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Risk factors and clinical significance of elevated mitral valve gradient following valve repair for degenerative disease Abstract Abstract OBJECTIVES The risk factors and clinical effect of elevated mitral valve (MV) gradients after valve repair for degenerative valve disease remain insufficiently understood. METHODS Between January 2004 and December 2015, a total of 484 patients underwent valve repair for degenerative disease. A true-sized full annuloplasty ring was implanted in all cases. We analysed the effect of preoperative and intraoperative factors on the postrepair gradient. Additionally, we explored the effect of postrepair gradients on long-term outcomes. RESULTS On linear regression analysis, postrepair MV gradients were associated with patient age (coefficient = −0.110, standard error = 0.005, P = 0.034), body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008), implanted annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) and the use of Physio I ring (coefficient = 0.414, standard error = 0.122, P = 0.001). On multivariable analysis, postrepair MV gradient was not associated with overall survival [hazard ratio (HR) 1.034, 95% confidence interval (CI) 0.889–1.203; P = 0.66] or freedom from atrial fibrillation (HR 0.849, 95% CI 0.682–1.057; P = 0.14), but did emerge as a risk factor for MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029). Two out of 11 reinterventions were performed due to MV stenosis and in both patients, high postrepair gradients were seen readily on predischarge echocardiography. CONCLUSIONS Following valve repair for degenerative MV disease, elevated gradients occur even when true-sized annuloplasty is performed. The late clinical results of valve repair with elevated postrepair gradient are impaired and further studies are needed to explore preventive measures aimed at resolving the issue. INTRODUCTION Surgical mitral valve (MV) repair is the treatment of choice for mitral regurgitation (MR) due to degenerative disease with high valve reparability, repair durability and freedom from reoperation rates readily established [1, 2]. When the results of MV repair are examined in further detail, the problem of elevated postrepair gradients following an otherwise successful repair has emerged as a subject of debate [3–5]. The problem of elevated postrepair MV gradients was initially described in patients after restrictive mitral annuloplasty for ischaemic MR [4] but may also be of clinical importance in patients with degenerative MR [3, 5]. To justify the growing enthusiasm for early surgery of yet asymptomatic patients with degenerative MR, optimal patient- and valve-related results are needed. Data on the risk factors and clinical impact of elevated MV gradients following valve repair for degenerative disease remain scarce. The aim of this study was to analyse the risk factors of elevated postrepair MV gradients and its effect on patient- and valve-related outcomes in a cohort of patients who underwent successful MV repair for degenerative disease. METHODS Patients All adult patients (≥18 years of age) who underwent surgical intervention (n = 528) for MR due to degenerative disease between January 2004 and December 2015 at our institution were eligible for inclusion. We excluded patients with a history of previous cardiac surgery (n = 18) and patients in whom MV replacement was performed (n = 9). Of the remaining 501 patients, 17 additional patients were excluded for the following reasons: early mortality (n = 6), non-use of annuloplasty ring (n = 4) or missing predischarge echocardiogram (n = 7). The final study cohort compromised 484 patients who all underwent successful MV repair with a complete annuloplasty ring. Measurements of MV gradients were acquired from continuous wave Doppler acquisitions of the diastolic inflow of the MV. Mean MV gradient was calculated as the average of 3 and 5 cycles or patients in sinus rhythm and atrial fibrillation, respectively. All acquisitions were performed according to a standardized protocol of our echo lab to ensure data reproducibility. All measurements were performed by experienced echocardiographists. Study end points All end points were defined according to the Guidelines for reporting mortality and morbidity after cardiac valve interventions [6]. Primary end points included all-cause mortality and freedom from MV reintervention. Secondary end points included freedom from atrial fibrillation. We excluded other types of atrial tachycardias (e.g. atrial flutter or incisional atrial tachycardia) because of aetiological differences associated with the development postrepair atrial tachycardias [7]. Only patients in preoperative sinus rhythm (n = 312) were included in the latter analysis. Surgical technique and perioperative care When indicated, anterior MV leaflet prolapse was addressed with chordal replacement. Posterior MV leaflet prolapse was addressed with a combination of leaflet resection and chordal replacement techniques. The decision on which technique to use was based on the extent of leaflet prolapse and excessive tissue in height and/or width. Earlier in this series, annular plication was more frequently used to help restore the continuity of the posterior MV leaflet. Later, leaflet sliding techniques were employed. Commissural prolapse was primarily addressed with papillary muscle head repositioning. All patients included in the current study underwent full annuloplasty ring implantation. Ring sizing was standardly based on the surface area of the anterior MV leaflet and was not influenced by the type of anterior and/or posterior MV leaflet repair technique used. No over- or downsizing was performed in any of the patients. Intraoperative transoesophageal echocardiography was performed by an experienced cardiologist to document the intraoperative result of MV repair. Additionally, predischarge transthoracic echocardiography (performed on postoperative day 4–7) was performed to exclude any significant residual MR. Systolic anterior motion was observed in 2 patients and treated conservatively. Oral anticoagulation was initiated for a period of 3 months with a target Internationalized Normalized Ratio of 2.0–3.0. In presence of other indications, the target Internationalized Normalized Ratio range and treatment duration were adjusted accordingly. Follow-up Preoperative, intraoperative and postoperative data were retrospectively collected from our computerized database. Follow-up survival, clinical and echocardiographic data were collected through regular clinical visits at our institution or affiliated clinics and hospitals, and through questionnaires to patients. Patient follow-up was based on the available recommendations [8]. Records pertaining to reported office visits, echocardiography and rhythm information, operations, cardioversions, catheter ablation or hospitalizations were obtained and analysed. Rhythm follow-up was based on electrocardiograms obtained during regular follow-up. Additional rhythm monitoring (e.g. 24-h Holter monitoring) was performed on clinical grounds (e.g. complaints of heart palpitations) and the indication for this was left at the discretion of the attending cardiologist. A total of 1126 (mean 2.3/patient, range 0–8) follow-up echocardiograms were available for analysis. The study was approved by our Institutional Ethics Committee and patient consent was obtained to allow collection and analysis of any relevant clinical and echocardiographic data. Follow-up was completed in February 2017. Statistical analysis Continuous data are presented as means ± standard deviation for normally distributed data or medians and interquartile range (IQR) when not normally distributed. Categorical data are presented as counts and percentages. The distribution of variables was evaluated using the Kolmogorov–Smirnov test. A univariable and multivariable linear regression model, with postrepair MV gradient as a dependent continuous variable, was built to explore the factors associated with postrepair MV gradient. Variable inclusion was based on the previously established effect on MV gradient. To assess for the presence of violations in model assumptions, residuals were plotted versus fitted values and investigated graphically. Univariable and multivariable Cox proportional hazards regression analysis was used to explore risk factors for the occurrence of time-to-event outcomes. Based on known clinical validity and taking into account the ratio of events to risk factors, the following factors were included in respective multivariate models: ‘for mortality’: age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR, atrial fibrillation and postrepair MV gradient; ‘for reintervention’: anterior MV leaflet repair and postrepair MV gradient; and ‘for atrial fibrillation’: age, tricuspid valve repair, preoperative left atrial diameter and postrepair MV gradient. Cubic third-degree splines were used to adjust for possible non-linear association of mean MV gradient with time-to-event outcome in the proportional hazards model. The Wald test was used to test for the presence of non-linear effect. In addition to P-value-based hypothesis testing, non-linearity of mean MV gradient was assessed graphically by plotting the fitted splines for mean MV gradient, together with 95% confidence intervals (CIs) on the log-hazard scale versus mean MV gradient. To study the evolution of mean MV gradients during the follow-up period, a mixed-model based linear regression analysis of MV gradient on follow-up time which accounts for repeated within-patient observation was carried out. To account for potential heteroscedasticity or non-normality, bootstrap-based standard errors were investigated. In addition, a post hoc exploration of model residuals was explored to investigate these same model assumptions as well as the linearity assumption of MV gradient decent versus follow-up time. No evidence of serious model deviations was found and hence the regular standard errors and hypothesis test are reported. All tests were 2-tailed and a P-value of <0.05 was considered statistically significant. Statistical analysis was performed using IBM Statistics for Windows, version 23.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.) and R, version 3.5.1 using the Survival package, version 2.43–3 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS Baseline characteristics and mitral valve repair details Baseline characteristics of the whole study group are presented in Table 1. Median patient age was 66.5 (IQR 57.8–73.8) years and the majority of patients were male. The repair and procedure details are presented in Table 2. A full ring was used in all patients; the majority of patients (n = 456; 94.2%) underwent either a Physio I (n = 223; 46.1%) or Physio II (n = 233; 48.1%) ring (Edwards Lifesciences, Irvine, CA, USA) implantation. In 42 (8.7%) patients, a ring size 30 or smaller was implanted. Table 1: Baseline characteristics n = 484 Age (years) 66.5 (57.8–73.8) Gender (female) 171 (35.3) Body surface area (m2) 1.93 ± 0.22 NYHA I 146 (30.2) II 243 (50.2) III–IV 95 (19.6) Hypertension 221 (45.7) Atrial fibrillation 172 (35.5) Renal impairment (ml/min/1.73 m2) Moderate (CC 50–85) 226 (46.7) Severe (CC <50) 41 (8.5) Diabetes mellitus 22 (4.5) Chronic lung disease 42 (8.7) Mitral annular calcification 49 (10.1) Echocardiographic characteristics LVEF ≤60% 134 (27.7) LVEDD (mm)a 54 ± 7 LVESD (mm)a 33 ± 7 LAD (mm)a 45.0 (40.0–49.0) EuroSCORE II 1.76 (0.99–3.24) Degenerative disease subtype Barlow’s disease 140 (28.9) Forme fruste Barlow’s disease 51 (10.5) Site of leaflet prolapse Posterior leaflet 299 (61.8) Single scallop prolapse 234 (48.3) Anterior leaflet 41 (8.5) Bileaflet 144 (29.7) Data are presented as n (%) and means ± SD or medians (IQR). a Available for ≥95% of patients. CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation. Table 2: Mitral valve repair details n = 484 Mitral valve annulus Plication 102 (21.1) Anterior mitral valve leaflet repair (neochords) 125 (25.8) Posterior mitral valve leaflet Resection 321 (66.3) Leaflet sliding 222 (45.9) Neochords 206 (42.6) Chordal transfer 9 (1.9) Indentation closure 85 (17.6) Commissural repair 111 (22.9) Annuloplasty ring type Physio I ring 223 (46.1) Physio II ring 233 (48.1) Other 28 (5.8) Annuloplasty ring size 24 1 (0.2) 26 10 (2.1) 28 31 (6.4) 30 62 (12.8) 32 112 (23.1) 34 98 (20.3) 36 77 (15.9) 38 52 (10.7) 40 41 (8.5) Intraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40) Concomitant procedures Tricuspid valve repair 321 (51.4) Radiofrequency ablation for atrial fibrillation 148 (30.6) Coronary artery bypass surgery 96 (19.8) Aortic valve intervention 28 (5.8) Data are presented as n (%) and medians (IQR). IQR: interquartile range. Postrepair mitral valve gradient A moderate positive correlation (r = 0.356, n = 391, P < 0.001) between the intraoperative and predischarge MV gradient was seen (Supplementary material, Figure S1). The haemodynamic results of valve repair are demonstrated in Table 3. As expected, postrepair MV gradients decreased with the size of annuloplasty ring implanted (Fig. 1). On linear regression analysis, increasing patient age (coefficient = −0.11, standard error = 0.005, P = 0.034) and annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) were correlated with lower postrepair MV gradients (Table 4). On the other hand, increasing body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008) and, interestingly, use of the Physio I ring (coefficient = 0.414, standard error = 0.122, P < 0.001) were correlated with higher postrepair MV gradients. The linear regression model demonstrated good fit with no evidence of heteroscedasticity or non-linearity (Supplementary material, Figure S2). Figure 1: Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers. Table 3: Postoperative echocardiographic results n = 484 Predischarge mitral valve gradient (mmHg) 3.46 ± 1.43 Predischarge heart rate (min−1) 80 ± 15 Predischarge stroke volume (ml)a 74 (58–93) Predischarge cardiac index (l/m2)a 5.7 (4.6–7.4) Predischarge haemoglobin value (mmol/l) 6.4 ± 0.8 Data are presented as means ± standard deviations and medians (IQR). a Available for ≥90% of patients. IQR: interquartile range. Table 4: Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients Univariable analysis Multivariable analysis Coefficient Standard error P-value Coefficient Standard error P-value Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65 Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034 Body surface area 0.294 0.302 0.33 0.905 0.340 0.008 Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95 Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48 Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23 PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14 PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41 Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001 Annuloplasty ring type Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001 Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001 Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001 PMVL: posterior mitral valve leaflet. Late clinical results From cubic spline-based analyses, no evidence of non-linearity for post repair MV gradient was found for all time-to-event outcomes (Supplementary materials, Figures S3–S5). Hence, postrepair MV gradient was entered into the Cox proportional hazards regression analysis models as a continuous variable for all subsequent analyses. During a median follow-up period of 5.8 (IQR 3.4–9.3) years (99.5% complete, 2 patients were lost to follow-up due to emigration), 84 patients died. When corrected for patient age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR and atrial fibrillation, postrepair MV gradients was not associated with patient survival [hazard ratio (HR) 1.034, 95% CI 0.889–1.203; P = 0.66; Supplementary material, Table S1]. Follow-up on clinical related events was 90% complete with a mean duration of 5.2 (IQR 2.7–8.8) years. When adjusted for patient age, tricuspid valve repair and preoperative left atrial diameter, postrepair MV gradient was not associated with late atrial fibrillation occurrence (HR 0.849, 95% CI 0.682–1.057; P = 0.14; Supplementary material, Table S1). When adjusted for anterior MV leaflet repair, postrepair MV gradient was associated with a higher risk of MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029; Supplementary material, Table S1). A total of 11 late reinterventions were performed. The indication for reintervention was recurrent MR in 9 patients and elevated MV gradient in the remaining 2 patients. In both of the latter patients, a postrepair gradient of ≥5 mmHg (5.88 and 5.23 mmHg, respectively) was seen on predischarge echocardiography, despite an acceptable gradient seen on intraoperative echocardiography (2.53 and 4.23 mmHg, respectively). In the first of the latter patients, an annuloplasty ring size 26 was initially implanted and a re-repair due to heart failure symptoms (no significant