Juntendo Medical Journal

Objective: Although some parameters have been defined for predicting late-onset tricuspid regurgitation (TR) after mitral valve (MV) repair, few studies have focused on the early TR progression. The aim of this study was to evaluate the changes in unrepaired TR early after isolated MV repair for degenerative MR, and investigate the predictors of TR progression. Methods: We retrospectively identified 236 patients who underwent isolated MV repair in our institute between 2014 and 2019. Patients with severe preoperative TR, non-degenerative etiology, without echocardiography reports were excluded from the study. Early TR progression was defined as an increase in TR of at least one grade on pre-discharge echocardiography compared to preoperatively. Baseline characteristics were compared between patients with and without early TR progression. Results: A total of 214 patients were analyzed. Mean age was 59 years and 32.7% were female. At baseline, 77.6% had no TR, 20.6% had mild TR, and 1.9% had moderate TR. At follow-up before discharge, 15.4% (n=33) had TR progression. The TR progression group was older and showed lower body mass index (BMI) than the no-TR progression group. Although not significant, renal function tended to be lower in the TR progression group than in the no-TR progression group. Multivariable analysis revealed higher age and lower BMI as independent predictors of TR progression early after MV repair. Conclusions: Despite appropriate surgical correction of degenerative MR, progression of TR early after MV repair was observed in 15% of the patients. High age and low BMI were independently associated with TR progression early after MV repair. Further studies are necessary to examine the significance of early TR progression on long-term prognosis after MV repair.


Introduction
Advanced mitral regurgitation (MR) is often associated with functional tricuspid regurgitation (TR). Historically, TR associated with MR has been managed conservatively, since the pathology was thought to improve after mitral valve (MV) surgery 1) due to the reduction in right ventricular (RV) afterload. However, more recently, TR was revealed to show no improvement; rather, TR may progress after MV surgery in a substantial portion of patients 2) 3) . Unoperated TR has been reported to adversely impact survival and functional outcomes in patients with MR who undergo MV surgery 4) . Dreyfus et al. reported that concomitant tricuspid valve (TV) repair based on tricuspid annular size improves functional status irrespective of the grade of TR 5) . TV surgery after previous MV surgery is associated with high in-hospital mortality 6) ; but concomitant TV surgery at the time of MV repair is reported as safe and effective 4) 5) . Based on these findings, valvular heart disease guidelines currently recommend concomitant TV surgery not only for severe TR, but also for mild or moderate TR with tricuspid annular diameter (TAD) > 40 mm at the time of MV surgery 7) 8) . Nevertheless, debate is ongoing about aggressive concomitant TV surgery for mild or moderate TR to prevent progression of TR 9) 10) . Reflecting this controversy, the percentage of patients from high-volume centers undergoing concomitant tricuspid repair ranges from 7% to 65% 11) . In clinical practice, we have observed some cases with progression of TR early after isolated MV repair who were deemed to be at low risk of TR progression at preoperative evaluation. Patients with TR progression early after MV repair may be at risk of reoperation or reduced QOL. Few studies have focused on the early progression of TR after MV repair. We therefore aimed to examine the changes in unrepaired TR early after isolated MV repair for degenerative MR, and investigate the predictors of TR progression.

Study population
This was a single-center, retrospective observational study. A total of 236 consecutive patients who underwent isolated MV repair for severe MR at the Juntendo University Hospital from January 2014 to October 2019 were identified from a cardiovascular surgery database. Isolated MV repair was defined as MV repair without concomitant aortic or tricuspid valve surgery, coronary artery bypass graft surgery, aorta graft replacement, or congenital defect closure. Patients for whom preoperative or in-hospital postoperative echocardiography reports were missing were excluded from the analysis. We also excluded patients with severe preoperative TR and non-degenerative MR. Finally, a total of 214 patients were analyzed (Figure-1).
Demographic data, clinical data, and surgical information were collected from institutional medical records. Clinical data included cardiovascular risk factors, prevalence of paroxysmal or persistent atrial fibrillation (AF), hemoglobin levels, estimated glomerular filtration rate (eGFR), and brain natriuretic peptide (BNP) levels. Body mass index (BMI) was calculated as follows: BMI = weight (kg)/ height (m) 2 . European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) was used to estimate the risk of surgical mortality 12) .

Echocardiographic data
Pre-and postoperative transthoracic echocardiography (TTE) measurements were collected from the Juntendo University echocardiography database. All standard examinations, including Doppler color flow measurements, were made according to the current guidelines 13) using commercially available ultrasound systems by several Kaya E, et al: Tricuspid regurgitation early after mitral valve repair certified sonographers. From the apical two-and four-chamber views, left ventricular ejection fraction (LVEF) was quantified using the Simpsonʼs biplane method. Valvular regurgitation severity was graded as none, mild, moderate, or severe, according to standard quantitative and semi-quantitative methods recommended by guidelines 14) . Integrative assessment of TR severity was performed using a multiparametric approach (including jet size, jet eccentricity, and vena contracta width). Trivial TR was considered as no TR in this study. RV systolic function was evaluated using tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (TVsʼ). Since the dimension of the tricuspid annulus (TAD) was not recorded in some cases, TAD was measured from an apical four-chamber view, in late diastole when the tricuspid valve was maximally opened, as recommended by Foale et al. 15) , by reviewing stored digital images. Early TR progression was defined as an increase in TR of at least one grade on pre-discharge echocardiography compared to preoperative echocardiography. Patients were divided into two groups: a TR progression group; and a no-TR progression group.

