12–15 Numerous studies have shown that the presence of functional MS with physiological stress after repair is associated with functional limitations, along with increased rates of atrial fibrillation6 16 17 and heart failure even in the absence of recurrent MR.6 7
Predictors of FMS following MV repair have been explored in retrospective studies and case series.4–10 The size and type of annuloplasty prosthesis and technique of repair were previously reported as predictors of FMS.7 8 10 These studies are limited by sample size, high patient and surgical heterogeneity and lack of longitudinal MV-specific echocardiographic measurements. Further, prior retrospective evaluations were limited to the rest haemodynamics and neglected to assess MV function during loading conditions. Given that functional capacity is an important clinical consequence of FMS for patients undergoing MV surgery, evaluation of MV haemodynamics under stress including an assessment of functional capacity may provide patients and surgeons with important insight that may help guide clinical decision making.
Although echocardiography is the major modality used for the assessment and follow-up of patients with MR undergoing MV repair, few studies have focused on the utility of intraoperative imaging indices as predictors of MV function post repair. Identifying preoperative and intrainoperative echocardiographic endpoints that correlate with mid-term and long-term MV dysfunction remains highly relevant as they may provide guidance for timing of surgical repair and selection of patients at risk of long-term MV dysfunction for monitoring.
The Canadian Mitral Research Alliance (CAMRA) CardioLink-2 study compared mean MV gradient at peak exercise 12 months following surgical repair of MV prolapse with either leaflet resection or leaflet preservation, and found no difference between the two strategies.11 The purpose of this subanalysis of the CAMRA Cardiolink-2 study was to examine the relationship between intraoperative factors including annuloplasty size and MV haemodynamics at rest and during peak exercise 1 year after repair both in the combined cohort as well as within each repair group. Our secondary aim was to identify preoperative and intraoperative echocardiographic and clinical predictors of MV function and exercise capacity post repair.
Materials and methods
Study population
This was a post hoc subanalysis of the CAMRA study. The trial design of the CAMRA CardioLink-2 study has been published in detail previously.11 Briefly, the CAMRA study was a multicentre, non-blinded, double-armed, randomised controlled trial comparing two surgical techniques of MV repair for posterior leaflet prolapse: leaflet resection and leaflet preservation. Patients with posterior leaflet prolapse amenable to either a leaflet resection or leaflet preservation surgical repair strategy were enrolled in the study from seven specialised Canadian cardiac surgical centres. Exclusion criteria included patients with anterior leaflet or commissural prolapse, endocarditis, rheumatic MV disease, mitral annular calcification extending beyond the circumference of one leaflet scallop, significant left ventricular dysfunction (defined as left ventricular ejection fraction <40%) or inability to undergo bicycle ergometry.
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.
Surgical approach
Participants were randomised to either leaflet resection or leaflet preservation in a 1:1 fashion following intraoperative assessment of the MV and confirmation of its amenability to either repair technique. Complete annuloplasty with the Carpentier-Edwards Physio II Ring (Edwards Lifesciences, Irivine, California, USA) bands was used in all patients. Sizing of the Physio II Ring was based on the size of the anterior mitral leaflet. Leaflet resection involved triangular or quadrangular resection with or without concomitant sliding plasty. In this current post hoc analysis of the CAMRA study, the cohort was categorised according to the size of the Physio II Ring used into two groups using the median as the cut-off: Physio II Ring size of <34 mm, and those undergoing repair using Physio II Ring ≥34 mm in size.
Echocardiographic assessment
Echocardiographic examinations were conducted in accord with current guidelines.18 19 Transthoracic echocardiography was performed at three timepoints: baseline (preoperative), before discharge and at 12 months postoperatively. The effective regurgitant orifice area was categorised as mild (<0.2 cm2), moderate (0.20–0.39 cm2) or severe (≥0.4 cm2). The primary outcomes of the original trial, MV gradients at rest and peak exercise, were evaluated using stress echocardiography. Participants underwent exercise echocardiography using a supine bicycle protocol 12 months post repair to assess exercise capacity and intracardiac haemodynamics, including MV gradients and severity of MR at rest and peak exercise. Patients also underwent intraoperative TEE at the time of MV repair to evaluate MV haemodynamics. Intraoperative measurements were done following repair and after the patient was weaned off bypass. All echocardiograms were analysed in an independent core laboratory by assessors who were blinded to treatment allocation.