MR or other explanation for this observation were found) was performed 1.3 years after the initial operation. Upon reoperation, the annuloplasty ring was explanted, resolving the problem of elevated gradient. In the other patient, an annuloplasty ring size 32 was implanted during the initial operation. Severe pannus formation occurred and the patient underwent a valve replacement 1.1 years after the initial operation. Late echocardiographic results On mixed-model linear regression analysis on the evolution of mean MV gradient during the follow-up period, a slight decline in MV gradients was seen (estimate = −0.05, 95% CI −0.07 to −0.02; P < 0.001) during the follow-up period (Fig. 2). Figure 2: Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed. DISCUSSION The results of our study are in line with previous studies, and demonstrate that, following valve repair for degenerative disease, high postrepair gradients are of important clinical relevance. However, repair technique (in particular posterior MV leaflet resection) did not show a significant effect on postrepair gradients and no effect of postrepair gradients on the occurrence of late atrial fibrillation was observed. The mechanism of elevated postrepair MV gradients is poorly understood, but is in our opinion related to fixation of the posterior annular perimeter length. Indeed, in an adult sheep model, Dagum et al. [9] have shown that cyclic changes in the MV annular area, reaching a maximum in late diastole, are correlated with length changes of the posterior annular perimeter. After implantation of a true-sized partial or complete flexible annuloplasty device, complete fixation of the MV annular area, posterior and anterior annular perimeters throughout the cardiac cycle was observed. Similarly, Bothe et al. [10] reported that MV annuloplasty results in a significant reduction of the maximal MV opening area, independent of the type of annuloplasty device used (partial or full ring; flexible, semi-rigid or rigid). Moreover, the Physio I ring (as well as the majority of other full rings implanted) did not impair posterior MV leaflet motion. Additionally, while the Physio I ring did increase the excursion of the annular and belly region of the anterior MV leaflet, it did not affect the excursion of the anterior leaflet at the leaflet edge. No effect on anterior leaflet motion was seen after the implantation of a partial Cosgrove-Edwards band (Edwards Lifesciences). Their results suggest that no diastolic flow obstruction due to changes in anterior leaflet motion is to be expected after implantation of the majority of annuloplasty devices tested. In a study on 107 patients after MV repair for degenerative disease, Mesana et al. [5] suggested that full rings may be associated with higher postrepair gradients when compared to partial bands. Their results need to be interpreted with caution as the Duran ring (Medtronic Inc., Minneapolis, MN, USA), notoriously prone to significant pannus formation [11, 12], was used in most patients who underwent full ring implantation. As MV gradients were measured several years after the initial operation, the high gradients observed in this group are most likely due to pannus formation and not the type of annuloplasty device implanted. Murashita et al. [13] explored postrepair gradients in 1147 patients after MV repair for degenerative disease. In most patients, a standard 63 mm flexible band was implanted, irrespective of annular perimeter length or anterior leaflet size. In the first median follow-up period (124.5 days after operation), a mean gradient of 3.7 ± 1.6 mmHg was reported that declined to a mean gradient of 3.3 ± 1.8 mmHg in the second median follow-up period (600 days after operation). The gradients in the first median follow-up period seem somehow higher than early postrepair gradients observed in our population. On longitudinal analysis, a decline similar to the one observed by Murashita et al. was also observed in our population. While clearly limited, amongst others, by the unadjusted differences in patient populations, such observations challenge the alleged superiority of partial bands in terms of postrepair gradients. On the other side, excessive shortening of the posterior annular perimeter (resulting from downsizing described by the authors) is bound to have resulted in smaller MV areas than would have been achieved with a true-sized ring. The results of our analyses suggest that the postrepair gradient is partially associated with patient characteristics (both patient age and body surface area likely reflect the relation of these parameters to systemic metabolic needs and hereto related cardiac output). Moreover, our results demonstrate that the choice of annuloplasty device used might affect postrepair gradients. This is likely correspondent to the differences in the ratio between the anterior-posterior diameter (reflecting anterior MV leaflet surface area to which the ring is sized) and the length of the ‘posterior perimeter’ of the annuloplasty ring between different annuloplasty devices. We are unaware of any studies demonstrating that the increased saddle shape of the Physio II ring is related to improved diastolic MV opening properties when compared to annuloplasty devices with less pronounced saddle-shape. Because of the lack of studies, we cannot exclude the possibility that the Physio II ring results in superior diastolic opening properties of the anterior leaflet that might explain our observation. For the time being, this should, however, be seen as a theory and properly designed studies will need to be conducted in the future. In a recent meta-analysis, Mazine et al. [14] have speculated that in cases of posterior MV leaflet prolapse, chordal replacement techniques will result in lower MV gradients when compared to leaflet resection techniques. Our results failed to demonstrate any significant effect of posterior leaflet resection on postrepair gradient. This is likely related to the fact that we primarily used leaflet resection techniques to address excessive posterior MV leaflet tissue and structurally avoided excessive resection. Should this be avoided, no significant shortening of the posterior leaflet free edge, that could at least theoretically limit diastolic leaflet mobility, is to be expected. Functional MV stenosis should not present a reason not to perform adequate leaflet resection when this is indicated, an opinion previously emphasized by our group and others [15–18]. We did not observe any effect of elevated MV gradients on freedom from atrial fibrillation. On the contrary, elevated postrepair MV gradient was identified as a risk factor for late atrial fibrillation occurrence in recent studies by Kawamoto et al. [19] as well as Ma et al. [20]. We included only patients in sinus rhythm who did not undergo any ablation procedures, a characteristic that could provide an explanation for the differences observed between our results and those of Kawamoto et al. [19]. More importantly, we differentiated between atrial fibrillation and other types of atrial tachycardias as the mechanisms associated with the development of different atrial tachycardias after MV operations are known to fundamentally differ [7]. To adjust for potential unadjusted bias, future studies should include information on the type of incision made to expose the MV when exploring the effect of other factors on early and late atrial tachycardias. Previous studies also demonstrated that an elevated postrepair MV gradient impairs left atrial reverse remodelling [21]. Nevertheless, atrial fibrillation is most likely related to left atrial fibrosis that develops because of long-standing volume overload prior to the operation and is present even in patients in preoperative sinus rhythm [22]. More studies, with longer follow-up, are also needed to explore whether left atrial reverse remodelling in the presence of elevated postrepair gradient is impaired or only delayed. The results of our study do, however, suggest that the clinical burden of elevated postrepair gradient might be lower than previously suggested. The observation that the risk of reintervention might be related to postrepair MV gradient has not previously been reported. The incidence of reoperation for MV stenosis after previous repair is known to be low [13, 23], but reflects only the patients most affected by this condition. Other studies have additionally shown that high postrepair gradients will result in decreased exercise tolerance and quality of life [3, 5]. We followed the established concepts of valve repair for degenerative disease that include annular remodelling and stabilization. As fixation of the maximal posterior perimeter length and hereto related maximal MV area are likely inevitable with any type of annuloplasty device used, elevated postrepair gradients might not be avoidable in all patients. Omitting annuloplasty device implantation is controversial, as this is known to result in a higher risk of recurrent MR [24]. Possibly, new annuloplasty device design and identification of patients in whom annular characteristics are sufficiently preserved to support valve sufficiency in the long term even without annular stabilization would help reduce the burden of this problem. Limitations This is a single-centre retrospective study with study limitations inherent to the study design. The results are applicable to the type of MV repair techniques described only and further studies are needed to evaluate the effect or other repair techniques (e.g. edge-to-edge repair) and annuloplasty devises on the occurrence of elevated postrepair gradients. During the study period, the MV repair techniques have evolved with, in particular, annular plication being performed less frequently. As the type of leaflet repair did not affect the sizing of the annuloplasty device implanted, no relevant effect on the results presented is to be expected. Moreover, the number of reinterventions was low and prevented us from exploring the risk factors for MV reintervention specified to the indication for reintervention (i.p. recurrent MR versus elevated MV gradient). While we failed to identify a relation between postrepair MV gradient and survival or atrial fibrillation, we cannot exclude the possibility that a correlation does exist, but we were unable to detect it due to an insufficient number of patients and events. Our results should thus be seen as hypothesis-generating and will need to be confirmed by future studies. We have performed cubic spline analyses, but failed to identify a cut-off value that would ease the identification of patient a risk for complications related to elevated postrepair MV gradient in the clinical setting. Identification of a cut-off value should be pursued in future studies. Nevertheless, in line with previous studies, our results do support the efforts aimed at securing the lowest possible postrepair MV gradient. CONCLUSIONS Following MV repair with a semi-rigid annuloplasty ring, increased resting MV gradients are not uncommon. This is, among others, related to the implanted ring size and patient body surface area. Elevated postrepair MV gradients might result in poorer freedom from reintervention due to the added risk of reintervention for MV stenosis while survival and incidence of late atrial fibrillation development do not seem to be affected. Conflict of interest: none declared. Supplementary Material ezz178_Supplementary_Material Click here for additional data file. Presented at the 98th Annual Meeting of the American Association of Thoracic Surgeons, San Diego, CA, USA, 28 April–1 May 2018.

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article-title	Risk factors and clinical significance of elevated mitral valve gradient following valve repair for degenerative disease
abstract	Abstract OBJECTIVES The risk factors and clinical effect of elevated mitral valve (MV) gradients after valve repair for degenerative valve disease remain insufficiently understood. METHODS Between January 2004 and December 2015, a total of 484 patients underwent valve repair for degenerative disease. A true-sized full annuloplasty ring was implanted in all cases. We analysed the effect of preoperative and intraoperative factors on the postrepair gradient. Additionally, we explored the effect of postrepair gradients on long-term outcomes. RESULTS On linear regression analysis, postrepair MV gradients were associated with patient age (coefficient = −0.110, standard error = 0.005, P = 0.034), body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008), implanted annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) and the use of Physio I ring (coefficient = 0.414, standard error = 0.122, P = 0.001). On multivariable analysis, postrepair MV gradient was not associated with overall survival [hazard ratio (HR) 1.034, 95% confidence interval (CI) 0.889–1.203; P = 0.66] or freedom from atrial fibrillation (HR 0.849, 95% CI 0.682–1.057; P = 0.14), but did emerge as a risk factor for MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029). Two out of 11 reinterventions were performed due to MV stenosis and in both patients, high postrepair gradients were seen readily on predischarge echocardiography. CONCLUSIONS Following valve repair for degenerative MV disease, elevated gradients occur even when true-sized annuloplasty is performed. The late clinical results of valve repair with elevated postrepair gradient are impaired and further studies are needed to explore preventive measures aimed at resolving the issue.
title	Abstract
sec	OBJECTIVES The risk factors and clinical effect of elevated mitral valve (MV) gradients after valve repair for degenerative valve disease remain insufficiently understood.
title	OBJECTIVES
p	The risk factors and clinical effect of elevated mitral valve (MV) gradients after valve repair for degenerative valve disease remain insufficiently understood.
sec	METHODS Between January 2004 and December 2015, a total of 484 patients underwent valve repair for degenerative disease. A true-sized full annuloplasty ring was implanted in all cases. We analysed the effect of preoperative and intraoperative factors on the postrepair gradient. Additionally, we explored the effect of postrepair gradients on long-term outcomes.
title	METHODS
p	Between January 2004 and December 2015, a total of 484 patients underwent valve repair for degenerative disease. A true-sized full annuloplasty ring was implanted in all cases. We analysed the effect of preoperative and intraoperative factors on the postrepair gradient. Additionally, we explored the effect of postrepair gradients on long-term outcomes.
sec	RESULTS On linear regression analysis, postrepair MV gradients were associated with patient age (coefficient = −0.110, standard error = 0.005, P = 0.034), body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008), implanted annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) and the use of Physio I ring (coefficient = 0.414, standard error = 0.122, P = 0.001). On multivariable analysis, postrepair MV gradient was not associated with overall survival [hazard ratio (HR) 1.034, 95% confidence interval (CI) 0.889–1.203; P = 0.66] or freedom from atrial fibrillation (HR 0.849, 95% CI 0.682–1.057; P = 0.14), but did emerge as a risk factor for MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029). Two out of 11 reinterventions were performed due to MV stenosis and in both patients, high postrepair gradients were seen readily on predischarge echocardiography.
title	RESULTS
p	On linear regression analysis, postrepair MV gradients were associated with patient age (coefficient = −0.110, standard error = 0.005, P = 0.034), body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008), implanted annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) and the use of Physio I ring (coefficient = 0.414, standard error = 0.122, P = 0.001). On multivariable analysis, postrepair MV gradient was not associated with overall survival [hazard ratio (HR) 1.034, 95% confidence interval (CI) 0.889–1.203; P = 0.66] or freedom from atrial fibrillation (HR 0.849, 95% CI 0.682–1.057; P = 0.14), but did emerge as a risk factor for MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029). Two out of 11 reinterventions were performed due to MV stenosis and in both patients, high postrepair gradients were seen readily on predischarge echocardiography.
sec	CONCLUSIONS Following valve repair for degenerative MV disease, elevated gradients occur even when true-sized annuloplasty is performed. The late clinical results of valve repair with elevated postrepair gradient are impaired and further studies are needed to explore preventive measures aimed at resolving the issue.
title	CONCLUSIONS
p	Following valve repair for degenerative MV disease, elevated gradients occur even when true-sized annuloplasty is performed. The late clinical results of valve repair with elevated postrepair gradient are impaired and further studies are needed to explore preventive measures aimed at resolving the issue.
