Attitude towards a moderate aortic valve dysfunction during rheumatic mitral valve surgery: a retrospective cohort study

Introduction

Rheumatic heart disease (RHD), a significant global health challenge, affects an estimated 34.2 million individuals worldwide (1). China has the second-highest incidence of RHD globally, with more than 7 million reported cases, of which approximately 1.5 million patients require surgical intervention (1,2). RHD is the primary cause of valvular disease in China, and the incidence of rheumatic valvular disease increases with age (3).

The hallmark sign of RHD is the valvular involvement, particularly of the left side. The majority of patients with RHD have an organic involvement of the mitral valve (MV) while only 2% of patients have isolated aortic valve (AV) disease (1). A common challenge in clinical practice is rheumatic MV disease combined with AV disease (4). During other cardiac surgery, a concomitant aortic valve replacement (AVR) is recommended as a class I indication in current guidelines, in cases of severe aortic stenosis (AS) or aortic regurgitation (AR) (5). However, some guidelines still advocate AVR as class 2b but with a level of evidence C, when it comes to moderate AS or AR during other cardiac surgery (5), while the intervention for AV requires comprehensive consideration of age, comorbidities, and the risk of concomitant surgery as suggested by other guidelines (6).

Although several studies have reported the clinical outcomes of rheumatic MV disease combined with mild AV disease (4,7), there is a lack of literature on how to deal with rheumatic MV disease combined with moderate AV disease. Therefore, this study aimed to compare the clinical outcomes of patients who underwent rheumatic MV surgery with or without concurrent AV procedure, which included all-cause mortality, cardiac reoperation, and echocardiography outcomes, to clarify whether concomitant AV surgery should be performed for the population. This was a single-center, retrospective observational cohort study. We present this article in accordance with the STROCSS reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1283/rc) (8).

Methods

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Beijing An Zhen Hospital (No. KS2023059, approved on Sep 21, 2023) and informed consent was waived because of the retrospective nature of the study.

Patients

This study included 343 consecutive patients (age ≥18 years) who underwent rheumatic MV surgery, combined with moderate aortic valve dysfunction (AVD) at Beijing An Zhen Hospital in China from January 2015 to August 2022, comprising no treatment group (NT group, n=121) and aortic valvuloplasty or aortic valve replacement group (AVP or AVR group, n=222), as shown in Figure 1. These patients accounted for 21.0% (343/1,632) of patients who underwent rheumatic MV surgery at our institution during the same period. Patients who underwent other concomitant cardiac procedures such as radiofrequency ablation, left atrial thrombectomy, coronary artery bypass graft, and tricuspid valve surgery were included. Patients received transthoracic echocardiography (TTE) before and after surgery to evaluated the condition of valve dysfunction and valve calcification. The diagnosis of rheumatic valvular disease was mainly based on the TEE assessment combined with other laboratory tests including C-reactive protein, antistreptolysin O, and erythrocyte sedimentation rate. Methods to evaluate the grade of RHD using TEE have been reported in previous literature (9).

Figure 1 Study design and patients included. NT, no treatment; AVP, aortic valvuloplasty; AVR, aortic valve replacement; IPTW, inverse probability treatment weighting; AVD, aortic valve dysfunction.

Surgical technique

MV and AV procedures were performed through a median sternotomy. The decision on whether to perform AVP/AVR, followed by either a valve repair technique or a valve replacement, was mainly based on the preoperative evaluation of the valvular disease severity and the cardiac surgeon’s discretion. Details of the MV repair and AV repair have been described (10,11). Patients were fully informed regarding the indications and characteristics of mechanical and biological valve types in the case of valve replacement. Subsequently, they were allowed to independently select the type of prosthetic valve to be used. In general, patients with mild or more-than-mild tricuspid regurgitation (TR) at our center routinely underwent tricuspid valve surgery, while patients with atrial fibrillation (AF) mostly underwent radiofrequency ablation.

Study endpoints

The more-than-mild AVD during follow-up was the primary endpoint event, while the secondary endpoints encompassed all-cause mortality and cardiac reoperation both before discharge and during follow-up. The primary endpoint was demonstrated using TTE.

Follow up

Patients were followed up by outpatient service or through telephone conversation. The median follow-up duration and the mean follow-up duration was 39.9 months (P₂₅–P₇₅, 16.6–65.7 months) and 41.3 months, respectively. The rate of follow-up was 89.5%. Adverse events included all-cause death and cardiac reoperation.