Statistical analysis
Categorical data are reported as frequency and percentage, and continuous variables are expressed as means±SD, or medians and IQR, as appropriate. Student t-tests were used to assess the differences in clinical and cardiac parameters between the leaflet preservation and leaflet resection groups. A paired t-test was used to compare echocardiographic parameters across different timepoints (eg, intraoperative values to follow-up values at 12 months). Differences in frequencies were assessed using Fisher’s exact test. Linear regression analysis was used to identify associations between follow-up MV indices (rest and peak exercise gradients) at 12 months post-MV repair, and various preoperative and intraoperative echocardiographic and technical and/or procedural factors using a forward model-building approach. Similarly, linear regression analysis was used to identify preoperative and intraoperative predictors of exercise tolerance at 12 months post-MV repair. The multivariable models were adjusted for age, sex, body surface area (BSA), heart rate and surgical approach. Annuloplasty size was analysed both as a continuous and categorical variable. The normality of the residuals was graphically assessed with plots of residuals against fitted values and histograms. A two-tailed p value of 0.05 was considered statistically significant. All statistical analyses were performed using Stata V.17.0.
Results
Participant characteristics
Table 1 summarises the baseline demographic and clinical characteristics of the 104 study participants at the time of enrolment. Fifty-four patients were assigned to the leaflet resection group and 50 patients to the leaflet preservation group. There was one crossover to a leaflet preservation strategy and two investigator-initiated discontinuations, resulting in a total of 51 individuals ultimately undergoing surgical repair with leaflet resection. A total of 48 patients underwent surgical repair with leaflet preservation after two investigator-initiated discontinuations. The two investigator-initiated discontinuations in the resection group occurred in patients who needed chordal replacement to ensure an adequate mitral repair, and a resection approach was deemed not appropriate. The mean age of participants was 65±10 years, and 83% were male. In terms of comorbidities, 50% of patients had hypertension; 43% had dyslipidaemia; and 28% had atrial fibrillation. There were no differences in baseline echocardiographic parameters including left ventricular ejection fraction, left atrial volume, and MV mean and peak gradients between the two groups. The median annuloplasty size was 34 mm (IQR 32–36) and was similar between the two surgical groups. A total of four patients in each of the surgical groups (<1%) underwent tricuspid annuloplasty.
Baseline demographic and clinical characteristics for 104 patients undergoing MV repair stratified by MV repair type
Longitudinal change in MV and echocardiographic parameters
The results of the serial echocardiographic assessments performed intraoperatively, at discharge and 12 months postoperatively are summarised in table 2. Intraoperatively, the leaflet preservation group had lower mean and peak gradients compared with the leaflet resection group (2.1±1.1 and 5.6±2.6 mm Hg vs 2.7±1.2 and 6.7±2.6 mm Hg, respectively). There were no differences in MV gradients and mitral annular dimensions between the leaflet preservation and leaflet resection groups at discharge and 1 year postoperatively. The degree of MR did not differ between the two surgical groups across the various timepoints.
Difference in MV and other echocardiographic parameters across three timepoints: intraoperative values, time of discharge and 1 year post repair
Left atrial volume at discharge was lower compared with intraoperative values and continued to decrease up until 1 year postoperatively. A similar trend was observed with pulmonary arterial pressures. LVEF was lower at discharge compared with intraoperative values. LVEF improved at the 12-month mark compared with discharge values but did not recover to intraoperative levels. Right ventricular parameters including tricuspid valve maximum velocity and peak tricuspid gradients improved at discharge compared with intraoperative values and continued to improve 1 year post repair.