body	INTRODUCTION Surgical mitral valve (MV) repair is the treatment of choice for mitral regurgitation (MR) due to degenerative disease with high valve reparability, repair durability and freedom from reoperation rates readily established [1, 2]. When the results of MV repair are examined in further detail, the problem of elevated postrepair gradients following an otherwise successful repair has emerged as a subject of debate [3–5]. The problem of elevated postrepair MV gradients was initially described in patients after restrictive mitral annuloplasty for ischaemic MR [4] but may also be of clinical importance in patients with degenerative MR [3, 5]. To justify the growing enthusiasm for early surgery of yet asymptomatic patients with degenerative MR, optimal patient- and valve-related results are needed. Data on the risk factors and clinical impact of elevated MV gradients following valve repair for degenerative disease remain scarce. The aim of this study was to analyse the risk factors of elevated postrepair MV gradients and its effect on patient- and valve-related outcomes in a cohort of patients who underwent successful MV repair for degenerative disease. METHODS Patients All adult patients (≥18 years of age) who underwent surgical intervention (n = 528) for MR due to degenerative disease between January 2004 and December 2015 at our institution were eligible for inclusion. We excluded patients with a history of previous cardiac surgery (n = 18) and patients in whom MV replacement was performed (n = 9). Of the remaining 501 patients, 17 additional patients were excluded for the following reasons: early mortality (n = 6), non-use of annuloplasty ring (n = 4) or missing predischarge echocardiogram (n = 7). The final study cohort compromised 484 patients who all underwent successful MV repair with a complete annuloplasty ring. Measurements of MV gradients were acquired from continuous wave Doppler acquisitions of the diastolic inflow of the MV. Mean MV gradient was calculated as the average of 3 and 5 cycles or patients in sinus rhythm and atrial fibrillation, respectively. All acquisitions were performed according to a standardized protocol of our echo lab to ensure data reproducibility. All measurements were performed by experienced echocardiographists. Study end points All end points were defined according to the Guidelines for reporting mortality and morbidity after cardiac valve interventions [6]. Primary end points included all-cause mortality and freedom from MV reintervention. Secondary end points included freedom from atrial fibrillation. We excluded other types of atrial tachycardias (e.g. atrial flutter or incisional atrial tachycardia) because of aetiological differences associated with the development postrepair atrial tachycardias [7]. Only patients in preoperative sinus rhythm (n = 312) were included in the latter analysis. Surgical technique and perioperative care When indicated, anterior MV leaflet prolapse was addressed with chordal replacement. Posterior MV leaflet prolapse was addressed with a combination of leaflet resection and chordal replacement techniques. The decision on which technique to use was based on the extent of leaflet prolapse and excessive tissue in height and/or width. Earlier in this series, annular plication was more frequently used to help restore the continuity of the posterior MV leaflet. Later, leaflet sliding techniques were employed. Commissural prolapse was primarily addressed with papillary muscle head repositioning. All patients included in the current study underwent full annuloplasty ring implantation. Ring sizing was standardly based on the surface area of the anterior MV leaflet and was not influenced by the type of anterior and/or posterior MV leaflet repair technique used. No over- or downsizing was performed in any of the patients. Intraoperative transoesophageal echocardiography was performed by an experienced cardiologist to document the intraoperative result of MV repair. Additionally, predischarge transthoracic echocardiography (performed on postoperative day 4–7) was performed to exclude any significant residual MR. Systolic anterior motion was observed in 2 patients and treated conservatively. Oral anticoagulation was initiated for a period of 3 months with a target Internationalized Normalized Ratio of 2.0–3.0. In presence of other indications, the target Internationalized Normalized Ratio range and treatment duration were adjusted accordingly. Follow-up Preoperative, intraoperative and postoperative data were retrospectively collected from our computerized database. Follow-up survival, clinical and echocardiographic data were collected through regular clinical visits at our institution or affiliated clinics and hospitals, and through questionnaires to patients. Patient follow-up was based on the available recommendations [8]. Records pertaining to reported office visits, echocardiography and rhythm information, operations, cardioversions, catheter ablation or hospitalizations were obtained and analysed. Rhythm follow-up was based on electrocardiograms obtained during regular follow-up. Additional rhythm monitoring (e.g. 24-h Holter monitoring) was performed on clinical grounds (e.g. complaints of heart palpitations) and the indication for this was left at the discretion of the attending cardiologist. A total of 1126 (mean 2.3/patient, range 0–8) follow-up echocardiograms were available for analysis. The study was approved by our Institutional Ethics Committee and patient consent was obtained to allow collection and analysis of any relevant clinical and echocardiographic data. Follow-up was completed in February 2017. Statistical analysis Continuous data are presented as means ± standard deviation for normally distributed data or medians and interquartile range (IQR) when not normally distributed. Categorical data are presented as counts and percentages. The distribution of variables was evaluated using the Kolmogorov–Smirnov test. A univariable and multivariable linear regression model, with postrepair MV gradient as a dependent continuous variable, was built to explore the factors associated with postrepair MV gradient. Variable inclusion was based on the previously established effect on MV gradient. To assess for the presence of violations in model assumptions, residuals were plotted versus fitted values and investigated graphically. Univariable and multivariable Cox proportional hazards regression analysis was used to explore risk factors for the occurrence of time-to-event outcomes. Based on known clinical validity and taking into account the ratio of events to risk factors, the following factors were included in respective multivariate models: ‘for mortality’: age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR, atrial fibrillation and postrepair MV gradient; ‘for reintervention’: anterior MV leaflet repair and postrepair MV gradient; and ‘for atrial fibrillation’: age, tricuspid valve repair, preoperative left atrial diameter and postrepair MV gradient. Cubic third-degree splines were used to adjust for possible non-linear association of mean MV gradient with time-to-event outcome in the proportional hazards model. The Wald test was used to test for the presence of non-linear effect. In addition to P-value-based hypothesis testing, non-linearity of mean MV gradient was assessed graphically by plotting the fitted splines for mean MV gradient, together with 95% confidence intervals (CIs) on the log-hazard scale versus mean MV gradient. To study the evolution of mean MV gradients during the follow-up period, a mixed-model based linear regression analysis of MV gradient on follow-up time which accounts for repeated within-patient observation was carried out. To account for potential heteroscedasticity or non-normality, bootstrap-based standard errors were investigated. In addition, a post hoc exploration of model residuals was explored to investigate these same model assumptions as well as the linearity assumption of MV gradient decent versus follow-up time. No evidence of serious model deviations was found and hence the regular standard errors and hypothesis test are reported. All tests were 2-tailed and a P-value of <0.05 was considered statistically significant. Statistical analysis was performed using IBM Statistics for Windows, version 23.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.) and R, version 3.5.1 using the Survival package, version 2.43–3 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS Baseline characteristics and mitral valve repair details Baseline characteristics of the whole study group are presented in Table 1. Median patient age was 66.5 (IQR 57.8–73.8) years and the majority of patients were male. The repair and procedure details are presented in Table 2. A full ring was used in all patients; the majority of patients (n = 456; 94.2%) underwent either a Physio I (n = 223; 46.1%) or Physio II (n = 233; 48.1%) ring (Edwards Lifesciences, Irvine, CA, USA) implantation. In 42 (8.7%) patients, a ring size 30 or smaller was implanted. Table 1: Baseline characteristics n = 484 Age (years) 66.5 (57.8–73.8) Gender (female) 171 (35.3) Body surface area (m2) 1.93 ± 0.22 NYHA I 146 (30.2) II 243 (50.2) III–IV 95 (19.6) Hypertension 221 (45.7) Atrial fibrillation 172 (35.5) Renal impairment (ml/min/1.73 m2) Moderate (CC 50–85) 226 (46.7) Severe (CC <50) 41 (8.5) Diabetes mellitus 22 (4.5) Chronic lung disease 42 (8.7) Mitral annular calcification 49 (10.1) Echocardiographic characteristics LVEF ≤60% 134 (27.7) LVEDD (mm)a 54 ± 7 LVESD (mm)a 33 ± 7 LAD (mm)a 45.0 (40.0–49.0) EuroSCORE II 1.76 (0.99–3.24) Degenerative disease subtype Barlow’s disease 140 (28.9) Forme fruste Barlow’s disease 51 (10.5) Site of leaflet prolapse Posterior leaflet 299 (61.8) Single scallop prolapse 234 (48.3) Anterior leaflet 41 (8.5) Bileaflet 144 (29.7) Data are presented as n (%) and means ± SD or medians (IQR). a Available for ≥95% of patients. CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation. Table 2: Mitral valve repair details n = 484 Mitral valve annulus Plication 102 (21.1) Anterior mitral valve leaflet repair (neochords) 125 (25.8) Posterior mitral valve leaflet Resection 321 (66.3) Leaflet sliding 222 (45.9) Neochords 206 (42.6) Chordal transfer 9 (1.9) Indentation closure 85 (17.6) Commissural repair 111 (22.9) Annuloplasty ring type Physio I ring 223 (46.1) Physio II ring 233 (48.1) Other 28 (5.8) Annuloplasty ring size 24 1 (0.2) 26 10 (2.1) 28 31 (6.4) 30 62 (12.8) 32 112 (23.1) 34 98 (20.3) 36 77 (15.9) 38 52 (10.7) 40 41 (8.5) Intraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40) Concomitant procedures Tricuspid valve repair 321 (51.4) Radiofrequency ablation for atrial fibrillation 148 (30.6) Coronary artery bypass surgery 96 (19.8) Aortic valve intervention 28 (5.8) Data are presented as n (%) and medians (IQR). IQR: interquartile range. Postrepair mitral valve gradient A moderate positive correlation (r = 0.356, n = 391, P < 0.001) between the intraoperative and predischarge MV gradient was seen (Supplementary material, Figure S1). The haemodynamic results of valve repair are demonstrated in Table 3. As expected, postrepair MV gradients decreased with the size of annuloplasty ring implanted (Fig. 1). On linear regression analysis, increasing patient age (coefficient = −0.11, standard error = 0.005, P = 0.034) and annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) were correlated with lower postrepair MV gradients (Table 4). On the other hand, increasing body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008) and, interestingly, use of the Physio I ring (coefficient = 0.414, standard error = 0.122, P < 0.001) were correlated with higher postrepair MV gradients. The linear regression model demonstrated good fit with no evidence of heteroscedasticity or non-linearity (Supplementary material, Figure S2). Figure 1: Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers. Table 3: Postoperative echocardiographic results n = 484 Predischarge mitral valve gradient (mmHg) 3.46 ± 1.43 Predischarge heart rate (min−1) 80 ± 15 Predischarge stroke volume (ml)a 74 (58–93) Predischarge cardiac index (l/m2)a 5.7 (4.6–7.4) Predischarge haemoglobin value (mmol/l) 6.4 ± 0.8 Data are presented as means ± standard deviations and medians (IQR). a Available for ≥90% of patients. IQR: interquartile range. Table 4: Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients Univariable analysis Multivariable analysis Coefficient Standard error P-value Coefficient Standard error P-value Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65 Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034 Body surface area 0.294 0.302 0.33 0.905 0.340 0.008 Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95 Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48 Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23 PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14 PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41 Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001 Annuloplasty ring type Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001 Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001 Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001 PMVL: posterior mitral valve leaflet. Late clinical results From cubic spline-based analyses, no evidence of non-linearity for post repair MV gradient was found for all time-to-event outcomes (Supplementary materials, Figures S3–S5). Hence, postrepair MV gradient was entered into the Cox proportional hazards regression analysis models as a continuous variable for all subsequent analyses. During a median follow-up period of 5.8 (IQR 3.4–9.3) years (99.5% complete, 2 patients were lost to follow-up due to emigration), 84 patients died. When corrected for patient age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR and atrial fibrillation, postrepair MV gradients was not associated with patient survival [hazard ratio (HR) 1.034, 95% CI 0.889–1.203; P = 0.66; Supplementary material, Table S1]. Follow-up on clinical related events was 90% complete with a mean duration of 5.2 (IQR 2.7–8.8) years. When adjusted for patient age, tricuspid valve repair and preoperative left atrial diameter, postrepair MV gradient was not associated with late atrial fibrillation occurrence (HR 0.849, 95% CI 0.682–1.057; P = 0.14; Supplementary material, Table S1). When adjusted for anterior MV leaflet repair, postrepair MV gradient was associated with a higher risk of MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029; Supplementary material, Table S1). A total of 11 late reinterventions were performed. The indication for reintervention was recurrent MR in 9 patients and elevated MV gradient in the remaining 2 patients. In both of the latter patients, a postrepair gradient of ≥5 mmHg (5.88 and 5.23 mmHg, respectively) was seen on predischarge echocardiography, despite an acceptable gradient seen on intraoperative echocardiography (2.53 and 4.23 mmHg, respectively). In the first of the latter patients, an annuloplasty ring size 26 was initially implanted and a re-repair due to heart failure symptoms (no significant MR or other explanation for this observation were found) was performed 1.3 years after the initial operation. Upon reoperation, the annuloplasty ring was explanted, resolving the problem of elevated gradient. In the other patient, an annuloplasty ring size 32 was implanted during the initial operation. Severe pannus formation occurred and the patient underwent a valve replacement 1.1 years after the initial operation. Late echocardiographic results On mixed-model linear regression analysis on the evolution of mean MV gradient during the follow-up period, a slight decline in MV gradients was seen (estimate = −0.05, 95% CI −0.07 to −0.02; P < 0.001) during the follow-up period (Fig. 2). Figure 2: Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed. DISCUSSION The results of our study are in line with previous studies, and demonstrate that, following valve repair for degenerative disease, high postrepair gradients are of important clinical relevance. However, repair technique (in particular posterior MV leaflet resection) did not show a significant effect on postrepair gradients and no effect of postrepair gradients on the occurrence of late atrial fibrillation was observed. The mechanism of elevated postrepair MV gradients is poorly understood, but is in our opinion related to fixation of the posterior annular perimeter length. Indeed, in an adult sheep model, Dagum et al. [9] have shown that cyclic changes in the MV annular area, reaching a maximum in late diastole, are correlated with length changes of the posterior annular perimeter. After implantation of a true-sized partial or complete flexible annuloplasty device, complete fixation of the MV annular area, posterior and anterior annular perimeters throughout the cardiac cycle was observed. Similarly, Bothe et al. [10] reported that MV annuloplasty results in a significant reduction of the maximal MV opening area, independent of the type of annuloplasty device used (partial or full ring; flexible, semi-rigid or rigid). Moreover, the Physio I ring (as well as the majority of other full rings implanted) did not impair posterior MV leaflet motion. Additionally, while the Physio I ring did increase the excursion of the annular and belly region of the anterior MV leaflet, it did not affect the excursion of the anterior leaflet at the leaflet edge. No effect on anterior leaflet motion was seen after the implantation of a partial Cosgrove-Edwards band (Edwards Lifesciences). Their results suggest that no diastolic flow obstruction due to changes in anterior leaflet motion is to be expected after implantation of the majority of annuloplasty devices tested. In a study on 107 patients after MV repair for degenerative disease, Mesana et al. [5] suggested that full rings may be associated with higher postrepair gradients when compared to partial bands. Their results need to be interpreted with caution as the Duran ring (Medtronic Inc., Minneapolis, MN, USA), notoriously prone to significant pannus formation [11, 12], was used in most patients who underwent full ring implantation. As MV gradients were measured several years after the initial operation, the high gradients observed in this group are most likely due to pannus formation and not the type of annuloplasty device implanted. Murashita et al. [13] explored postrepair gradients in 1147 patients after MV repair for degenerative disease. In most patients, a standard 63 mm flexible band was implanted, irrespective of annular perimeter length or anterior leaflet size. In the first median follow-up period (124.5 days after operation), a mean gradient of 3.7 ± 1.6 mmHg was reported that declined to a mean gradient of 3.3 ± 1.8 mmHg in the second median follow-up period (600 days after operation). The gradients in the first median follow-up period seem somehow higher than early postrepair gradients observed in our population. On longitudinal analysis, a decline similar to the one observed by Murashita et al. was also observed in our population. While clearly limited, amongst others, by the unadjusted differences in patient populations, such observations challenge the alleged superiority of partial bands in terms of postrepair gradients. On the other side, excessive shortening of the posterior annular perimeter (resulting from downsizing described by the authors) is bound to have resulted in smaller MV areas than would have been achieved with a true-sized ring. The results of our analyses suggest that the postrepair gradient is partially associated with patient characteristics (both patient age and body surface area likely reflect the relation of these parameters to systemic metabolic needs and hereto related cardiac output). Moreover, our results demonstrate that the choice of annuloplasty device used might affect postrepair gradients. This is likely correspondent to the differences in the ratio between the anterior-posterior diameter (reflecting anterior MV leaflet surface area to which the ring is sized) and the length of the ‘posterior perimeter’ of the annuloplasty ring between different annuloplasty devices. We are unaware of any studies demonstrating that the increased saddle shape of the Physio II ring is related to improved diastolic MV opening properties when compared to annuloplasty devices with less pronounced saddle-shape. Because of the lack of studies, we cannot exclude the possibility that the Physio II ring results in superior diastolic opening properties of the anterior leaflet that might explain our observation. For the time being, this should, however, be seen as a theory and properly designed studies will need to be conducted in the future. In a recent meta-analysis, Mazine et al. [14] have speculated that in cases of posterior MV leaflet prolapse, chordal replacement techniques will result in lower MV gradients when compared to leaflet resection techniques. Our results failed to demonstrate any significant effect of posterior leaflet resection on postrepair gradient. This is likely related to the fact that we primarily used leaflet resection techniques to address excessive posterior MV leaflet tissue and structurally avoided excessive resection. Should this be avoided, no significant shortening of the posterior leaflet free edge, that could at least theoretically limit diastolic leaflet mobility, is to be expected. Functional MV stenosis should not present a reason not to perform adequate leaflet resection when this is indicated, an opinion previously emphasized by our group and others [15–18]. We did not observe any effect of elevated MV gradients on freedom from atrial fibrillation. On the contrary, elevated postrepair MV gradient was identified as a risk factor for late atrial fibrillation occurrence in recent studies by Kawamoto et al. [19] as well as Ma et al. [20]. We included only patients in sinus rhythm who did not undergo any ablation procedures, a characteristic that could provide an explanation for the differences observed between our results and those of Kawamoto et al. [19]. More importantly, we differentiated between atrial fibrillation and other types of atrial tachycardias as the mechanisms associated with the development of different atrial tachycardias after MV operations are known to fundamentally differ [7]. To adjust for potential unadjusted bias, future studies should include information on the type of incision made to expose the MV when exploring the effect of other factors on early and late atrial tachycardias. Previous studies also demonstrated that an elevated postrepair MV gradient impairs left atrial reverse remodelling [21]. Nevertheless, atrial fibrillation is most likely related to left atrial fibrosis that develops because of long-standing volume overload prior to the operation and is present even in patients in preoperative sinus rhythm [22]. More studies, with longer follow-up, are also needed to explore whether left atrial reverse remodelling in the presence of elevated postrepair gradient is impaired or only delayed. The results of our study do, however, suggest that the clinical burden of elevated postrepair gradient might be lower than previously suggested. The observation that the risk of reintervention might be related to postrepair MV gradient has not previously been reported. The incidence of reoperation for MV stenosis after previous repair is known to be low [13, 23], but reflects only the patients most affected by this condition. Other studies have additionally shown that high postrepair gradients will result in decreased exercise tolerance and quality of life [3, 5]. We followed the established concepts of valve repair for degenerative disease that include annular remodelling and stabilization. As fixation of the maximal posterior perimeter length and hereto related maximal MV area are likely inevitable with any type of annuloplasty device used, elevated postrepair gradients might not be avoidable in all patients. Omitting annuloplasty device implantation is controversial, as this is known to result in a higher risk of recurrent MR [24]. Possibly, new annuloplasty device design and identification of patients in whom annular characteristics are sufficiently preserved to support valve sufficiency in the long term even without annular stabilization would help reduce the burden of this problem. Limitations This is a single-centre retrospective study with study limitations inherent to the study design. The results are applicable to the type of MV repair techniques described only and further studies are needed to evaluate the effect or other repair techniques (e.g. edge-to-edge repair) and annuloplasty devises on the occurrence of elevated postrepair gradients. During the study period, the MV repair techniques have evolved with, in particular, annular plication being performed less frequently. As the type of leaflet repair did not affect the sizing of the annuloplasty device implanted, no relevant effect on the results presented is to be expected. Moreover, the number of reinterventions was low and prevented us from exploring the risk factors for MV reintervention specified to the indication for reintervention (i.p. recurrent MR versus elevated MV gradient). While we failed to identify a relation between postrepair MV gradient and survival or atrial fibrillation, we cannot exclude the possibility that a correlation does exist, but we were unable to detect it due to an insufficient number of patients and events. Our results should thus be seen as hypothesis-generating and will need to be confirmed by future studies. We have performed cubic spline analyses, but failed to identify a cut-off value that would ease the identification of patient a risk for complications related to elevated postrepair MV gradient in the clinical setting. Identification of a cut-off value should be pursued in future studies. Nevertheless, in line with previous studies, our results do support the efforts aimed at securing the lowest possible postrepair MV gradient. CONCLUSIONS Following MV repair with a semi-rigid annuloplasty ring, increased resting MV gradients are not uncommon. This is, among others, related to the implanted ring size and patient body surface area. Elevated postrepair MV gradients might result in poorer freedom from reintervention due to the added risk of reintervention for MV stenosis while survival and incidence of late atrial fibrillation development do not seem to be affected. Conflict of interest: none declared. Supplementary Material ezz178_Supplementary_Material Click here for additional data file.