Statistical analysis

Continuous data were summarized as mean ± standard deviation (SD) and as median and interquartile range for variables with normal and non-normal distribution, respectively. Categorical data were presented as frequencies and proportions. Student’s t-test was used to compare continuous variables, while the Mann-Whitney U-test was used for non-normally distributed variables. The Chi-square test or Fisher’s test was utilized for categorical data. The missing data were not filled in.

The baseline data were adjusted using the stabilized inverse probability treatment weighting (IPTW) method. The multivariable logistic regression was used to develop the propensity score (PS), while stabilized weights were calculated from the PS and used as weights for IPTW. The formula Pt/PS for the AVP or AVR group and (1 − Pt)/(1 − PS) for the NT group (Pt = the number of patients in the AVP or AVR group/total patients) was used to calculate the weight of patients. For comparing the NT and AVP or AVR groups, the PS model included age, sex, body mass index, AF, hypertension, stroke history, diabetes mellitus, coronary artery disease (CAD), New York Heart Association classification of cardiac function (NYHA), pulmonary artery hypertension (PAH), serum creatinine, mitral stenosis, mitral regurgitation, AS, AR, TR, AV calcification, preoperative left ventricular end-diastolic dimension, preoperative left ventricular end-systolic dimension, left atrial diameter, MV area, the surgical procedure of MV, and left atrial thrombectomy. The standardized mean difference (SMD) between groups before and after IPTW matching was derived from the divided differences in means by pooled SD and difference in proportions. The absolute SMD was less than 0.2, indicating the smallest possible difference between groups and a successful match. After IPTW, there were 103.8 and 226.9 patients in the NT and AVP or AVR groups, respectively. Poisson regression models were used to calculate relative risks (RRs), while the Cox proportional hazards models were used to calculate the hazard ratios (HRs) by adjusting for AS, AV calcification, and MV repair.

The Kaplan-Meier method was used to generate a survival curve, and survival rate comparisons between the two groups were performed using the log-rank test. R software version 4.2.2 was used to conduct all statistical analyses, and statistical significance was set at two-tailed P<0.05.

Results

Patient characteristics and IPTW

A total of 343 consecutive patients who underwent rheumatic MV surgery, combined with moderate AVD, were enrolled. The number of patients with simple moderate AS, simple moderate AR, and combined moderate AS and AR were 25, 251, and 67, respectively. The mean patient age was 55.18±10.12 years at the time of surgery, and 67.3% (n=231) of the patients were women. Patients in the NT group had a lighter NYHA grade (P=0.008), milder degree of AS (P<0.001), lighter condition of AV calcification (P<0.001), lower LVEF value (P=0.02), and a higher proportion of MV repair (P<0.001). The grade of AS was strongly correlated with AV calcification (P<0.001). No notable variations in the other baseline characteristics were noted between the two groups. Table 1 presents the baseline data before and after IPTW matching, encompassing demographic and clinical characteristics. After IPTW, there were 103.8 and 226.9 patients in the NT and AVP or AVR groups, respectively with similar demographic and clinical characteristics and reasonable absolute standardized differences, as shown in Table 1 and Figure 2.

Figure 2 Absolute standardized differences compared baseline characteristics between no treatment groups and aortic valvuloplasty or aortic valve replacement groups before and after matching, respectively. Absolute standardized mean difference, which was less than 0.2, represented a successful match. The dotted line denoted 0.1 threshold. AS, aortic stenosis; AV, aortic valve; mitralmv, mitral valve replacement using mechanical valves; NYHA, New York heart association classification of cardiac function; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic dimension; MS, mitral stenosis; mitralbv, mitral valve replacement using biological valves; LA, left atrium; TR, tricuspid regurgitation; SCr, serum creatinine; LVESD, left ventricular end-systolic dimension; AR, aortic regurgitation; CAD, coronary artery disease; MVA, mitral valve area; PAH, pulmonary artery hypertension; BMI, body mass index; MR, mitral regurgitation; HTN, hypertension; AF, atrial fibrillation; SMD, standardized mean difference; ITPW, inverse probability treatment weighting.