Effect of annuloplasty size on MV parameters
MV gradients at rest and during peak exercise 12 months post surgical MV repair are summarised in table 3. The use of larger annuloplasty sized rings was associated with lower mean and peak gradients at 12 months, as well as lower MV gradients at peak exercise (figure 1). Peak MV gradient at peak exercise was 21.8±7.6 mm Hg in the <34 mm group vs 13.9±5.4 mm Hg in the ≥34 mm group (p=0.001, figure 1). A total of 8 (17%) patients in the annuloplasty <34 group and 18 (32%) in the annuloplasty ≥34 group had mild MR at follow-up (p=0.09), and 2 (4%) patients in the annuloplasty <34 group and 3 (5%) in the annuloplasty ≥34 group had moderate MR at follow-up (p=0.09). There was a linear relationship between annuloplasty size and MV gradients in both the leaflet resection and leaflet preservation groups (figure 2). No difference in mean nor peak mitral gradient at rest between the two different study groups were observed when the results were stratified by annuloplasty size (<34 mm vs ≥34 mm). Similarly, mean and peak MV gradients during peak exercise were comparable between the groups using the two repair approaches (online supplemental figure 1).
Supplemental material
Rest and exercise echocardiography at 12 months by mitral valve repair technique and annuloplasty size
Mean and peak MV gradients at peak exercise in patients who underwent surgical MV repair by leaflet preservation and leaflet resection. Data are stratified by annuloplasty prosthesis size into annuloplasty prosthesis size <34 mm vs ≥34 mm. MV, mitral valve.
Relationship between MV gradients during peak exercise 1 year post MV repair and annuloplasty prosthesis size used. Data were stratified by repair type into leaflet preservation versus leaflet resection. MV, mitral valve.
Predictors of MV function 12 months post repair
The results of univariable and multivariable regression analysis for MV indices at 12 months post-MV repair are presented in online supplemental table 1) and table 4, respectively. Higher intraoperative mean and peak MV gradients, as well as higher discharge mean and peak MV gradients, were associated with higher mean and peak gradients at 12 months. Similarly, higher intraoperative MV gradients were associated with higher MV gradients during peak exercise. Preoperative mean gradients did not predict rest or exercise gradients at follow-up. In multivariable analysis, annuloplasty sizes of ≥34 mm were associated with lower mean and peak rest and exercise gradients at 12 months, after adjustment for repair approach, age, sex, HR and BSA.
Multivariable regression analysis for mean and peak MV gradients at rest and during peak exercise, and 6 min walk distance at 12 months follow-up post MV repair
Determinants of functional capacity at 12 months
Distance covered during the 6 min walk test did not differ between the leaflet resection and leaflet preservation groups (table 3). In univariable analysis, higher preoperative MV mean and peak gradients were associated with shorter distances achieved during the 6 min walk test (online supplemental table 1). This relationship persisted in multivariable analysis after adjusting for age, sex, BSA, repair approach as well as PA pressures at 12 months (table 4). Higher preoperative pulmonary artery pressure was associated with shorter distances walked 12 months postoperatively independent of age, sex, BSA, PA pressures at follow-up and repair strategy.
Discussion
In this subanalysis of the CAMRA CardioLink-2 study, we have demonstrated that a larger annuloplasty size, specifically a prosthesis ring size of ≥34 mm, is independently associated with improved MV haemodynamics both at rest and during peak exercise up to 1 year post-MV repair, irrespective of the surgical repair strategy. Intraoperative MV gradients immediately post MV repair can be used to predict MV haemodynamics both at rest and during peak exercise 1 year post repair. Lastly, preoperative increased pulmonary arterial pressures are associated with reduced exercise capacity 1 year post repair.
