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Introduction
Valvular heart disease is considered a major public health problem, with mitral regurpitation (MR) beinp the most common. Surgical mitral valve repair or replacement is indicated in severe MR causing symptoms or cardiomyopathy2. However, about half of the patients with severe MR are deemed poor surgical candidates due to operative risks secondary to advanced ape and multiple comorbidities. Therefore, for carefully selected patients with hiph operative risk, transcatheter edpe-to-edpe mitral valve repair (TEER) with MitraClip (MC) is an appealing and less invasive therapeutic modality that has become part of practice guidelines3. While percutaneous repair of mitral valve has shown to be safe in EVEREST II trial4, patient treated with TEER with MC had persistent reduction in both deaths and heart failure hospitalization at 5 years^.

The decision to undergo mitral valve repair surgically or percutaneously, depends on the individual patient factors, such as valve morphology, degree of the mitral stenosis and co-morbid conditions rather than the gender. While gender disparity in outcomes of patients undergoing mitral valve surgery is well documented, there is a paucity of outcome data on gender-related differences in patients undergoing TEER. It has also been reported that more men undergo mitral valve surgery and women tend to have less favorable post-operative clinical outcomes in terms of recurrent heart failures. On the other hand, the studies that address TEER outcomes based on gender are very few and the data is very conflicting. Therefore, we performed a meta-analysis and sought to provide comprehensive evaluation of the impact of gender on the clinical outcomes or TEER in patients with severe MR.

Methods
Data sources and search strategy
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)7 guidelines were followed to conduct and report this meta-analysis (Figure 1). We searched electronic databases of PubMed, EMBASE and Cochrane Central Register of Clinical Trials with no language restriction from inception through February 2023 using the search terms: MitraClip OR Edge to Edge MitraClip AND Gender specific outcomes. Two investigators (UM and PG) independently performed the database search and agreed on final study selection. In addition, a manual search was performed for relevant references from the selected articles and published reviews.

Study selection
Randomized trials and observational studies (retrospective and prospective) reporting tender-based outcomes of all‐cause mortality, mitral regurpitation severity, NYHA class for heart failure and readmission for heart failure in patients with TEER were included. Studies were excluded if they lacked a control group, reported hazard or odds ratio, had inadequate data on baseline characteristics and were in non‐English language with no English translation.

Data extraction
From selected studies, data were independently extracted by two investigators (UM and PG) and cross verified by a third investigator (JD). We obtained data on study characteristics (study desipn, patient selection, inclusion and exclusion criteria, follow-up duration, number of patients, endpoints), patient characteristics (ape, sex, race, co- morbidities, medications and indication for mitral valve repair), and outcomes of mortality, NYHA  class, MR severity and readmission for heart failure. For MR severity, data with MR prades of 3 and above at maximum reported follow up was extracted for analysis. Data for NYHA class reporting only III and IV was extracted and included in meta-analysis.

Outcomes
All-cause and cardiovascular mortality, residual mitral regurgitation, NYHA class and readmission for heart failure after TEER were the major
outcomes investigated in this meta-analysis.

Statistical analysis
We performed statistical analyses with Review Manager (RevMan 5.4). Odds ratio (OR) with 95% confidence interval (CI) was calculated usinp number of events and total number of patients. Pooled ORs ratios and 95% Cls were calculated usinp the more conservative DerSimonian and Laird random-effects model . All tests were 2-sided and a p-value less than 0.05 was deemed significant. Heterogeneity was assessed by the 1 2 statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than chance. I‘> 5@%was considered significant heterogeneity.

Results:
Search Results:
Literature search produced 242 articles. After removing the duplicate articles and excluding the irrelevant articles, 17 studies’-25 with 33,747 patients (19,303 males and 14,444 females) were included in the meta-analysis.Sixteen studies were available as full text and 1 study was available as abstract only. Average follow up duration was 16 months (ranging 6.1-60 months).

All-cause mortality:
Fourteen studies 7 9t 2/ 23 with 33,076 patients (18,894 included males and 14,182 females) were in the analysis.

Residual Mitral Regurgitation:
Seven studies9,10,13.15,182024 with 1,544 patients (952 males, 592 females) were included in the meta-analysis (Figure 3). There was no difference in residual mitral regurgitation at follow up (OR: 0.59, 95% CI: (0.34-1.02), p=0.06). A sensitivity analysis excluding the abstract did not alter the results (OR: 0.68, 95% CI: (0.35-1.32), p=0.26). 

NYHA Class:
Seven studies103)51820.2224with 2,350 patients (1,469 males, 881 females) were included in this meta-analysis (Figure 4). NYHA class was significantly higher in female patients as compared to male patients at the end of follow up (OR: 0.62, 95% CI: (0.51-0.74), p<0.00001). A sensitivity analysis excluding the abstract did not alter the results (OR: 0.62, 95% CI: (0.52-0.76), p<0.00001). 