sec	INTRODUCTION Surgical mitral valve (MV) repair is the treatment of choice for mitral regurgitation (MR) due to degenerative disease with high valve reparability, repair durability and freedom from reoperation rates readily established [1, 2]. When the results of MV repair are examined in further detail, the problem of elevated postrepair gradients following an otherwise successful repair has emerged as a subject of debate [3–5]. The problem of elevated postrepair MV gradients was initially described in patients after restrictive mitral annuloplasty for ischaemic MR [4] but may also be of clinical importance in patients with degenerative MR [3, 5]. To justify the growing enthusiasm for early surgery of yet asymptomatic patients with degenerative MR, optimal patient- and valve-related results are needed. Data on the risk factors and clinical impact of elevated MV gradients following valve repair for degenerative disease remain scarce. The aim of this study was to analyse the risk factors of elevated postrepair MV gradients and its effect on patient- and valve-related outcomes in a cohort of patients who underwent successful MV repair for degenerative disease.
title	INTRODUCTION
p	Surgical mitral valve (MV) repair is the treatment of choice for mitral regurgitation (MR) due to degenerative disease with high valve reparability, repair durability and freedom from reoperation rates readily established [1, 2]. When the results of MV repair are examined in further detail, the problem of elevated postrepair gradients following an otherwise successful repair has emerged as a subject of debate [3–5].
p	The problem of elevated postrepair MV gradients was initially described in patients after restrictive mitral annuloplasty for ischaemic MR [4] but may also be of clinical importance in patients with degenerative MR [3, 5]. To justify the growing enthusiasm for early surgery of yet asymptomatic patients with degenerative MR, optimal patient- and valve-related results are needed. Data on the risk factors and clinical impact of elevated MV gradients following valve repair for degenerative disease remain scarce.
p	The aim of this study was to analyse the risk factors of elevated postrepair MV gradients and its effect on patient- and valve-related outcomes in a cohort of patients who underwent successful MV repair for degenerative disease.
sec	METHODS Patients All adult patients (≥18 years of age) who underwent surgical intervention (n = 528) for MR due to degenerative disease between January 2004 and December 2015 at our institution were eligible for inclusion. We excluded patients with a history of previous cardiac surgery (n = 18) and patients in whom MV replacement was performed (n = 9). Of the remaining 501 patients, 17 additional patients were excluded for the following reasons: early mortality (n = 6), non-use of annuloplasty ring (n = 4) or missing predischarge echocardiogram (n = 7). The final study cohort compromised 484 patients who all underwent successful MV repair with a complete annuloplasty ring. Measurements of MV gradients were acquired from continuous wave Doppler acquisitions of the diastolic inflow of the MV. Mean MV gradient was calculated as the average of 3 and 5 cycles or patients in sinus rhythm and atrial fibrillation, respectively. All acquisitions were performed according to a standardized protocol of our echo lab to ensure data reproducibility. All measurements were performed by experienced echocardiographists. Study end points All end points were defined according to the Guidelines for reporting mortality and morbidity after cardiac valve interventions [6]. Primary end points included all-cause mortality and freedom from MV reintervention. Secondary end points included freedom from atrial fibrillation. We excluded other types of atrial tachycardias (e.g. atrial flutter or incisional atrial tachycardia) because of aetiological differences associated with the development postrepair atrial tachycardias [7]. Only patients in preoperative sinus rhythm (n = 312) were included in the latter analysis. Surgical technique and perioperative care When indicated, anterior MV leaflet prolapse was addressed with chordal replacement. Posterior MV leaflet prolapse was addressed with a combination of leaflet resection and chordal replacement techniques. The decision on which technique to use was based on the extent of leaflet prolapse and excessive tissue in height and/or width. Earlier in this series, annular plication was more frequently used to help restore the continuity of the posterior MV leaflet. Later, leaflet sliding techniques were employed. Commissural prolapse was primarily addressed with papillary muscle head repositioning. All patients included in the current study underwent full annuloplasty ring implantation. Ring sizing was standardly based on the surface area of the anterior MV leaflet and was not influenced by the type of anterior and/or posterior MV leaflet repair technique used. No over- or downsizing was performed in any of the patients. Intraoperative transoesophageal echocardiography was performed by an experienced cardiologist to document the intraoperative result of MV repair. Additionally, predischarge transthoracic echocardiography (performed on postoperative day 4–7) was performed to exclude any significant residual MR. Systolic anterior motion was observed in 2 patients and treated conservatively. Oral anticoagulation was initiated for a period of 3 months with a target Internationalized Normalized Ratio of 2.0–3.0. In presence of other indications, the target Internationalized Normalized Ratio range and treatment duration were adjusted accordingly. Follow-up Preoperative, intraoperative and postoperative data were retrospectively collected from our computerized database. Follow-up survival, clinical and echocardiographic data were collected through regular clinical visits at our institution or affiliated clinics and hospitals, and through questionnaires to patients. Patient follow-up was based on the available recommendations [8]. Records pertaining to reported office visits, echocardiography and rhythm information, operations, cardioversions, catheter ablation or hospitalizations were obtained and analysed. Rhythm follow-up was based on electrocardiograms obtained during regular follow-up. Additional rhythm monitoring (e.g. 24-h Holter monitoring) was performed on clinical grounds (e.g. complaints of heart palpitations) and the indication for this was left at the discretion of the attending cardiologist. A total of 1126 (mean 2.3/patient, range 0–8) follow-up echocardiograms were available for analysis. The study was approved by our Institutional Ethics Committee and patient consent was obtained to allow collection and analysis of any relevant clinical and echocardiographic data. Follow-up was completed in February 2017. Statistical analysis Continuous data are presented as means ± standard deviation for normally distributed data or medians and interquartile range (IQR) when not normally distributed. Categorical data are presented as counts and percentages. The distribution of variables was evaluated using the Kolmogorov–Smirnov test. A univariable and multivariable linear regression model, with postrepair MV gradient as a dependent continuous variable, was built to explore the factors associated with postrepair MV gradient. Variable inclusion was based on the previously established effect on MV gradient. To assess for the presence of violations in model assumptions, residuals were plotted versus fitted values and investigated graphically. Univariable and multivariable Cox proportional hazards regression analysis was used to explore risk factors for the occurrence of time-to-event outcomes. Based on known clinical validity and taking into account the ratio of events to risk factors, the following factors were included in respective multivariate models: ‘for mortality’: age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR, atrial fibrillation and postrepair MV gradient; ‘for reintervention’: anterior MV leaflet repair and postrepair MV gradient; and ‘for atrial fibrillation’: age, tricuspid valve repair, preoperative left atrial diameter and postrepair MV gradient. Cubic third-degree splines were used to adjust for possible non-linear association of mean MV gradient with time-to-event outcome in the proportional hazards model. The Wald test was used to test for the presence of non-linear effect. In addition to P-value-based hypothesis testing, non-linearity of mean MV gradient was assessed graphically by plotting the fitted splines for mean MV gradient, together with 95% confidence intervals (CIs) on the log-hazard scale versus mean MV gradient. To study the evolution of mean MV gradients during the follow-up period, a mixed-model based linear regression analysis of MV gradient on follow-up time which accounts for repeated within-patient observation was carried out. To account for potential heteroscedasticity or non-normality, bootstrap-based standard errors were investigated. In addition, a post hoc exploration of model residuals was explored to investigate these same model assumptions as well as the linearity assumption of MV gradient decent versus follow-up time. No evidence of serious model deviations was found and hence the regular standard errors and hypothesis test are reported. All tests were 2-tailed and a P-value of <0.05 was considered statistically significant. Statistical analysis was performed using IBM Statistics for Windows, version 23.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.) and R, version 3.5.1 using the Survival package, version 2.43–3 (R Foundation for Statistical Computing, Vienna, Austria).
title	METHODS
sec	Patients All adult patients (≥18 years of age) who underwent surgical intervention (n = 528) for MR due to degenerative disease between January 2004 and December 2015 at our institution were eligible for inclusion. We excluded patients with a history of previous cardiac surgery (n = 18) and patients in whom MV replacement was performed (n = 9). Of the remaining 501 patients, 17 additional patients were excluded for the following reasons: early mortality (n = 6), non-use of annuloplasty ring (n = 4) or missing predischarge echocardiogram (n = 7). The final study cohort compromised 484 patients who all underwent successful MV repair with a complete annuloplasty ring. Measurements of MV gradients were acquired from continuous wave Doppler acquisitions of the diastolic inflow of the MV. Mean MV gradient was calculated as the average of 3 and 5 cycles or patients in sinus rhythm and atrial fibrillation, respectively. All acquisitions were performed according to a standardized protocol of our echo lab to ensure data reproducibility. All measurements were performed by experienced echocardiographists.
title	Patients
p	All adult patients (≥18 years of age) who underwent surgical intervention (n = 528) for MR due to degenerative disease between January 2004 and December 2015 at our institution were eligible for inclusion. We excluded patients with a history of previous cardiac surgery (n = 18) and patients in whom MV replacement was performed (n = 9). Of the remaining 501 patients, 17 additional patients were excluded for the following reasons: early mortality (n = 6), non-use of annuloplasty ring (n = 4) or missing predischarge echocardiogram (n = 7). The final study cohort compromised 484 patients who all underwent successful MV repair with a complete annuloplasty ring.
p	Measurements of MV gradients were acquired from continuous wave Doppler acquisitions of the diastolic inflow of the MV. Mean MV gradient was calculated as the average of 3 and 5 cycles or patients in sinus rhythm and atrial fibrillation, respectively. All acquisitions were performed according to a standardized protocol of our echo lab to ensure data reproducibility. All measurements were performed by experienced echocardiographists.
sec	Study end points All end points were defined according to the Guidelines for reporting mortality and morbidity after cardiac valve interventions [6]. Primary end points included all-cause mortality and freedom from MV reintervention. Secondary end points included freedom from atrial fibrillation. We excluded other types of atrial tachycardias (e.g. atrial flutter or incisional atrial tachycardia) because of aetiological differences associated with the development postrepair atrial tachycardias [7]. Only patients in preoperative sinus rhythm (n = 312) were included in the latter analysis.
title	Study end points
p	All end points were defined according to the Guidelines for reporting mortality and morbidity after cardiac valve interventions [6]. Primary end points included all-cause mortality and freedom from MV reintervention. Secondary end points included freedom from atrial fibrillation. We excluded other types of atrial tachycardias (e.g. atrial flutter or incisional atrial tachycardia) because of aetiological differences associated with the development postrepair atrial tachycardias [7]. Only patients in preoperative sinus rhythm (n = 312) were included in the latter analysis.
sec	Surgical technique and perioperative care When indicated, anterior MV leaflet prolapse was addressed with chordal replacement. Posterior MV leaflet prolapse was addressed with a combination of leaflet resection and chordal replacement techniques. The decision on which technique to use was based on the extent of leaflet prolapse and excessive tissue in height and/or width. Earlier in this series, annular plication was more frequently used to help restore the continuity of the posterior MV leaflet. Later, leaflet sliding techniques were employed. Commissural prolapse was primarily addressed with papillary muscle head repositioning. All patients included in the current study underwent full annuloplasty ring implantation. Ring sizing was standardly based on the surface area of the anterior MV leaflet and was not influenced by the type of anterior and/or posterior MV leaflet repair technique used. No over- or downsizing was performed in any of the patients. Intraoperative transoesophageal echocardiography was performed by an experienced cardiologist to document the intraoperative result of MV repair. Additionally, predischarge transthoracic echocardiography (performed on postoperative day 4–7) was performed to exclude any significant residual MR. Systolic anterior motion was observed in 2 patients and treated conservatively. Oral anticoagulation was initiated for a period of 3 months with a target Internationalized Normalized Ratio of 2.0–3.0. In presence of other indications, the target Internationalized Normalized Ratio range and treatment duration were adjusted accordingly.