Previous retrospective studies into the effect of annuloplasty prosthesis size on MV haemodynamics have reported an inverse association between annuloplasty size and MV gradients at rest immediately post MV repair.8 These studies have reported increased risk of FMS with the use of smaller annuloplasty sizes,8 17 20–23 which in turn was associated with increased risk of atrial fibrillation and heart failure.6 16 17 23 The heterogeneity of the patient populations, variability in surgical repair techniques and retrospective design of these earlier studies precluded any adjustment for potential confounding factors on the association between annuloplasty size and MV functional outcomes. Our findings extend on those of previous studies and show that a larger annuloplasty size is associated with reduced MV gradients both immediately after repair and 1 year post MV repair. Our study is the first to show that using a larger annuloplasty is associated with improved MV haemodynamics at rest as well as during peak exercise, independent of repair strategy used and patient’s age, sex and BSA. Specifically, in our cohort, an annuloplasty size of ≥34 mm conferred a lower risk of MV dysfunction 1 year following repair irrespective of the surgical approach used. Interestingly however, lower MV gradients during peak exercise in our study did not translate into longer distance walked during the 6 min walk test and may be explained by the limited sensitivity of the methodology used. Further studies are required to determine the long-term clinical effects of lower transmitral gradients and larger annuloplasty rings beyond the first-year post repair.
In the current analysis, intraoperative MV gradients assessed by transesophageal echocardiography were predictive of MV gradients at discharge and at 1 year post repair. Further, lower intraoperative MV gradients by TEE were associated with lower mean and peak gradients during peak exercise 1 year later, independent of repair strategy. Interestingly, preoperative gradients did not predict MV gradients at follow-up. This suggests that intraoperative gradients immediately following MV repair can be used to identify patients at risk of developing functional MS within the first year after MV repair. While there was no guidance given to surgeons regarding when to revise a repair, the consensus among recruiting mitral surgeons in this trial was to re-repair or replace the MV if the post repair mean gradient was >5 mm Hg in the operating room after separation from cardiopulmonary bypass. Previous studies have shown that elevated postrepair mitral gradients are associated with an increased risk of developing of atrial fibrillation, higher pulmonary artery systolic pressure, elevated brain natriuretic peptide levels, as well as reduced exercise capacity and quality of life.6 7 24 Further longitudinal studies are needed to assess whether intraoperative MV indices reliably predict late outcomes beyond the first year after MV repair.
The presence of preoperative pulmonary hypertension has been associated with postoperative LV dysfunction, heart failure and death,25–27 and the presence of pulmonary hypertension during exercise has been found to predict adverse events in asymptomatic patients with MR.26 Elevated preoperative pulmonary arterial pressures in the CAMRA study were independently associated with reduced exercise capacity 1 year after MV repair as measured by the 6 min walk test, despite the pulmonary artery pressures significantly decreasing 1 year post repair compared with preoperative values. This may be related to irreversible or pathological remodelling and vasoconstriction of the pulmonary vasculature in response to chronic MR that contributes to increased pulmonary artery pressures and reduced exercise capacity.25 Recognising the limitations of Doppler measurements of pulmonary arterial pressures,28 we found that further follow-up with more direct measures of pulmonary artery pressures is needed to better delineate the reversibility of the pulmonary changes in MR and whether there are longer-term implications of preoperative pulmonary hypertension beyond the first year of repair.
This study has some important strengths. First, echocardiographic data were collected prospectively and analysed in a core lab using standardised protocols, allowing for direct comparison and longitudinal evaluation of MV parameters. Second, assessment of stress echocardiographic data allows for more comprehensive assessment of MV function under loading conditions compared with rest haemodynamics alone. Third, there have been no previous head-to-head comparisons of the different surgical approaches for MV repair that allowed for adjustment of confounding variables in multivariable subanalysis. There are, however, also some limitations to this study. First, the CAMRA cohort had a low incidence of comorbidities and was relatively young (mean age 65 years). Therefore, the findings may not be generalisable to all patients undergoing MV repair who may carry a higher burden of comorbid conditions. Second, as the follow-up period was 1 year after MV repair, inferences beyond this timepoint cannot be made. Given that this was a subanalysis, the findings can only be considered hypothesis-generating and exploratory. Lastly, all patients underwent MV repair using a complete ring, and therefore our results cannot be generalisable to patients undergoing repair using an incomplete ring (band) who may have different MV haemodynamics, or patients undergoing additional repair techniques.