Perioperative outcomes and predictors for AV surgery

The perioperative data were described in Table S1. The study demonstrated that four patients (0.9%) died among the patients included, with no significant difference in in-hospital mortality between the two groups (0 vs. 1.4%, P=0.50). All patients who experienced premature deaths in the hospital were in the AVP or AVR group. In the AVP or AVR group, one patient died because of multiple organ dysfunction syndromes, one patient had severe coagulation dysfunction and then died owing to intracranial hemorrhage, and the other patient was diagnosed with thrombotic intestinal obstruction and died because of septic shock. No significant differences were observed in adverse postoperative events, including reoperation in hospital (P=0.99) and new-onset stroke (P=0.98). The postoperative degree of AR for the NT group was more severe than that of the AVP or AVR group (P<0.001). Multivariable logistic regression analysis identified that AS, AV calcification, and concomitant MV replacement were associated with increased feasibility of AV surgery as shown in Table S2. Multivariable logistic regression analysis identified AS and concomitant MV replacement as being associated with reduced feasibility of AVP for patients who underwent concomitant AV surgery.

Follow-up clinical outcomes

The overall follow-up rate was 89.5%, whereas 10.5% of patients were untraceable because of the loss of contact. There were two patients (1.8%) in the NT group and eight (4.0%) in the AVP or AVR group with premature deaths from any cause during follow-up. However, there was no significant difference (P=0.49). Two patients (1.8%) in the NT group underwent reoperation for the MV during follow-up. In the AVP or AVR group, there were five patients (2.3%) who underwent reoperation for the MV and one (0.5%) who underwent reoperation because of the perivalvular leakage of the AV. The follow-up duration of the NT group was significantly longer than that of the AVP or AVR group (P=0.03). No significant difference in terms of MV dysfunction and tricuspid valve dysfunction was noted during follow-up, while the grade of AR of the NT group was more severe than that of the AVP or AVR group (P<0.001), as shown in Table S3. Four patients (3.3%) in the NT group had severe AVD, while only one patient (0.5%) in the AVP or AVR group had severe AVD resulting from a perivalvular leak (P=0.054). However, even in the NT group, only 29 patients (27.9%) had more-than-mild AVD during follow-up, while most of patients (110/121, 90.9%) in the NT group were combined with predominant AR lesion. Considering that the mean AV vena contracta width (VCW) of them was 4 mm, among patients with VCW less than 4mm, 75.0% had their grade of AR reduced to none or mild degree during follow-up, whereas the proportion was 65.7% among those with VCW of 4mm or greater. The condition of AVD during follow-up was improved compared to those before the operation in all groups, as shown in Figure 3.

Figure 3 Severity of aortic stenosis (A) and aortic regurgitation (B) before operation, after operation and during follow-up for different surgical groups. NT, no treatment; Repair, aortic valvuloplasty.

There were 29 patients (27.9%) in the NT group and 15 (8.0%) in the AVP or AVR group with more-than-mild aortic dysfunction during follow-up. Patients in the NT group had a higher risk of follow-up more-than-mild aortic dysfunction than that of the AVP or AVR group [RR, 3.48; 95% confidence interval (CI): 1.89–6.65; P<0.001], while there was no significant difference in the secondary endpoint events between the two groups (HR, 0.63; 95% CI: 0.25–1.61; P=0.33). Multiple Poisson regression analyses found patients in the NT group as an independent risk factor for the incidence of primary endpoint event after IPTW (RR, 2.98; 95% CI: 1.61–5.62; P<0.001), while Cox proportional hazards regression analyses found no significant difference in the secondary endpoint events after surgery between the two groups (HR, 0.34; 95% CI: 0.11–1.00; P=0.051), with adjustment for AS, AV calcification, and MV repair, as shown in Table 2. The log-rank test showed similar results. No significant difference was noted in the event-free survival after surgery between the two groups before and after IPTW (log-rank P=0.33, log-rank P=0.06, respectively), as shown in Figure S1.

In the subgroup analyses based on age, sex, hypertension, AF, NYHA grade, PAH, MV dysfunction, and AVD and MV surgery, the trend of increased risk of AVD in the NT group during follow-up was consistent and no interaction was detected, as illustrated in Figure 4.

Figure 4 Follow-up more-than-mild aortic valve dysfunction in subgroup analysis. NT, no treatment; AVP, aortic valvuloplasty; AVR, aortic valve replacement; NYHA, New York heart association classification of cardiac function; PAH, pulmonary artery hypertension; AS, aortic stenosis; RR, relative risks; CI, confidence interval.