title	Surgical technique and perioperative care
p	When indicated, anterior MV leaflet prolapse was addressed with chordal replacement. Posterior MV leaflet prolapse was addressed with a combination of leaflet resection and chordal replacement techniques. The decision on which technique to use was based on the extent of leaflet prolapse and excessive tissue in height and/or width. Earlier in this series, annular plication was more frequently used to help restore the continuity of the posterior MV leaflet. Later, leaflet sliding techniques were employed. Commissural prolapse was primarily addressed with papillary muscle head repositioning.
p	All patients included in the current study underwent full annuloplasty ring implantation. Ring sizing was standardly based on the surface area of the anterior MV leaflet and was not influenced by the type of anterior and/or posterior MV leaflet repair technique used. No over- or downsizing was performed in any of the patients.
p	Intraoperative transoesophageal echocardiography was performed by an experienced cardiologist to document the intraoperative result of MV repair. Additionally, predischarge transthoracic echocardiography (performed on postoperative day 4–7) was performed to exclude any significant residual MR. Systolic anterior motion was observed in 2 patients and treated conservatively. Oral anticoagulation was initiated for a period of 3 months with a target Internationalized Normalized Ratio of 2.0–3.0. In presence of other indications, the target Internationalized Normalized Ratio range and treatment duration were adjusted accordingly.
sec	Follow-up Preoperative, intraoperative and postoperative data were retrospectively collected from our computerized database. Follow-up survival, clinical and echocardiographic data were collected through regular clinical visits at our institution or affiliated clinics and hospitals, and through questionnaires to patients. Patient follow-up was based on the available recommendations [8]. Records pertaining to reported office visits, echocardiography and rhythm information, operations, cardioversions, catheter ablation or hospitalizations were obtained and analysed. Rhythm follow-up was based on electrocardiograms obtained during regular follow-up. Additional rhythm monitoring (e.g. 24-h Holter monitoring) was performed on clinical grounds (e.g. complaints of heart palpitations) and the indication for this was left at the discretion of the attending cardiologist. A total of 1126 (mean 2.3/patient, range 0–8) follow-up echocardiograms were available for analysis. The study was approved by our Institutional Ethics Committee and patient consent was obtained to allow collection and analysis of any relevant clinical and echocardiographic data. Follow-up was completed in February 2017.
title	Follow-up
p	Preoperative, intraoperative and postoperative data were retrospectively collected from our computerized database. Follow-up survival, clinical and echocardiographic data were collected through regular clinical visits at our institution or affiliated clinics and hospitals, and through questionnaires to patients. Patient follow-up was based on the available recommendations [8]. Records pertaining to reported office visits, echocardiography and rhythm information, operations, cardioversions, catheter ablation or hospitalizations were obtained and analysed. Rhythm follow-up was based on electrocardiograms obtained during regular follow-up. Additional rhythm monitoring (e.g. 24-h Holter monitoring) was performed on clinical grounds (e.g. complaints of heart palpitations) and the indication for this was left at the discretion of the attending cardiologist. A total of 1126 (mean 2.3/patient, range 0–8) follow-up echocardiograms were available for analysis.
p	The study was approved by our Institutional Ethics Committee and patient consent was obtained to allow collection and analysis of any relevant clinical and echocardiographic data. Follow-up was completed in February 2017.
sec	Statistical analysis Continuous data are presented as means ± standard deviation for normally distributed data or medians and interquartile range (IQR) when not normally distributed. Categorical data are presented as counts and percentages. The distribution of variables was evaluated using the Kolmogorov–Smirnov test. A univariable and multivariable linear regression model, with postrepair MV gradient as a dependent continuous variable, was built to explore the factors associated with postrepair MV gradient. Variable inclusion was based on the previously established effect on MV gradient. To assess for the presence of violations in model assumptions, residuals were plotted versus fitted values and investigated graphically. Univariable and multivariable Cox proportional hazards regression analysis was used to explore risk factors for the occurrence of time-to-event outcomes. Based on known clinical validity and taking into account the ratio of events to risk factors, the following factors were included in respective multivariate models: ‘for mortality’: age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR, atrial fibrillation and postrepair MV gradient; ‘for reintervention’: anterior MV leaflet repair and postrepair MV gradient; and ‘for atrial fibrillation’: age, tricuspid valve repair, preoperative left atrial diameter and postrepair MV gradient. Cubic third-degree splines were used to adjust for possible non-linear association of mean MV gradient with time-to-event outcome in the proportional hazards model. The Wald test was used to test for the presence of non-linear effect. In addition to P-value-based hypothesis testing, non-linearity of mean MV gradient was assessed graphically by plotting the fitted splines for mean MV gradient, together with 95% confidence intervals (CIs) on the log-hazard scale versus mean MV gradient. To study the evolution of mean MV gradients during the follow-up period, a mixed-model based linear regression analysis of MV gradient on follow-up time which accounts for repeated within-patient observation was carried out. To account for potential heteroscedasticity or non-normality, bootstrap-based standard errors were investigated. In addition, a post hoc exploration of model residuals was explored to investigate these same model assumptions as well as the linearity assumption of MV gradient decent versus follow-up time. No evidence of serious model deviations was found and hence the regular standard errors and hypothesis test are reported. All tests were 2-tailed and a P-value of <0.05 was considered statistically significant. Statistical analysis was performed using IBM Statistics for Windows, version 23.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.) and R, version 3.5.1 using the Survival package, version 2.43–3 (R Foundation for Statistical Computing, Vienna, Austria).
title	Statistical analysis
p	Continuous data are presented as means ± standard deviation for normally distributed data or medians and interquartile range (IQR) when not normally distributed. Categorical data are presented as counts and percentages. The distribution of variables was evaluated using the Kolmogorov–Smirnov test.
p	A univariable and multivariable linear regression model, with postrepair MV gradient as a dependent continuous variable, was built to explore the factors associated with postrepair MV gradient. Variable inclusion was based on the previously established effect on MV gradient. To assess for the presence of violations in model assumptions, residuals were plotted versus fitted values and investigated graphically. Univariable and multivariable Cox proportional hazards regression analysis was used to explore risk factors for the occurrence of time-to-event outcomes. Based on known clinical validity and taking into account the ratio of events to risk factors, the following factors were included in respective multivariate models: ‘for mortality’: age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR, atrial fibrillation and postrepair MV gradient; ‘for reintervention’: anterior MV leaflet repair and postrepair MV gradient; and ‘for atrial fibrillation’: age, tricuspid valve repair, preoperative left atrial diameter and postrepair MV gradient. Cubic third-degree splines were used to adjust for possible non-linear association of mean MV gradient with time-to-event outcome in the proportional hazards model. The Wald test was used to test for the presence of non-linear effect. In addition to P-value-based hypothesis testing, non-linearity of mean MV gradient was assessed graphically by plotting the fitted splines for mean MV gradient, together with 95% confidence intervals (CIs) on the log-hazard scale versus mean MV gradient.
p	To study the evolution of mean MV gradients during the follow-up period, a mixed-model based linear regression analysis of MV gradient on follow-up time which accounts for repeated within-patient observation was carried out. To account for potential heteroscedasticity or non-normality, bootstrap-based standard errors were investigated. In addition, a post hoc exploration of model residuals was explored to investigate these same model assumptions as well as the linearity assumption of MV gradient decent versus follow-up time. No evidence of serious model deviations was found and hence the regular standard errors and hypothesis test are reported.
p	All tests were 2-tailed and a P-value of <0.05 was considered statistically significant. Statistical analysis was performed using IBM Statistics for Windows, version 23.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.) and R, version 3.5.1 using the Survival package, version 2.43–3 (R Foundation for Statistical Computing, Vienna, Austria).
sec	RESULTS Baseline characteristics and mitral valve repair details Baseline characteristics of the whole study group are presented in Table 1. Median patient age was 66.5 (IQR 57.8–73.8) years and the majority of patients were male. The repair and procedure details are presented in Table 2. A full ring was used in all patients; the majority of patients (n = 456; 94.2%) underwent either a Physio I (n = 223; 46.1%) or Physio II (n = 233; 48.1%) ring (Edwards Lifesciences, Irvine, CA, USA) implantation. In 42 (8.7%) patients, a ring size 30 or smaller was implanted. Table 1: Baseline characteristics n = 484 Age (years) 66.5 (57.8–73.8) Gender (female) 171 (35.3) Body surface area (m2) 1.93 ± 0.22 NYHA I 146 (30.2) II 243 (50.2) III–IV 95 (19.6) Hypertension 221 (45.7) Atrial fibrillation 172 (35.5) Renal impairment (ml/min/1.73 m2) Moderate (CC 50–85) 226 (46.7) Severe (CC <50) 41 (8.5) Diabetes mellitus 22 (4.5) Chronic lung disease 42 (8.7) Mitral annular calcification 49 (10.1) Echocardiographic characteristics LVEF ≤60% 134 (27.7) LVEDD (mm)a 54 ± 7 LVESD (mm)a 33 ± 7 LAD (mm)a 45.0 (40.0–49.0) EuroSCORE II 1.76 (0.99–3.24) Degenerative disease subtype Barlow’s disease 140 (28.9) Forme fruste Barlow’s disease 51 (10.5) Site of leaflet prolapse Posterior leaflet 299 (61.8) Single scallop prolapse 234 (48.3) Anterior leaflet 41 (8.5) Bileaflet 144 (29.7) Data are presented as n (%) and means ± SD or medians (IQR). a Available for ≥95% of patients. CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation. Table 2: Mitral valve repair details n = 484 Mitral valve annulus Plication 102 (21.1) Anterior mitral valve leaflet repair (neochords) 125 (25.8) Posterior mitral valve leaflet Resection 321 (66.3) Leaflet sliding 222 (45.9) Neochords 206 (42.6) Chordal transfer 9 (1.9) Indentation closure 85 (17.6) Commissural repair 111 (22.9) Annuloplasty ring type Physio I ring 223 (46.1) Physio II ring 233 (48.1) Other 28 (5.8) Annuloplasty ring size 24 1 (0.2) 26 10 (2.1) 28 31 (6.4) 30 62 (12.8) 32 112 (23.1) 34 98 (20.3) 36 77 (15.9) 38 52 (10.7) 40 41 (8.5) Intraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40) Concomitant procedures Tricuspid valve repair 321 (51.4) Radiofrequency ablation for atrial fibrillation 148 (30.6) Coronary artery bypass surgery 96 (19.8) Aortic valve intervention 28 (5.8) Data are presented as n (%) and medians (IQR). IQR: interquartile range. Postrepair mitral valve gradient A moderate positive correlation (r = 0.356, n = 391, P < 0.001) between the intraoperative and predischarge MV gradient was seen (Supplementary material, Figure S1). The haemodynamic results of valve repair are demonstrated in Table 3. As expected, postrepair MV gradients decreased with the size of annuloplasty ring implanted (Fig. 1). On linear regression analysis, increasing patient age (coefficient = −0.11, standard error = 0.005, P = 0.034) and annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) were correlated with lower postrepair MV gradients (Table 4). On the other hand, increasing body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008) and, interestingly, use of the Physio I ring (coefficient = 0.414, standard error = 0.122, P < 0.001) were correlated with higher postrepair MV gradients. The linear regression model demonstrated good fit with no evidence of heteroscedasticity or non-linearity (Supplementary material, Figure S2). Figure 1: Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers. Table 3: Postoperative echocardiographic results n = 484 Predischarge mitral valve gradient (mmHg) 3.46 ± 1.43 Predischarge heart rate (min−1) 80 ± 15 Predischarge stroke volume (ml)a 74 (58–93) Predischarge cardiac index (l/m2)a 5.7 (4.6–7.4) Predischarge haemoglobin value (mmol/l) 6.4 ± 0.8 Data are presented as means ± standard deviations and medians (IQR). a Available for ≥90% of patients. IQR: interquartile range. Table 4: Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients Univariable analysis Multivariable analysis Coefficient Standard error P-value Coefficient Standard error P-value Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65 Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034 Body surface area 0.294 0.302 0.33 0.905 0.340 0.008 Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95 Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48 Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23 PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14 PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41 Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001 Annuloplasty ring type Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001 Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001 Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001 PMVL: posterior mitral valve leaflet. Late clinical results From cubic spline-based analyses, no evidence of non-linearity for post repair MV gradient was found for all time-to-event outcomes (Supplementary materials, Figures S3–S5). Hence, postrepair MV gradient was entered into the Cox proportional hazards regression analysis models as a continuous variable for all subsequent analyses. During a median follow-up period of 5.8 (IQR 3.4–9.3) years (99.5% complete, 2 patients were lost to follow-up due to emigration), 84 patients died. When corrected for patient age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR and atrial fibrillation, postrepair MV gradients was not associated with patient survival [hazard ratio (HR) 1.034, 95% CI 0.889–1.203; P = 0.66; Supplementary material, Table S1]. Follow-up on clinical related events was 90% complete with a mean duration of 5.2 (IQR 2.7–8.8) years. When adjusted for patient age, tricuspid valve repair and preoperative left atrial diameter, postrepair MV gradient was not associated with late atrial fibrillation occurrence (HR 0.849, 95% CI 0.682–1.057; P = 0.14; Supplementary material, Table S1). When adjusted for anterior MV leaflet repair, postrepair MV gradient was associated with a higher risk of MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029; Supplementary material, Table S1). A total of 11 late reinterventions were performed. The indication for reintervention was recurrent MR in 9 patients and elevated MV gradient in the remaining 2 patients. In both of the latter patients, a postrepair gradient of ≥5 mmHg (5.88 and 5.23 mmHg, respectively) was seen on predischarge echocardiography, despite an acceptable gradient seen on intraoperative echocardiography (2.53 and 4.23 mmHg, respectively). In the first of the latter patients, an annuloplasty ring size 26 was initially implanted and a re-repair due to heart failure symptoms (no significant MR or other explanation for this observation were found) was performed 1.3 years after the initial operation. Upon reoperation, the annuloplasty ring was explanted, resolving the problem of elevated gradient. In the other patient, an annuloplasty ring size 32 was implanted during the initial operation. Severe pannus formation occurred and the patient underwent a valve replacement 1.1 years after the initial operation. Late echocardiographic results On mixed-model linear regression analysis on the evolution of mean MV gradient during the follow-up period, a slight decline in MV gradients was seen (estimate = −0.05, 95% CI −0.07 to −0.02; P < 0.001) during the follow-up period (Fig. 2). Figure 2: Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed.