Despite these limitations, this is the first study to investigate the effect of annuloplasty size on MV haemodynamics at rest and peak exercise in a prospective fashion, and directly compare the impact of prosthesis size between two surgical techniques in a randomised trial. This study also identified preoperative and intraoperative predictors of MV function post MV repair. The findings from this study may be used to identify patients intraoperatively who may be at increased risk of MV dysfunction in the first year post repair. The utility of these measurements in predicting long-term outcomes post MV repair requires further longitudinal follow-up.
Conclusion
Annuloplasty prosthesis sizes of ≥34 mm resulted in improved MV haemodynamics both at rest and during peak exercise up to 1 year post MV repair, irrespective of repair strategy used. The risk of developing functional MS and elevated transmitral gradients following MV repair with a leaflet resection strategy may be mitigated by the use of a larger annuloplasty prosthesis size. Intraoperative MV gradients immediately post MV repair as assessed by transesophageal echocardiography can be used to identify patients at risk of FMS within the first year after repair. Exercise capacity is greater after MV repair in patients without preoperative pulmonary hypertension.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants; potential subjects were screened and enrolled at seven specialised Canadian cardiac surgical centres. The study protocol was reviewed and approved independently by the appropriate institutional research ethics board. The ethics committee is St. Michael’s Hospital, Toronto, Ontario, Canada. All participants provided written informed consent preoperatively.
Acknowledgments
This study was made possible by the collaborative efforts of doctors, nurses and administrators at the recruiting hospitals. We thank everyone who contributed their time and expertise, in particular the trial participants.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors RKR contributed to the planning, conduct and reporting of the work described in the article, data analysis and interpretation of the data, as well as writing of manuscript. KC and SV contributed to the planning, conduct and reporting of the work described in the article, as well as the interpretation of the data. VC, DM, AQ, MH, BDV, MWAC, DL, HT, BY and HL-P contributed to the manuscript writing, reporting of the work described and critical review of the manuscript. KC is the guarantor. All authors reviewed and critically revised the manuscript and approved the final version of the submitted manuscript.
Funding The CAMRA CardioLink-2 study was funded by an operating grant from the Heart and Stroke Foundation of Ontario (GIA 16-00014666).
Competing interests SV holds a tier 1 Canada Research chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, EOCI Pharmacomm, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Otsuka, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals and the Toronto Knowledge Translation Working Group. He is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organisation. CDM is supported by a merit award from the University of Toronto Department of Anesthesiology and Pain Medicine and reports advisory board honoraria/consulting fees from Amgen, AstraZeneca, BioAge, Boehringer Ingelheim and PhaseBio and DSMB stipends from Beth Israel Deaconess Medical Center, Cerus and Takeda. BDV reports acting as a consultant for Edwards LifeSciences. MC is supported by the Ray and Margaret Elliot Chair in Surgical Innovation and reports speakers’ honoraria from Medtronic, Edwards Lifesciences, Terumo Aortic, Abbott Vascular and Cryolife. HL-P holds the Brazilian Ball Chair in Cardiology and reports receiving honoraria for speaking engagements from Lantheus Medical Imaging and Janssen. KC is listed as an inventor on a patent application by Boehringer Ingelheim on the use of dipeptidyl peptidase-4 inhibitors in heart failure and reports receiving research grants to his institution from AstraZeneca, Servier and Boehringer Ingelheim; support for travel to scientific meetings from Boehringer Ingelheim; and honoraria for speaking engagements and ad hoc participation in advisory boards from Servier, Merck, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Ferring, Novo Nordisk, Novartis and Janssen.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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