After excluding patients who underwent AVP (n=56), patients in the NT group had a higher risk of follow-up more-than-mild aortic dysfunction than that of the AVR group (RR, 12.73; 95% CI: 4.53–53.18; P<0.001) in the sensitivity analysis, while no significant difference in the secondary endpoint events was observed between the two groups.

Discussion

The following were the primary findings of this retrospective study of patients with moderate AVD during rheumatic MV surgery: (I) concomitant AV surgery, especially AVR, significantly improved AV condition during follow-up; (II) no significant difference was noted in terms of secondary endpoint events and severe AVD after surgery in both the groups; and (III) most patients in the NT group demonstrated none or mild AVD during follow-up, most of whom were combined with predominant moderate AR.

The 2020 American Heart Association guidelines suggest that AVR may be considered when patients are undergoing other cardiac surgeris for patients with moderate or severe AS or AR. However, there is a relatively low (2b) class of recommendation without the support of high-level evidence (5). The 2021 European Society of Cardiology guidelines suggest that the choice of surgical technique should take age, perioperative risk, and the interaction between different valve lesions into account for multi-valve diseases (6). The lack of evidence of treatment for multi-valve diseases, which is more common in RHD and congestive heart disease, is indicated by the inconsistency of guidelines (6). In this study, 343 consecutive patients who underwent rheumatic MV surgery combined with moderate AVD were selected, and the difference in baseline data was reduced using IPTW and multivariable regression adjustment. The condition of AVD in the AVP or AVR group was found to be significantly ameliorated during follow-up.

This study found that AS, AV calcification, and concomitant MV replacement were associated with increased feasibility of AV surgery and that patients with moderate AS or MV replacement were prone to undergoing AVR rather than AVP. This result was consistent with the previous literature. Choudhary et al. demonstrated that for patients with mild AVD after MV surgery, subsequent AVR was more frequent in patients with AS rather than AR (12). Kim et al. (7) also reported that AS is the main contributor to late AVD over AR (7). Weingarten et al. reported that AVR for moderate AS when performing mitral surgery could reduce aortic disease progression; however, its sample size was small (13). The association between concomitant AV surgery and MV replacement seemed logical. Patients with moderate AVD requiring warfarin for mechanical AV prosthesis are prone to undergoing MV replacement (14).

However, no significant difference was noted in both groups in terms of secondary endpoint events and severe AVD after surgery. Patients in the NT group had a lower risk of experiencing secondary endpoint events; however, no significant difference was observed. This is probably because patients in the NT group had better cardiac conditions, lower grades of AS, and tended to undergo MV repair procedures. In addition, there was no significant difference in severe AV. This might be because of the relatively brief follow-up period, considering that the progression of severe AVD is uncommon and slow (12). This result is consistent with the previous studies. Ho et al. reported that in patients undergoing rheumatic MV surgery, those with untreated moderate AVD were more prone to developing severe AVD than those with only mild AVD. However, patients in both groups scarcely required subsequent AVR (15). Kim et al. enrolled 275 patients with mild-to-moderate AVD undergoing MV surgery in a retrospective study. The 5- and 10-year cumulative incidence of the composite of severe AVD and requirement for AVR, within the preoperative mild-to-moderate AVD group was 2.9% and 7.4%, respectively. However, this study only enrolled 19 patients with moderate AVD. Hence, there could be a significant difference in progression to severe AVD between the two groups with an extended follow-up duration.

Our study suggested that although AV surgery was not performed, most patients in the NT group still demonstrated none or mild AVD during follow-up. The condition of AVD, mainly AR, could be ameliorated to various extents regardless of the VCW size, with the treatment of rheumatic MV disease. The possible reason for this phenomenon may be summarized as follows: on the one hand, preoperative left ventricular enlargement leads to relative AR, but after MV surgery and/or radiofrequency ablation, the condition of AVD is improved because of left ventricular remodeling and hemodynamic improvement. On the other hand, the use of diuretics after surgery also contributed to reducing cardiac preload and thus ameliorating the degree of AR. Therefore, delaying surgical treatment of the AV and regular follow-ups were safe and reasonable for patients with predominant moderate AR. However, it is suggested that patients with moderate AS, AV calcification, and concomitant MV replacement undergo AV procedure, if applicable.