title	RESULTS
sec	Baseline characteristics and mitral valve repair details Baseline characteristics of the whole study group are presented in Table 1. Median patient age was 66.5 (IQR 57.8–73.8) years and the majority of patients were male. The repair and procedure details are presented in Table 2. A full ring was used in all patients; the majority of patients (n = 456; 94.2%) underwent either a Physio I (n = 223; 46.1%) or Physio II (n = 233; 48.1%) ring (Edwards Lifesciences, Irvine, CA, USA) implantation. In 42 (8.7%) patients, a ring size 30 or smaller was implanted. Table 1: Baseline characteristics n = 484 Age (years) 66.5 (57.8–73.8) Gender (female) 171 (35.3) Body surface area (m2) 1.93 ± 0.22 NYHA I 146 (30.2) II 243 (50.2) III–IV 95 (19.6) Hypertension 221 (45.7) Atrial fibrillation 172 (35.5) Renal impairment (ml/min/1.73 m2) Moderate (CC 50–85) 226 (46.7) Severe (CC <50) 41 (8.5) Diabetes mellitus 22 (4.5) Chronic lung disease 42 (8.7) Mitral annular calcification 49 (10.1) Echocardiographic characteristics LVEF ≤60% 134 (27.7) LVEDD (mm)a 54 ± 7 LVESD (mm)a 33 ± 7 LAD (mm)a 45.0 (40.0–49.0) EuroSCORE II 1.76 (0.99–3.24) Degenerative disease subtype Barlow’s disease 140 (28.9) Forme fruste Barlow’s disease 51 (10.5) Site of leaflet prolapse Posterior leaflet 299 (61.8) Single scallop prolapse 234 (48.3) Anterior leaflet 41 (8.5) Bileaflet 144 (29.7) Data are presented as n (%) and means ± SD or medians (IQR). a Available for ≥95% of patients. CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation. Table 2: Mitral valve repair details n = 484 Mitral valve annulus Plication 102 (21.1) Anterior mitral valve leaflet repair (neochords) 125 (25.8) Posterior mitral valve leaflet Resection 321 (66.3) Leaflet sliding 222 (45.9) Neochords 206 (42.6) Chordal transfer 9 (1.9) Indentation closure 85 (17.6) Commissural repair 111 (22.9) Annuloplasty ring type Physio I ring 223 (46.1) Physio II ring 233 (48.1) Other 28 (5.8) Annuloplasty ring size 24 1 (0.2) 26 10 (2.1) 28 31 (6.4) 30 62 (12.8) 32 112 (23.1) 34 98 (20.3) 36 77 (15.9) 38 52 (10.7) 40 41 (8.5) Intraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40) Concomitant procedures Tricuspid valve repair 321 (51.4) Radiofrequency ablation for atrial fibrillation 148 (30.6) Coronary artery bypass surgery 96 (19.8) Aortic valve intervention 28 (5.8) Data are presented as n (%) and medians (IQR). IQR: interquartile range.
title	Baseline characteristics and mitral valve repair details
p	Baseline characteristics of the whole study group are presented in Table 1. Median patient age was 66.5 (IQR 57.8–73.8) years and the majority of patients were male. The repair and procedure details are presented in Table 2. A full ring was used in all patients; the majority of patients (n = 456; 94.2%) underwent either a Physio I (n = 223; 46.1%) or Physio II (n = 233; 48.1%) ring (Edwards Lifesciences, Irvine, CA, USA) implantation. In 42 (8.7%) patients, a ring size 30 or smaller was implanted.
table-wrap	Table 1: Baseline characteristics n = 484 Age (years) 66.5 (57.8–73.8) Gender (female) 171 (35.3) Body surface area (m2) 1.93 ± 0.22 NYHA I 146 (30.2) II 243 (50.2) III–IV 95 (19.6) Hypertension 221 (45.7) Atrial fibrillation 172 (35.5) Renal impairment (ml/min/1.73 m2) Moderate (CC 50–85) 226 (46.7) Severe (CC <50) 41 (8.5) Diabetes mellitus 22 (4.5) Chronic lung disease 42 (8.7) Mitral annular calcification 49 (10.1) Echocardiographic characteristics LVEF ≤60% 134 (27.7) LVEDD (mm)a 54 ± 7 LVESD (mm)a 33 ± 7 LAD (mm)a 45.0 (40.0–49.0) EuroSCORE II 1.76 (0.99–3.24) Degenerative disease subtype Barlow’s disease 140 (28.9) Forme fruste Barlow’s disease 51 (10.5) Site of leaflet prolapse Posterior leaflet 299 (61.8) Single scallop prolapse 234 (48.3) Anterior leaflet 41 (8.5) Bileaflet 144 (29.7) Data are presented as n (%) and means ± SD or medians (IQR). a Available for ≥95% of patients. CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation.
label	Table 1:
caption	Baseline characteristics
p	Baseline characteristics
table	n = 484 Age (years) 66.5 (57.8–73.8) Gender (female) 171 (35.3) Body surface area (m2) 1.93 ± 0.22 NYHA I 146 (30.2) II 243 (50.2) III–IV 95 (19.6) Hypertension 221 (45.7) Atrial fibrillation 172 (35.5) Renal impairment (ml/min/1.73 m2) Moderate (CC 50–85) 226 (46.7) Severe (CC <50) 41 (8.5) Diabetes mellitus 22 (4.5) Chronic lung disease 42 (8.7) Mitral annular calcification 49 (10.1) Echocardiographic characteristics LVEF ≤60% 134 (27.7) LVEDD (mm)a 54 ± 7 LVESD (mm)a 33 ± 7 LAD (mm)a 45.0 (40.0–49.0) EuroSCORE II 1.76 (0.99–3.24) Degenerative disease subtype Barlow’s disease 140 (28.9) Forme fruste Barlow’s disease 51 (10.5) Site of leaflet prolapse Posterior leaflet 299 (61.8) Single scallop prolapse 234 (48.3) Anterior leaflet 41 (8.5) Bileaflet 144 (29.7)
tr	n = 484
th	n = 484
tr	ge (years) 66.5 (57.8–73.8)
td	ge (years)
td	6.5 (57.8–73.8)
tr	ender (female) 171 (35.3)
td	ender (female)
td	71 (35.3)
tr	ody surface area (m2) 1.93 ± 0.22
td	ody surface area (m2)
td	.93 ± 0.22
tr	YHA
td	YHA
tr	I 146 (30.2)
td	I
td	46 (30.2)
tr	II 243 (50.2)
td	II
td	43 (50.2)
tr	III–IV 95 (19.6)
td	III–IV
td	5 (19.6)
tr	ypertension 221 (45.7)
td	ypertension
td	21 (45.7)
tr	trial fibrillation 172 (35.5)
td	trial fibrillation
td	72 (35.5)
tr	enal impairment (ml/min/1.73 m2)
td	enal impairment (ml/min/1.73 m2)
tr	Moderate (CC 50–85) 226 (46.7)
td	Moderate (CC 50–85)
td	26 (46.7)
tr	Severe (CC <50) 41 (8.5)
td	Severe (CC <50)
td	1 (8.5)
tr	iabetes mellitus 22 (4.5)
td	iabetes mellitus
td	2 (4.5)
tr	hronic lung disease 42 (8.7)
td	hronic lung disease
td	2 (8.7)
tr	itral annular calcification 49 (10.1)
td	itral annular calcification
td	9 (10.1)
tr	chocardiographic characteristics
td	chocardiographic characteristics
tr	LVEF ≤60% 134 (27.7)
td	LVEF ≤60%
td	34 (27.7)
tr	LVEDD (mm)a 54 ± 7
td	LVEDD (mm)a
td	4 ± 7
tr	LVESD (mm)a 33 ± 7
td	LVESD (mm)a
td	3 ± 7
tr	LAD (mm)a 45.0 (40.0–49.0)
td	LAD (mm)a
td	5.0 (40.0–49.0)
tr	uroSCORE II 1.76 (0.99–3.24)
td	uroSCORE II
td	.76 (0.99–3.24)
tr	egenerative disease subtype
td	egenerative disease subtype
tr	Barlow’s disease 140 (28.9)
td	Barlow’s disease
td	40 (28.9)
tr	Forme fruste Barlow’s disease 51 (10.5)
td	Forme fruste Barlow’s disease
td	1 (10.5)
tr	ite of leaflet prolapse
td	ite of leaflet prolapse
tr	Posterior leaflet 299 (61.8)
td	Posterior leaflet
td	99 (61.8)
tr	Single scallop prolapse 234 (48.3)
td	Single scallop prolapse
td	34 (48.3)
tr	Anterior leaflet 41 (8.5)
td	Anterior leaflet
td	1 (8.5)
tr	Bileaflet 144 (29.7)
td	Bileaflet
td	44 (29.7)
table-wrap-foot	Data are presented as n (%) and means ± SD or medians (IQR). a Available for ≥95% of patients. CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation.
footnote	Data are presented as n (%) and means ± SD or medians (IQR).
p	Data are presented as n (%) and means ± SD or medians (IQR).
footnote	a Available for ≥95% of patients.
label	a
p	Available for ≥95% of patients.
footnote	CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation.
p	CC: creatinine clearance; IQR: interquartile range; LAD: left atrial diameter; LVEDD: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; NYHA: New York Heart Association; SD: standard deviation.
table-wrap	Table 2: Mitral valve repair details n = 484 Mitral valve annulus Plication 102 (21.1) Anterior mitral valve leaflet repair (neochords) 125 (25.8) Posterior mitral valve leaflet Resection 321 (66.3) Leaflet sliding 222 (45.9) Neochords 206 (42.6) Chordal transfer 9 (1.9) Indentation closure 85 (17.6) Commissural repair 111 (22.9) Annuloplasty ring type Physio I ring 223 (46.1) Physio II ring 233 (48.1) Other 28 (5.8) Annuloplasty ring size 24 1 (0.2) 26 10 (2.1) 28 31 (6.4) 30 62 (12.8) 32 112 (23.1) 34 98 (20.3) 36 77 (15.9) 38 52 (10.7) 40 41 (8.5) Intraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40) Concomitant procedures Tricuspid valve repair 321 (51.4) Radiofrequency ablation for atrial fibrillation 148 (30.6) Coronary artery bypass surgery 96 (19.8) Aortic valve intervention 28 (5.8) Data are presented as n (%) and medians (IQR). IQR: interquartile range.
label	Table 2:
caption	Mitral valve repair details
p	Mitral valve repair details
table	n = 484 Mitral valve annulus Plication 102 (21.1) Anterior mitral valve leaflet repair (neochords) 125 (25.8) Posterior mitral valve leaflet Resection 321 (66.3) Leaflet sliding 222 (45.9) Neochords 206 (42.6) Chordal transfer 9 (1.9) Indentation closure 85 (17.6) Commissural repair 111 (22.9) Annuloplasty ring type Physio I ring 223 (46.1) Physio II ring 233 (48.1) Other 28 (5.8) Annuloplasty ring size 24 1 (0.2) 26 10 (2.1) 28 31 (6.4) 30 62 (12.8) 32 112 (23.1) 34 98 (20.3) 36 77 (15.9) 38 52 (10.7) 40 41 (8.5) Intraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40) Concomitant procedures Tricuspid valve repair 321 (51.4) Radiofrequency ablation for atrial fibrillation 148 (30.6) Coronary artery bypass surgery 96 (19.8) Aortic valve intervention 28 (5.8)
tr	n = 484
th	n = 484
tr	itral valve annulus
td	itral valve annulus
tr	Plication 102 (21.1)
td	Plication
td	02 (21.1)
tr	nterior mitral valve leaflet repair (neochords) 125 (25.8)
td	nterior mitral valve leaflet repair (neochords)
td	25 (25.8)
tr	osterior mitral valve leaflet
td	osterior mitral valve leaflet
tr	Resection 321 (66.3)
td	Resection
td	21 (66.3)
tr	Leaflet sliding 222 (45.9)
td	Leaflet sliding
td	22 (45.9)
tr	Neochords 206 (42.6)
td	Neochords
td	06 (42.6)
tr	Chordal transfer 9 (1.9)
td	Chordal transfer
td	(1.9)
tr	Indentation closure 85 (17.6)
td	Indentation closure
td	5 (17.6)
tr	ommissural repair 111 (22.9)
td	ommissural repair
td	11 (22.9)
tr	nnuloplasty ring type
td	nnuloplasty ring type
tr	Physio I ring 223 (46.1)
td	Physio I ring
td	23 (46.1)
tr	Physio II ring 233 (48.1)
td	Physio II ring
td	33 (48.1)
tr	Other 28 (5.8)
td	Other
td	8 (5.8)
tr	nnuloplasty ring size
td	nnuloplasty ring size
tr	24 1 (0.2)
td	24
td	(0.2)
tr	26 10 (2.1)
td	26
td	0 (2.1)
tr	28 31 (6.4)
td	28
td	1 (6.4)
tr	30 62 (12.8)
td	30
td	2 (12.8)
tr	32 112 (23.1)
td	32
td	12 (23.1)
tr	34 98 (20.3)
td	34
td	8 (20.3)
tr	36 77 (15.9)
td	36
td	7 (15.9)
tr	38 52 (10.7)
td	38
td	2 (10.7)
tr	40 41 (8.5)
td	40
td	1 (8.5)
tr	ntraoperative mitral valve gradient (mmHg) 1.66 (1.16–2.40)
td	ntraoperative mitral valve gradient (mmHg)
td	.66 (1.16–2.40)
tr	oncomitant procedures
td	oncomitant procedures
tr	Tricuspid valve repair 321 (51.4)
td	Tricuspid valve repair
td	21 (51.4)
tr	Radiofrequency ablation for atrial fibrillation 148 (30.6)
td	Radiofrequency ablation for atrial fibrillation
td	48 (30.6)
tr	Coronary artery bypass surgery 96 (19.8)
td	Coronary artery bypass surgery
td	6 (19.8)
tr	Aortic valve intervention 28 (5.8)
td	Aortic valve intervention
td	8 (5.8)
table-wrap-foot	Data are presented as n (%) and medians (IQR). IQR: interquartile range.
footnote	Data are presented as n (%) and medians (IQR).
p	Data are presented as n (%) and medians (IQR).
footnote	IQR: interquartile range.
p	IQR: interquartile range.
sec	Postrepair mitral valve gradient A moderate positive correlation (r = 0.356, n = 391, P < 0.001) between the intraoperative and predischarge MV gradient was seen (Supplementary material, Figure S1). The haemodynamic results of valve repair are demonstrated in Table 3. As expected, postrepair MV gradients decreased with the size of annuloplasty ring implanted (Fig. 1). On linear regression analysis, increasing patient age (coefficient = −0.11, standard error = 0.005, P = 0.034) and annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) were correlated with lower postrepair MV gradients (Table 4). On the other hand, increasing body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008) and, interestingly, use of the Physio I ring (coefficient = 0.414, standard error = 0.122, P < 0.001) were correlated with higher postrepair MV gradients. The linear regression model demonstrated good fit with no evidence of heteroscedasticity or non-linearity (Supplementary material, Figure S2). Figure 1: Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers. Table 3: Postoperative echocardiographic results n = 484 Predischarge mitral valve gradient (mmHg) 3.46 ± 1.43 Predischarge heart rate (min−1) 80 ± 15 Predischarge stroke volume (ml)a 74 (58–93) Predischarge cardiac index (l/m2)a 5.7 (4.6–7.4) Predischarge haemoglobin value (mmol/l) 6.4 ± 0.8 Data are presented as means ± standard deviations and medians (IQR). a Available for ≥90% of patients. IQR: interquartile range. Table 4: Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients Univariable analysis Multivariable analysis Coefficient Standard error P-value Coefficient Standard error P-value Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65 Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034 Body surface area 0.294 0.302 0.33 0.905 0.340 0.008 Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95 Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48 Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23 PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14 PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41 Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001 Annuloplasty ring type Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001 Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001 Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001 PMVL: posterior mitral valve leaflet.