Readmission Rate:
Seven studies9,10.13,18,19,22,25 with 1,894 patients (1207 males, 687 females) reported readmission rate for heart failure and were included in the analysis figure 5). There was no difference in readmission rate between the groups (OR: 1.04, 95% CI: (0.69-1.57), p=0.83). A sensitivity analysis excluding the abstract did not alter the results (OR: 0.89, 95% CI: (0.62-1.29), p=0.55). 

Discussion
Female gender is known to be a predictor of adverse outcomes after surgical mitral valve replacement largely due to advanced age at presentation, worse baseline characteristics and higher incidence of mitral valve replacement as opposed to repair26. There can be other explanations for poor surgical outcome in female patients including smaller body surface area, which correlates with a smaller mitral valve annular area that may account for this difference. Moreover, female patients are more prone to have unfavorable valvular anatomy including calcification and degenerative changes at the valvular level? making the repair challenging. A study by Vassileva et al.26 demonstrated higher long-term mortality in female patients after surgical repair of the mitral valve (4.2% versus 3.5%). This difference was thought to be mainly  because of worse baseline risk profile of women compared with men, as the mortality rate was similar between the groups after risk adjustment. While there is paucity of data on gender-based outcomes after TEER, the pooled data allowed us to explore various aspects related to the gender differences and their potential influence on the effectiveness of the TEER with MC. In our meta-analysis which is the largest to date, we found no difference in all-cause mortality, residual MR and readmission for heart failure based on gender after TEER.

However, differences were seen in heart failure symptoms post-procedure, with NYHA class III/1V significantly higher in female patients. 
A prospective study by Tigges et a12°, showed better survival in females at 2 years follow up after TEER, however, the study included a male dominant cohort with higher comorbidities. As pointed in their study, the male gender was not found to be the predictor of mortality in multivariate analysis, supporting the fact that mortality was not directly related to the procedure itself. This is in contrast to study performed by Attizzani et al 0, that also included male subjects with worse baseline clinical characteristics and yet found no significant gender-based differences in all-cause mortality after TEER. Additionally, their results did not change after adjusting their Kaplan-Meier estimates for baseline characteristics, further consolidating the notion of no gender-based mortality difference after TEER. These findings are in accordance with our meta-analysis that also suggests similar all-cause mortality in females and males after mitral valve repair with TEER and stresses the appropriateness of TEER as a treatment option regardless of gender.

Several studies have reported substantial clinical improvement after TEER, as well as considerable MR reduction immediately post procedure and at long term follow up. Both genders appear to benefit equally based on these studies 0  3. However, in our meta- analysis, female patients had significantly higher NYHA functional class III/IV at follow up. Moreover, male gender showed a statistically non-significant trend towards improvement in residual MR (p=0.09), which might possibly explain why female patients had poor NYHA class at follow up. On the other hand, readmission for heart failure symptoms, which is an important gauge of procedural success of TEER, was not significantly different between males and females, which is in line with the findings of several studies included in our metanalysis.

It is important to note, however, that there are caveats in the interpretation of the significant difference in NYHA class between males and females in our meta-analysis. NYHA classification is subjective, and to some extent, is dependent on patient’s expectation post-procedure. Furthermore, there is insufficient data to indicate whether increased HF symptoms at follow up are due to residual MR or increased gradients post MC, especially that the difference in the degree of MR reduction between the two groups was not statistically significant. Nonetheless, appropriately powered studies comparing the gender differences among patients treated with TEER will help clarify the findings of our meta-analysis.

Limitations:
While our meta-analysis provides valuable insights into the gender differences associated with the transcatheter edge to edge repair with MitraClip, there are certain limitations that need to be acknowledged. One limitation of our meta-analysis is that it was predominantly based on observational studies. Therefore, there might have been confounding factors that were not accounted for in our study. Another limitation is that many of the included studies did not report all outcomes evaluated in our meta-analysis. Hence, more studies evaluating all potential outcomes are still needed. A third limitation is that NYHA classification is subjective and can be poorly reproducible. Therefore, the finding of worse NYHA class after TEER in female patients should be taken with caution. Finally, Chamber dimensions before and after the procedure were not reported uniformly and the available data were insufficient to perform a meta-analysis.

Conclusion:
Our meta-analysis shows no gender-based difference in all-cause mortality, MR grade and HF readmission rate after transcatheter edge to edge mitral valve repair. However, improvement in NYHA functional class was less significant in female patients at follow up. Randomized trials are needed to elucidate our findings.

Corresponding Author:
Usman Mustafa
Louisiana State University Health Sciences Center, Shreveport Louisiana, USA
Email: [email protected]

Conflicts of interest:
The authors report no conflicts of interest regarding the content herein.

Funding Statement:
The authors report no financial relationships regarding the content herein.

Acknowledgement: None

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