This study had certain limitations. First, it was a single-center retrospective study that introduced bias in the selection of patients. Therefore, to ensure comparability between the two groups, IPTW and multiple regression analysis. Second, this study has only assembled patients’ latest TTE findings; however, the regular annual follow-up TTE results were lacking, making it challenging to comprehensively understand the progress of AVD. Third, the difference between the NT and AVP groups was not assessed in the sensitivity analysis because of the limited sample size. Finally, although patients enrolled in this study were diagnosed with moderate AVD, there was still heterogeneity in the severity of AVD among them. This is an ongoing study, and more data will be collected regarding patient cumulation and prolonged follow-up duration.

Conclusions

For patients with moderate AVD during rheumatic valve surgery, concomitant AV surgery significantly improved AV condition during follow-up. However, for patients with predominant moderate AR, it was safe and reasonable to delay surgical treatment of AV and to undergo regular follow-ups.

Acknowledgments

Funding: This study was supported by Science and Technology Major Project of Beijing An Zhen Hospital (No. KCZD202203) and Noncommunicable Chronic Disease-National Science and Technology Major Project (No. 2023ZD0514000).

Footnote

Reporting Checklist: The authors have completed the STROCSS reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1283/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1283/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1283/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1283/coif). M.W. received the support from Noncommunicable Chronic Disease-National Science and Technology Major Project (No. 2023ZD0514000), and the payments were made to Beijing An Zhen Hospital. W.J. received the support from Science and Technology Major Project of Beijing An Zhen Hospital (KCZD202203), and the payments were made to Beijing An Zhen Hospital. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Beijing An Zhen Hospital (No. KS2023059, approved on Sep 21, 2023) and informed consent was waived because of the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Remenyi B, ElGuindy A, Smith SC Jr, et al. Valvular aspects of rheumatic heart disease. Lancet 2016;387:1335-46. [Crossref] [PubMed]
2. Watkins DA, Johnson CO, Colquhoun SM, et al. Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015. N Engl J Med 2017;377:713-22. [Crossref] [PubMed]
3. Yang Y, Wang Z, Chen Z, et al. Current status and etiology of valvular heart disease in China: a population-based survey. BMC Cardiovasc Disord 2021;21:339. [Crossref] [PubMed]
4. Hwang HY, Kim KH, Ahn H. Attitude after a mild aortic valve lesion during rheumatic mitral valve surgery. J Thorac Cardiovasc Surg 2014;147:1540-6. [Crossref] [PubMed]
5. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;143:e72-e227. [Crossref] [PubMed]
6. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2022;43:561-632. [Crossref] [PubMed]
7. Kim HR, Kim WK, Kim HJ, et al. The fate of aortic valve after rheumatic mitral valve surgery. J Thorac Cardiovasc Surg 2023;165:622-629.e2. [Crossref] [PubMed]
8. Mathew G, Agha R, Albrecht J, et al. STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery. Int J Surg 2021;96:106165. [Crossref] [PubMed]
9. Pandian NG, Kim JK, Arias-Godinez JA, et al. Recommendations for the Use of Echocardiography in the Evaluation of Rheumatic Heart Disease: A Report from the American Society of Echocardiography. J Am Soc Echocardiogr 2023;36:3-28. [Crossref] [PubMed]
10. Fu J, Li Y, Zhang H, et al. Outcomes of mitral valve repair compared with replacement for patients with rheumatic heart disease. J Thorac Cardiovasc Surg 2021;162:72-82.e7. [Crossref] [PubMed]
11. Afifi A, Hosny H, Yacoub M. Rheumatic aortic valve disease-when and who to repair? Ann Cardiothorac Surg 2019;8:383-9. [Crossref] [PubMed]
12. Choudhary SK, Talwar S, Juneja R, et al. Fate of mild aortic valve disease after mitral valve intervention. J Thorac Cardiovasc Surg 2001;122:583-6. [Crossref] [PubMed]
13. Weingarten N, Rekhtman D, Iyengar A, et al. Aortic valve replacement for moderate aortic stenosis during mitral surgery improves survival free from severe stenosis. Asian Cardiovasc Thorac Ann 2023;31:475-82. [Crossref] [PubMed]
14. Spiliotopoulos K, Armstrong S, Maganti M, et al. Does the mitral valve prosthesis adversely affect the hemodynamic performance of the aortic valve prosthesis in patients with double valve replacement? J Thorac Cardiovasc Surg 2012;143:S74-7. [Crossref] [PubMed]
15. Ho THQ, Pham TTT. Aortic regurgitation progression after mitral valve replacement for rheumatic heart disease. Asian Cardiovasc Thorac Ann 2023;31:188-93. [Crossref] [PubMed]