title	Postrepair mitral valve gradient
p	A moderate positive correlation (r = 0.356, n = 391, P < 0.001) between the intraoperative and predischarge MV gradient was seen (Supplementary material, Figure S1). The haemodynamic results of valve repair are demonstrated in Table 3. As expected, postrepair MV gradients decreased with the size of annuloplasty ring implanted (Fig. 1). On linear regression analysis, increasing patient age (coefficient = −0.11, standard error = 0.005, P = 0.034) and annuloplasty ring size (coefficient = −0.181, standard error = 0.018, P < 0.001) were correlated with lower postrepair MV gradients (Table 4). On the other hand, increasing body surface area (coefficient = 0.905, standard error = 0.340, P = 0.008) and, interestingly, use of the Physio I ring (coefficient = 0.414, standard error = 0.122, P < 0.001) were correlated with higher postrepair MV gradients. The linear regression model demonstrated good fit with no evidence of heteroscedasticity or non-linearity (Supplementary material, Figure S2).
figure	Figure 1: Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers.
label	Figure 1:
caption	Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers.
p	Postrepair resting mitral valve gradients in relation to the implanted annuloplasty ring size. Smallest size rings (≤size 28) had the most pronounced effect on postrepair gradients. The middle horizontal line presents the median and the upper and lower borders of the box present the upper and lower quartiles. The upper and lower whiskers present the maximum and minimum values of non-outliers. Extra dots present the outliers.
table-wrap	Table 3: Postoperative echocardiographic results n = 484 Predischarge mitral valve gradient (mmHg) 3.46 ± 1.43 Predischarge heart rate (min−1) 80 ± 15 Predischarge stroke volume (ml)a 74 (58–93) Predischarge cardiac index (l/m2)a 5.7 (4.6–7.4) Predischarge haemoglobin value (mmol/l) 6.4 ± 0.8 Data are presented as means ± standard deviations and medians (IQR). a Available for ≥90% of patients. IQR: interquartile range.
label	Table 3:
caption	Postoperative echocardiographic results
p	Postoperative echocardiographic results
table	n = 484 Predischarge mitral valve gradient (mmHg) 3.46 ± 1.43 Predischarge heart rate (min−1) 80 ± 15 Predischarge stroke volume (ml)a 74 (58–93) Predischarge cardiac index (l/m2)a 5.7 (4.6–7.4) Predischarge haemoglobin value (mmol/l) 6.4 ± 0.8
tr	n = 484
th	n = 484
tr	redischarge mitral valve gradient (mmHg) 3.46 ± 1.43
td	redischarge mitral valve gradient (mmHg)
td	.46 ± 1.43
tr	redischarge heart rate (min−1) 80 ± 15
td	redischarge heart rate (min−1)
td	0 ± 15
tr	redischarge stroke volume (ml)a 74 (58–93)
td	redischarge stroke volume (ml)a
td	4 (58–93)
tr	redischarge cardiac index (l/m2)a 5.7 (4.6–7.4)
td	redischarge cardiac index (l/m2)a
td	.7 (4.6–7.4)
tr	redischarge haemoglobin value (mmol/l) 6.4 ± 0.8
td	redischarge haemoglobin value (mmol/l)
td	.4 ± 0.8
table-wrap-foot	Data are presented as means ± standard deviations and medians (IQR). a Available for ≥90% of patients. IQR: interquartile range.
footnote	Data are presented as means ± standard deviations and medians (IQR).
p	Data are presented as means ± standard deviations and medians (IQR).
footnote	a Available for ≥90% of patients.
label	a
p	Available for ≥90% of patients.
footnote	IQR: interquartile range.
p	IQR: interquartile range.
table-wrap	Table 4: Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients Univariable analysis Multivariable analysis Coefficient Standard error P-value Coefficient Standard error P-value Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65 Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034 Body surface area 0.294 0.302 0.33 0.905 0.340 0.008 Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95 Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48 Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23 PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14 PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41 Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001 Annuloplasty ring type Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001 Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001 Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001 PMVL: posterior mitral valve leaflet.
label	Table 4:
caption	Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients
p	Univariable and multivariable linear regression analysis on risk factors associated with postrepair mitral valve gradients
table	Univariable analysis Multivariable analysis Coefficient Standard error P-value Coefficient Standard error P-value Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65 Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034 Body surface area 0.294 0.302 0.33 0.905 0.340 0.008 Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95 Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48 Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23 PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14 PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41 Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001 Annuloplasty ring type Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001 Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001 Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001
tr	Univariable analysis Multivariable analysis
th	Univariable analysis
th	Multivariable analysis
tr	Coefficient Standard error P-value Coefficient Standard error P-value
th	Coefficient
th	Standard error
th	P-value
th	Coefficient
th	Standard error
th	P-value
tr	Gender (female) 0.114 0.137 0.40 0.069 0.153 0.65
td	Gender (female)
td	0.114
td	0.137
td	0.40
td	0.069
td	0.153
td	0.65
tr	Age (years) 0.000 0.006 0.98 −0.110 0.005 0.034
td	Age (years)
td	0.000
td	0.006
td	0.98
td	−0.110
td	0.005
td	0.034
tr	Body surface area 0.294 0.302 0.33 0.905 0.340 0.008
td	Body surface area
td	0.294
td	0.302
td	0.33
td	0.905
td	0.340
td	0.008
tr	Atrial fibrillation −0.137 0.136 0.32 −0.008 0.121 0.95
td	Atrial fibrillation
td	−0.137
td	0.136
td	0.32
td	−0.008
td	0.121
td	0.95
tr	Posterior mitral annular plication 0.347 0.160 0.030 0.109 0.155 0.48
td	Posterior mitral annular plication
td	0.347
td	0.160
td	0.030
td	0.109
td	0.155
td	0.48
tr	Annular decalcification −0.682 0.223 0.002 −0.235 0.195 0.23
td	Annular decalcification
td	−0.682
td	0.223
td	0.002
td	−0.235
td	0.195
td	0.23
tr	PMVL resection 0.028 0.139 0.84 0.188 0.126 0.14
td	PMVL resection
td	0.028
td	0.139
td	0.84
td	0.188
td	0.126
td	0.14
tr	PMVL indentation closure −0.154 0.172 0.37 −0.123 0.149 0.41
td	PMVL indentation closure
td	−0.154
td	0.172
td	0.37
td	−0.123
td	0.149
td	0.41
tr	Annuloplasty ring size −0.164 0.017 <0.001 −0.181 0.018 <0.001
td	Annuloplasty ring size
td	−0.164
td	0.017
td	<0.001
td	−0.181
td	0.018
td	<0.001
tr	Annuloplasty ring type
td	Annuloplasty ring type
tr	Physio I ring 0.486 0.129 <0.001 0.414 0.122 0.001
td	Physio I ring
td	0.486
td	0.129
td	<0.001
td	0.414
td	0.122
td	0.001
tr	Postoperative blood haemoglobin value −0.288 0.082 <0.001 −0.301 0.071 <0.001
td	Postoperative blood haemoglobin value
td	−0.288
td	0.082
td	<0.001
td	−0.301
td	0.071
td	<0.001
tr	Postoperative heart rate 0.029 0.004 <0.001 0.024 0.004 <0.001
td	Postoperative heart rate
td	0.029
td	0.004
td	<0.001
td	0.024
td	0.004
td	<0.001
table-wrap-foot	PMVL: posterior mitral valve leaflet.
footnote	PMVL: posterior mitral valve leaflet.
p	PMVL: posterior mitral valve leaflet.
sec	Late clinical results From cubic spline-based analyses, no evidence of non-linearity for post repair MV gradient was found for all time-to-event outcomes (Supplementary materials, Figures S3–S5). Hence, postrepair MV gradient was entered into the Cox proportional hazards regression analysis models as a continuous variable for all subsequent analyses. During a median follow-up period of 5.8 (IQR 3.4–9.3) years (99.5% complete, 2 patients were lost to follow-up due to emigration), 84 patients died. When corrected for patient age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR and atrial fibrillation, postrepair MV gradients was not associated with patient survival [hazard ratio (HR) 1.034, 95% CI 0.889–1.203; P = 0.66; Supplementary material, Table S1]. Follow-up on clinical related events was 90% complete with a mean duration of 5.2 (IQR 2.7–8.8) years. When adjusted for patient age, tricuspid valve repair and preoperative left atrial diameter, postrepair MV gradient was not associated with late atrial fibrillation occurrence (HR 0.849, 95% CI 0.682–1.057; P = 0.14; Supplementary material, Table S1). When adjusted for anterior MV leaflet repair, postrepair MV gradient was associated with a higher risk of MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029; Supplementary material, Table S1). A total of 11 late reinterventions were performed. The indication for reintervention was recurrent MR in 9 patients and elevated MV gradient in the remaining 2 patients. In both of the latter patients, a postrepair gradient of ≥5 mmHg (5.88 and 5.23 mmHg, respectively) was seen on predischarge echocardiography, despite an acceptable gradient seen on intraoperative echocardiography (2.53 and 4.23 mmHg, respectively). In the first of the latter patients, an annuloplasty ring size 26 was initially implanted and a re-repair due to heart failure symptoms (no significant MR or other explanation for this observation were found) was performed 1.3 years after the initial operation. Upon reoperation, the annuloplasty ring was explanted, resolving the problem of elevated gradient. In the other patient, an annuloplasty ring size 32 was implanted during the initial operation. Severe pannus formation occurred and the patient underwent a valve replacement 1.1 years after the initial operation.
title	Late clinical results
p	From cubic spline-based analyses, no evidence of non-linearity for post repair MV gradient was found for all time-to-event outcomes (Supplementary materials, Figures S3–S5). Hence, postrepair MV gradient was entered into the Cox proportional hazards regression analysis models as a continuous variable for all subsequent analyses.
p	During a median follow-up period of 5.8 (IQR 3.4–9.3) years (99.5% complete, 2 patients were lost to follow-up due to emigration), 84 patients died. When corrected for patient age, gender, chronic pulmonary disease, renal impairment, left ventricular function, symptomatic MR and atrial fibrillation, postrepair MV gradients was not associated with patient survival [hazard ratio (HR) 1.034, 95% CI 0.889–1.203; P = 0.66; Supplementary material, Table S1].
p	Follow-up on clinical related events was 90% complete with a mean duration of 5.2 (IQR 2.7–8.8) years. When adjusted for patient age, tricuspid valve repair and preoperative left atrial diameter, postrepair MV gradient was not associated with late atrial fibrillation occurrence (HR 0.849, 95% CI 0.682–1.057; P = 0.14; Supplementary material, Table S1).
p	When adjusted for anterior MV leaflet repair, postrepair MV gradient was associated with a higher risk of MV reintervention (HR 1.378, 95% CI 1.033–1.838; P = 0.029; Supplementary material, Table S1). A total of 11 late reinterventions were performed. The indication for reintervention was recurrent MR in 9 patients and elevated MV gradient in the remaining 2 patients. In both of the latter patients, a postrepair gradient of ≥5 mmHg (5.88 and 5.23 mmHg, respectively) was seen on predischarge echocardiography, despite an acceptable gradient seen on intraoperative echocardiography (2.53 and 4.23 mmHg, respectively). In the first of the latter patients, an annuloplasty ring size 26 was initially implanted and a re-repair due to heart failure symptoms (no significant MR or other explanation for this observation were found) was performed 1.3 years after the initial operation. Upon reoperation, the annuloplasty ring was explanted, resolving the problem of elevated gradient. In the other patient, an annuloplasty ring size 32 was implanted during the initial operation. Severe pannus formation occurred and the patient underwent a valve replacement 1.1 years after the initial operation.
sec	Late echocardiographic results On mixed-model linear regression analysis on the evolution of mean MV gradient during the follow-up period, a slight decline in MV gradients was seen (estimate = −0.05, 95% CI −0.07 to −0.02; P < 0.001) during the follow-up period (Fig. 2). Figure 2: Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed.
title	Late echocardiographic results
p	On mixed-model linear regression analysis on the evolution of mean MV gradient during the follow-up period, a slight decline in MV gradients was seen (estimate = −0.05, 95% CI −0.07 to −0.02; P < 0.001) during the follow-up period (Fig. 2).
figure	Figure 2: Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed.
label	Figure 2:
caption	Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed.
p	Longitudinal changes in mean resting mitral valve gradients. During the follow-up period, a slight decrease, when compared with the predischarge postrepair mean mitral valve gradient, can be observed.