Statistical analysis
Continuous variables are expressed as mean and standard deviation (SD). Categorical variables are expressed as numbers and percentages. Differences between groups were compared using Studentʼs t-test and the chi-square or Fisherʼs exact test, respectively, for continuous and categorical variables. To normalize the skewed distribution, logtransformed BNP level was used as a continuous variable.
Multivariate analysis using logistic regression modeling was applied to determine risk factors for early TR progression. Results are presented as odds ratios with 95% confidence intervals (CI). All tests were two-tailed, and values of p < 0.05 were considered to indicate statistical significance. All statistical analyses were performed using SPSS version 26.0 (SPSS Inc., Chicago, IL, USA). Table- Prevalence of moderate TR at discharge was only 1.9% (n = 4). All patients with moderate TR at discharge showed no or only mild TR preoperatively ( Figure-2). Patients in the TR progression group were significantly older and displayed a smaller BMI than those in the no-TR progression group (65.3 ± 11.2 years vs. 57.9 ± 13.5 years, p = 0.003 and 21.3 kg/m 2 ± 2.3 vs. 22.9 ± 3.6 kg/m 2 , p = 0.017, respectively). Although not significant, eGFR was lower in the TR progression group (69.2 ± 17.3 vs. 76.9 ± 22.2, p = 0.06). The prevalence of AF did not differ significantly between the TR progression and no-TR progression groups (12.1% vs. 14.4%, p = 1.00). Left ventricular diastolic dimension (LVDd) tended to be smaller in the TR progression group than in the no-TR progression group, but this difference was not significant (52.1 ± 5.8 vs. 54.5 ± 6.8, p = 0.057). LVEF did not differ significantly between groups (68.7 ± 8.0 % vs. 68.1 ± 7.5 %, p = 0.69). Tricuspid annular plane systolic excursion (TAPSE), tricuspid annular velocity, and TAD did not differ significantly between groups. Only five patients (2.7%) showed TAD ≥40 mm.

Patient characteristics are shown in
Table-3 summarizes the surgical data. All patients were repaired with flexible or semi-rigid annular rings. Ring size and percentage of concomitant Maze procedures did not differ significantly between groups. Only two patients (0.9%) had early recurrence of more than moderate MR after MV repair. Patients underwent MV repair with complete (n = 174) or partial median sternotomy (n = 28) or mini-thoracotomy (n = 12). At the time of post-operative echocardiography, AF was observed in 6.1% of TR progression group and 3.3% of no-TR progression group (p = 0.36). Values are mean ± standard deviation or number (%) BMI = body mass index, NYHA = New York Heart Association, CAD = coronary artery disease, COPD = chronic obstructive pulmonary disease, eGFR = estimated glomerular filtration rate, Log BNP = Brain natriuretic peptide (log-transformed), Hb = hemoglobin levels, ACEI = angiotensin converting enzyme inhibitor, ARB = angiotensin receptor blocker   Univariate analysis showed that age and BMI were significantly associated with TR progression. When age, BMI, hemoglobin level, and LVDd were included as covariates in the multivariate analysis, age and BMI were independent predictors of TR progression (Table-4).

Discussion
This study investigated the prevalence and factors associated with TR progression early after isolated MV repair for degenerative MR. We found that 15% of our study population showed TR progression of at least one grade after MV repair. In the multivariate analysis, age and BMI were independent factors associated with early TR progression.
There are few papers that describe changes in the severity of TR in the early stage after MV repair. Murashita et al. 16) reported that the mean TR grade at discharge was significantly reduced (0.7 ± 0.5) compared to preoperative (0.9 ± 0.5) in the patients who underwent MV repair without    20) . In our study population, TAD measurements did not differ between the TR progression and no-TR progression groups. In addition, only five patients (2.7%) displayed TAD ≥40 mm. This is because most MR patients with dilated TA underwent concomitant TV repair by our surgeons, in accordance with the current guidelines, and were not included in this analysis.
In multivariate analysis, age and BMI were independent predictors for early TR progression in our study. Many studies have shown preoperative AF as an independent predictor of TR progression late after MV surgery 2) 10) 17) . Patients with advanced AF may show no improvement in RV size or function, even after a reduction in RV afterload by MV repair. In our study population, the majority of AF patients underwent concomitant Maze procedure. This may have led to our result differing from those of previous reports. Although not statistically significant, postoperative AF was observed more frequently in the TR progression group than in the no-TR progression group. Aggressive rhythm control may suppress TR progression in MR patients with AF.
In our study, patients in the TR progression group showed lower BMI than those in the no-TR progression group. Why lower BMI is associated with TR progression remains unclear. BMI is not only an indicator of obesity, but is also affected by cardiac cachexia or fluid retention, so further studies are necessary in this regard.
This study has several limitations. First, this was a single-center, retrospective study with a relatively small cohort. Second, selection bias may have occurred because we excluded patients without echocardiographic data. Third, although multivariate analysis was used, we could not account for other potential confounders. Fourth, the body fluid volume at the time of echocardiography may affect the severity of TR, but details of body weight changes and doses of diuretics have not been obtained. Finally, we did not evaluate the impact of

Conclusion
Despite appropriate surgical correction of degenerative MR, progression of TR early after MV repair was observed in 15% of the patients. High age and low BMI were independently associated with TR progression early after MV repair. Larger prospective studies are necessary to evaluate the impact of early TR progression on long-term prognosis after MV repair.

Funding
No funding was received.

Disclosures
The authors declare that there are no conflicts of interest.

Contributions
EK did the data acquisition, data analysis and wrote the manuscript. SM designed the work and interpreted the analyzed data. TY prepared surgical information and gave advice on surgical findings. AA revised the manuscript critically for important content. HD revised the manuscript critically for important content.
TM made final approval of the version to be published.