sec	DISCUSSION The results of our study are in line with previous studies, and demonstrate that, following valve repair for degenerative disease, high postrepair gradients are of important clinical relevance. However, repair technique (in particular posterior MV leaflet resection) did not show a significant effect on postrepair gradients and no effect of postrepair gradients on the occurrence of late atrial fibrillation was observed. The mechanism of elevated postrepair MV gradients is poorly understood, but is in our opinion related to fixation of the posterior annular perimeter length. Indeed, in an adult sheep model, Dagum et al. [9] have shown that cyclic changes in the MV annular area, reaching a maximum in late diastole, are correlated with length changes of the posterior annular perimeter. After implantation of a true-sized partial or complete flexible annuloplasty device, complete fixation of the MV annular area, posterior and anterior annular perimeters throughout the cardiac cycle was observed. Similarly, Bothe et al. [10] reported that MV annuloplasty results in a significant reduction of the maximal MV opening area, independent of the type of annuloplasty device used (partial or full ring; flexible, semi-rigid or rigid). Moreover, the Physio I ring (as well as the majority of other full rings implanted) did not impair posterior MV leaflet motion. Additionally, while the Physio I ring did increase the excursion of the annular and belly region of the anterior MV leaflet, it did not affect the excursion of the anterior leaflet at the leaflet edge. No effect on anterior leaflet motion was seen after the implantation of a partial Cosgrove-Edwards band (Edwards Lifesciences). Their results suggest that no diastolic flow obstruction due to changes in anterior leaflet motion is to be expected after implantation of the majority of annuloplasty devices tested. In a study on 107 patients after MV repair for degenerative disease, Mesana et al. [5] suggested that full rings may be associated with higher postrepair gradients when compared to partial bands. Their results need to be interpreted with caution as the Duran ring (Medtronic Inc., Minneapolis, MN, USA), notoriously prone to significant pannus formation [11, 12], was used in most patients who underwent full ring implantation. As MV gradients were measured several years after the initial operation, the high gradients observed in this group are most likely due to pannus formation and not the type of annuloplasty device implanted. Murashita et al. [13] explored postrepair gradients in 1147 patients after MV repair for degenerative disease. In most patients, a standard 63 mm flexible band was implanted, irrespective of annular perimeter length or anterior leaflet size. In the first median follow-up period (124.5 days after operation), a mean gradient of 3.7 ± 1.6 mmHg was reported that declined to a mean gradient of 3.3 ± 1.8 mmHg in the second median follow-up period (600 days after operation). The gradients in the first median follow-up period seem somehow higher than early postrepair gradients observed in our population. On longitudinal analysis, a decline similar to the one observed by Murashita et al. was also observed in our population. While clearly limited, amongst others, by the unadjusted differences in patient populations, such observations challenge the alleged superiority of partial bands in terms of postrepair gradients. On the other side, excessive shortening of the posterior annular perimeter (resulting from downsizing described by the authors) is bound to have resulted in smaller MV areas than would have been achieved with a true-sized ring. The results of our analyses suggest that the postrepair gradient is partially associated with patient characteristics (both patient age and body surface area likely reflect the relation of these parameters to systemic metabolic needs and hereto related cardiac output). Moreover, our results demonstrate that the choice of annuloplasty device used might affect postrepair gradients. This is likely correspondent to the differences in the ratio between the anterior-posterior diameter (reflecting anterior MV leaflet surface area to which the ring is sized) and the length of the ‘posterior perimeter’ of the annuloplasty ring between different annuloplasty devices. We are unaware of any studies demonstrating that the increased saddle shape of the Physio II ring is related to improved diastolic MV opening properties when compared to annuloplasty devices with less pronounced saddle-shape. Because of the lack of studies, we cannot exclude the possibility that the Physio II ring results in superior diastolic opening properties of the anterior leaflet that might explain our observation. For the time being, this should, however, be seen as a theory and properly designed studies will need to be conducted in the future. In a recent meta-analysis, Mazine et al. [14] have speculated that in cases of posterior MV leaflet prolapse, chordal replacement techniques will result in lower MV gradients when compared to leaflet resection techniques. Our results failed to demonstrate any significant effect of posterior leaflet resection on postrepair gradient. This is likely related to the fact that we primarily used leaflet resection techniques to address excessive posterior MV leaflet tissue and structurally avoided excessive resection. Should this be avoided, no significant shortening of the posterior leaflet free edge, that could at least theoretically limit diastolic leaflet mobility, is to be expected. Functional MV stenosis should not present a reason not to perform adequate leaflet resection when this is indicated, an opinion previously emphasized by our group and others [15–18]. We did not observe any effect of elevated MV gradients on freedom from atrial fibrillation. On the contrary, elevated postrepair MV gradient was identified as a risk factor for late atrial fibrillation occurrence in recent studies by Kawamoto et al. [19] as well as Ma et al. [20]. We included only patients in sinus rhythm who did not undergo any ablation procedures, a characteristic that could provide an explanation for the differences observed between our results and those of Kawamoto et al. [19]. More importantly, we differentiated between atrial fibrillation and other types of atrial tachycardias as the mechanisms associated with the development of different atrial tachycardias after MV operations are known to fundamentally differ [7]. To adjust for potential unadjusted bias, future studies should include information on the type of incision made to expose the MV when exploring the effect of other factors on early and late atrial tachycardias. Previous studies also demonstrated that an elevated postrepair MV gradient impairs left atrial reverse remodelling [21]. Nevertheless, atrial fibrillation is most likely related to left atrial fibrosis that develops because of long-standing volume overload prior to the operation and is present even in patients in preoperative sinus rhythm [22]. More studies, with longer follow-up, are also needed to explore whether left atrial reverse remodelling in the presence of elevated postrepair gradient is impaired or only delayed. The results of our study do, however, suggest that the clinical burden of elevated postrepair gradient might be lower than previously suggested. The observation that the risk of reintervention might be related to postrepair MV gradient has not previously been reported. The incidence of reoperation for MV stenosis after previous repair is known to be low [13, 23], but reflects only the patients most affected by this condition. Other studies have additionally shown that high postrepair gradients will result in decreased exercise tolerance and quality of life [3, 5]. We followed the established concepts of valve repair for degenerative disease that include annular remodelling and stabilization. As fixation of the maximal posterior perimeter length and hereto related maximal MV area are likely inevitable with any type of annuloplasty device used, elevated postrepair gradients might not be avoidable in all patients. Omitting annuloplasty device implantation is controversial, as this is known to result in a higher risk of recurrent MR [24]. Possibly, new annuloplasty device design and identification of patients in whom annular characteristics are sufficiently preserved to support valve sufficiency in the long term even without annular stabilization would help reduce the burden of this problem. Limitations This is a single-centre retrospective study with study limitations inherent to the study design. The results are applicable to the type of MV repair techniques described only and further studies are needed to evaluate the effect or other repair techniques (e.g. edge-to-edge repair) and annuloplasty devises on the occurrence of elevated postrepair gradients. During the study period, the MV repair techniques have evolved with, in particular, annular plication being performed less frequently. As the type of leaflet repair did not affect the sizing of the annuloplasty device implanted, no relevant effect on the results presented is to be expected. Moreover, the number of reinterventions was low and prevented us from exploring the risk factors for MV reintervention specified to the indication for reintervention (i.p. recurrent MR versus elevated MV gradient). While we failed to identify a relation between postrepair MV gradient and survival or atrial fibrillation, we cannot exclude the possibility that a correlation does exist, but we were unable to detect it due to an insufficient number of patients and events. Our results should thus be seen as hypothesis-generating and will need to be confirmed by future studies. We have performed cubic spline analyses, but failed to identify a cut-off value that would ease the identification of patient a risk for complications related to elevated postrepair MV gradient in the clinical setting. Identification of a cut-off value should be pursued in future studies. Nevertheless, in line with previous studies, our results do support the efforts aimed at securing the lowest possible postrepair MV gradient.
title	DISCUSSION
p	The results of our study are in line with previous studies, and demonstrate that, following valve repair for degenerative disease, high postrepair gradients are of important clinical relevance. However, repair technique (in particular posterior MV leaflet resection) did not show a significant effect on postrepair gradients and no effect of postrepair gradients on the occurrence of late atrial fibrillation was observed.
p	The mechanism of elevated postrepair MV gradients is poorly understood, but is in our opinion related to fixation of the posterior annular perimeter length. Indeed, in an adult sheep model, Dagum et al. [9] have shown that cyclic changes in the MV annular area, reaching a maximum in late diastole, are correlated with length changes of the posterior annular perimeter. After implantation of a true-sized partial or complete flexible annuloplasty device, complete fixation of the MV annular area, posterior and anterior annular perimeters throughout the cardiac cycle was observed. Similarly, Bothe et al. [10] reported that MV annuloplasty results in a significant reduction of the maximal MV opening area, independent of the type of annuloplasty device used (partial or full ring; flexible, semi-rigid or rigid). Moreover, the Physio I ring (as well as the majority of other full rings implanted) did not impair posterior MV leaflet motion. Additionally, while the Physio I ring did increase the excursion of the annular and belly region of the anterior MV leaflet, it did not affect the excursion of the anterior leaflet at the leaflet edge. No effect on anterior leaflet motion was seen after the implantation of a partial Cosgrove-Edwards band (Edwards Lifesciences). Their results suggest that no diastolic flow obstruction due to changes in anterior leaflet motion is to be expected after implantation of the majority of annuloplasty devices tested.
p	In a study on 107 patients after MV repair for degenerative disease, Mesana et al. [5] suggested that full rings may be associated with higher postrepair gradients when compared to partial bands. Their results need to be interpreted with caution as the Duran ring (Medtronic Inc., Minneapolis, MN, USA), notoriously prone to significant pannus formation [11, 12], was used in most patients who underwent full ring implantation. As MV gradients were measured several years after the initial operation, the high gradients observed in this group are most likely due to pannus formation and not the type of annuloplasty device implanted. Murashita et al. [13] explored postrepair gradients in 1147 patients after MV repair for degenerative disease. In most patients, a standard 63 mm flexible band was implanted, irrespective of annular perimeter length or anterior leaflet size. In the first median follow-up period (124.5 days after operation), a mean gradient of 3.7 ± 1.6 mmHg was reported that declined to a mean gradient of 3.3 ± 1.8 mmHg in the second median follow-up period (600 days after operation). The gradients in the first median follow-up period seem somehow higher than early postrepair gradients observed in our population. On longitudinal analysis, a decline similar to the one observed by Murashita et al. was also observed in our population. While clearly limited, amongst others, by the unadjusted differences in patient populations, such observations challenge the alleged superiority of partial bands in terms of postrepair gradients. On the other side, excessive shortening of the posterior annular perimeter (resulting from downsizing described by the authors) is bound to have resulted in smaller MV areas than would have been achieved with a true-sized ring.
p	The results of our analyses suggest that the postrepair gradient is partially associated with patient characteristics (both patient age and body surface area likely reflect the relation of these parameters to systemic metabolic needs and hereto related cardiac output). Moreover, our results demonstrate that the choice of annuloplasty device used might affect postrepair gradients. This is likely correspondent to the differences in the ratio between the anterior-posterior diameter (reflecting anterior MV leaflet surface area to which the ring is sized) and the length of the ‘posterior perimeter’ of the annuloplasty ring between different annuloplasty devices. We are unaware of any studies demonstrating that the increased saddle shape of the Physio II ring is related to improved diastolic MV opening properties when compared to annuloplasty devices with less pronounced saddle-shape. Because of the lack of studies, we cannot exclude the possibility that the Physio II ring results in superior diastolic opening properties of the anterior leaflet that might explain our observation. For the time being, this should, however, be seen as a theory and properly designed studies will need to be conducted in the future.
p	In a recent meta-analysis, Mazine et al. [14] have speculated that in cases of posterior MV leaflet prolapse, chordal replacement techniques will result in lower MV gradients when compared to leaflet resection techniques. Our results failed to demonstrate any significant effect of posterior leaflet resection on postrepair gradient. This is likely related to the fact that we primarily used leaflet resection techniques to address excessive posterior MV leaflet tissue and structurally avoided excessive resection. Should this be avoided, no significant shortening of the posterior leaflet free edge, that could at least theoretically limit diastolic leaflet mobility, is to be expected. Functional MV stenosis should not present a reason not to perform adequate leaflet resection when this is indicated, an opinion previously emphasized by our group and others [15–18].
p	We did not observe any effect of elevated MV gradients on freedom from atrial fibrillation. On the contrary, elevated postrepair MV gradient was identified as a risk factor for late atrial fibrillation occurrence in recent studies by Kawamoto et al. [19] as well as Ma et al. [20]. We included only patients in sinus rhythm who did not undergo any ablation procedures, a characteristic that could provide an explanation for the differences observed between our results and those of Kawamoto et al. [19]. More importantly, we differentiated between atrial fibrillation and other types of atrial tachycardias as the mechanisms associated with the development of different atrial tachycardias after MV operations are known to fundamentally differ [7]. To adjust for potential unadjusted bias, future studies should include information on the type of incision made to expose the MV when exploring the effect of other factors on early and late atrial tachycardias. Previous studies also demonstrated that an elevated postrepair MV gradient impairs left atrial reverse remodelling [21]. Nevertheless, atrial fibrillation is most likely related to left atrial fibrosis that develops because of long-standing volume overload prior to the operation and is present even in patients in preoperative sinus rhythm [22]. More studies, with longer follow-up, are also needed to explore whether left atrial reverse remodelling in the presence of elevated postrepair gradient is impaired or only delayed. The results of our study do, however, suggest that the clinical burden of elevated postrepair gradient might be lower than previously suggested.
p	The observation that the risk of reintervention might be related to postrepair MV gradient has not previously been reported. The incidence of reoperation for MV stenosis after previous repair is known to be low [13, 23], but reflects only the patients most affected by this condition. Other studies have additionally shown that high postrepair gradients will result in decreased exercise tolerance and quality of life [3, 5]. We followed the established concepts of valve repair for degenerative disease that include annular remodelling and stabilization. As fixation of the maximal posterior perimeter length and hereto related maximal MV area are likely inevitable with any type of annuloplasty device used, elevated postrepair gradients might not be avoidable in all patients. Omitting annuloplasty device implantation is controversial, as this is known to result in a higher risk of recurrent MR [24]. Possibly, new annuloplasty device design and identification of patients in whom annular characteristics are sufficiently preserved to support valve sufficiency in the long term even without annular stabilization would help reduce the burden of this problem.
sec	Limitations This is a single-centre retrospective study with study limitations inherent to the study design. The results are applicable to the type of MV repair techniques described only and further studies are needed to evaluate the effect or other repair techniques (e.g. edge-to-edge repair) and annuloplasty devises on the occurrence of elevated postrepair gradients. During the study period, the MV repair techniques have evolved with, in particular, annular plication being performed less frequently. As the type of leaflet repair did not affect the sizing of the annuloplasty device implanted, no relevant effect on the results presented is to be expected. Moreover, the number of reinterventions was low and prevented us from exploring the risk factors for MV reintervention specified to the indication for reintervention (i.p. recurrent MR versus elevated MV gradient). While we failed to identify a relation between postrepair MV gradient and survival or atrial fibrillation, we cannot exclude the possibility that a correlation does exist, but we were unable to detect it due to an insufficient number of patients and events. Our results should thus be seen as hypothesis-generating and will need to be confirmed by future studies. We have performed cubic spline analyses, but failed to identify a cut-off value that would ease the identification of patient a risk for complications related to elevated postrepair MV gradient in the clinical setting. Identification of a cut-off value should be pursued in future studies. Nevertheless, in line with previous studies, our results do support the efforts aimed at securing the lowest possible postrepair MV gradient.
title	Limitations
p	This is a single-centre retrospective study with study limitations inherent to the study design. The results are applicable to the type of MV repair techniques described only and further studies are needed to evaluate the effect or other repair techniques (e.g. edge-to-edge repair) and annuloplasty devises on the occurrence of elevated postrepair gradients. During the study period, the MV repair techniques have evolved with, in particular, annular plication being performed less frequently. As the type of leaflet repair did not affect the sizing of the annuloplasty device implanted, no relevant effect on the results presented is to be expected. Moreover, the number of reinterventions was low and prevented us from exploring the risk factors for MV reintervention specified to the indication for reintervention (i.p. recurrent MR versus elevated MV gradient). While we failed to identify a relation between postrepair MV gradient and survival or atrial fibrillation, we cannot exclude the possibility that a correlation does exist, but we were unable to detect it due to an insufficient number of patients and events. Our results should thus be seen as hypothesis-generating and will need to be confirmed by future studies. We have performed cubic spline analyses, but failed to identify a cut-off value that would ease the identification of patient a risk for complications related to elevated postrepair MV gradient in the clinical setting. Identification of a cut-off value should be pursued in future studies. Nevertheless, in line with previous studies, our results do support the efforts aimed at securing the lowest possible postrepair MV gradient.
sec	CONCLUSIONS Following MV repair with a semi-rigid annuloplasty ring, increased resting MV gradients are not uncommon. This is, among others, related to the implanted ring size and patient body surface area. Elevated postrepair MV gradients might result in poorer freedom from reintervention due to the added risk of reintervention for MV stenosis while survival and incidence of late atrial fibrillation development do not seem to be affected. Conflict of interest: none declared.
title	CONCLUSIONS
p	Following MV repair with a semi-rigid annuloplasty ring, increased resting MV gradients are not uncommon. This is, among others, related to the implanted ring size and patient body surface area. Elevated postrepair MV gradients might result in poorer freedom from reintervention due to the added risk of reintervention for MV stenosis while survival and incidence of late atrial fibrillation development do not seem to be affected.
p	Conflict of interest: none declared.
sec	Supplementary Material ezz178_Supplementary_Material Click here for additional data file.
title	Supplementary Material
label	ezz178_Supplementary_Material
caption	Click here for additional data file.
p	Click here for additional data file.
back	Presented at the 98th Annual Meeting of the American Association of Thoracic Surgeons, San Diego, CA, USA, 28 April–1 May 2018.
sec	Presented at the 98th Annual Meeting of the American Association of Thoracic Surgeons, San Diego, CA, USA, 28 April–1 May 2018.
p	Presented at the 98th Annual Meeting of the American Association of Thoracic Surgeons, San Diego, CA, USA, 28 April–1 May 2018.

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