Impact of tricuspid regurgitation and right ventricular dysfunction on outcomes after transcatheter aortic valve replacement: A systematic review and meta‐analysis

Far less attention has been paid to the prognostic effect of right‐side heart disease on outcomes after transcatheter aortic valve replacement (TAVR) when compared with the left side. Therefore, we performed a systematic review and meta‐analysis on the impact of tricuspid regurgitation (TR) and right ventricular (RV) dysfunction on outcomes after TAVR. We hypothesized that TR and RV dysfunction may have a deleterious effect on outcomes after TAVR. Article revealing the prognostic effect of TR and RV dysfunction on outcomes after TAVR were being integrated. Random or fixed effect model was adopted in accordance with the heterogeneity. There were nine studies with a total of 6466 patients enrolled after a comprehensive literature search of the MEDLINE/PubMed, EMBASE, ISI Web of Science, and Cochrane databases. The overall analysis revealed that moderate or severe TR at baseline increased all‐cause mortality after TAVR (HR = 1.79, CI 95% 1.52‐2.11, P < 0.001). Both baseline RV dysfunction (HR = 1.53, CI 95% 1.27‐1.83, P < 0.001) and presence of RV dilation (HR = 1.83, CI 95% 1.47‐2.27, P < 0.001) were associated with all‐cause mortality. Both baseline moderate or severe TR and RV dysfunction worsen prognosis after TAVR and careful assessment of right heart function should be done for clinical decision by the heart team before the TAVR procedure.

Far less attention has been paid to the prognostic effect of right-side heart disease on outcomes after transcatheter aortic valve replacement (TAVR) when compared with the left side. Therefore, we performed a systematic review and meta-analysis on the impact of tricuspid regurgitation (TR) and right ventricular (RV) dysfunction on outcomes after TAVR. We hypothesized that TR and RV dysfunction may have a deleterious effect on outcomes after TAVR. Article revealing the prognostic effect of TR and RV dysfunction on outcomes after TAVR were being integrated.
Random or fixed effect model was adopted in accordance with the heterogeneity. There were nine studies with a total of 6466 patients enrolled after a comprehensive literature search of the MEDLINE/PubMed, EMBASE, ISI Web of Science, and Cochrane databases. The overall analysis revealed that moderate or severe TR at baseline increased all-cause mortality after TAVR (HR = 1.79, CI 95% 1.52-2.11, P < 0.001). Both baseline RV dysfunction (HR = 1.53, CI 95% 1.27-1.83, P < 0.001) and presence of RV dilation (HR = 1.83, CI 95% 1.47-2.27, P < 0.001) were associated with all-cause mortality. Both baseline moderate or severe TR and RV dysfunction worsen prognosis after TAVR and careful assessment of right heart function should be done for clinical decision by the heart team before the TAVR procedure.

K E Y W O R D S
all-cause mortality, prognosis, right ventricular function, transcatheter aortic valve replacement, tricuspid regurgitation

| INTRODUCTION
Transcatheter aortic valve replacement (TAVR) is a novel alternative to inoperable, high risk even moderate risk symptomatic severe aortic stenosis (AS) patients. However, short-and long-term morbidity and mortality after TAVR are still an issue of concern. 1,2 Several predictors of outcome after TAVR are well established, 3,4 such as moderate or severe aortic regurgitation, new-onset left bundle branch block, pulmonary artery hypertension, reduced left ventricular ejection fraction (LVEF).
Recently, more and more studies are paying attention to the prognosis of tricuspid regurgitation (TR) and right ventricular (RV) dysfunction on outcome after aortic valve replacement. [5][6][7][8][9][10][11][12][13][14][15] In surgical valve aortic replacement, RV function is an independent predictor of all-cause mortality after the procedure, and whether TR can be regarded as an independent predictor is still controversial. [16][17][18] However, in TAVR, the prognosis of RV function and TR on outcomes is contradictory. A study in the subgroup of PARTNER shows that moderate or severe TR and RV sizes are associated with increased allcause mortality, but RV dysfunction is not. 6 While in a recent-single center prospective registry study, only RV function, but not TR remained associated with outcome after TAVR. 8 Therefore, we performed a systematic review and meta-analysis of the literature to assess the impact of baseline TR and RV dysfunction on outcome after TAVR.

| Data extraction, endpoints, and definition
Two reviewers independently screened the articles for eligibility according to the inclusion and exclusion criteria. The reviewers compared the selected studies and any discrepancy was resolved by consensus with a third reviewer.
TR severity was graded in these works of literature as none/trace (grade 0), mild (grade 1), moderate (grade 2), or severe (grade 3) integrating structural, Doppler, and quantitative parameters according to the American Society of Echocardiography, including assessment of vena contracta width, proximal isovelocity surface area radius, tricuspid valve morphology, right atrial (RA) and RV size, inferior vena cava size, jet area, jet density and contour, and hepatic vein flow. 21 Moderate and severe TR were categorized as "significant TR" while none, trace and mild as "nonsignificant TR." According to ASE guideline, 22  Information extracted included author(s), publication year, study region(s) and design, included patients number, type of device and approach, duration of follow-up, baseline characteristics of patients, and outcomes of interest. We extracted hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) from the included studies. 23 The primary endpoint was all-cause mortality.

| Data analysis and synthesis
Meta-analysis was performed in RevMan Software Version 5.3 and Stata Software Version 14.0. Heterogeneity was assessed by I 2 index, with 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. When the heterogeneity of meta-analysis was ≥50%, we adopted the random effects model, and when the heterogeneity was <50%, we used the fixed effect model. Given the number of the included studies was less than 10, publication bias was not assessed. 24 A P < 0.05 (two-tailed) was considered significant. We also performed the metaanalysis to figure out the impact of TAPSE, FAC, RIMP, and S 0 on all-cause mortality after TAVR. Sensitivity analysis was performed by removing one study at a time to test the robustness of the results. The quality of the enrolled studies was evaluated by two independent reviewers according to the Newcastle-Ottawa Scale ranging from 0 to 8.  Table 1.
The TR severity is divided into two comparable groups, none/ trace/mild TR, and moderate/severe TR. The RV function is categorized by normal or abnormal. All descriptions of RV dysfunction and RV size in included studies were shown in Supporting information Table S1.

| Sensitivity analysis
When the sensitivity analysis was performed by removing one study at a time, the overall effect of TR and RV dysfunction on all-cause  mortality were not changed. When it comes to RV size on all-cause mortality, the situation was different. After removing the study of Saki Ito, the I 2 of the meta-analysis decreased to 0, the P value of the heterogeneity to 0.85, while the overall effect of RV size and its significance remained unchanged (HR = 1.64, CI 95% 1.29-2.09, P < 0.0001) ( Figure S1).

| DISCUSSION
This is actually the first meta-analysis to evaluate the impact of right heart function on outcomes after TAVR. We included nine studies enrolling 6466 patients and found that (a) preoperative TR is assigned to increased all-cause mortality after TAVR, (b) preoperative RV dysfunction is related to all-cause mortality which is often related to the influence of TAPSE and RV myocardial performance, (c) pre-TAVR RV size could possibly be linked to increased all-cause mortality.
Although the significant TR late in left heart valve procedure is apparent, 16  Few studies provided data on the impact of the baseline RV dysfunction on outcome after SAVR or TAVR. Baseline RV dysfunction worsens the short-term outcomes after surgical aortic valve replacement (SAVR). 5,25,26 However, the prognostic impact of baseline RV dysfunction on outcomes after TAVR is not well established yet. In our pooled analysis, we found that the coexistence of baseline RV in patients with AS is associated with increased all-cause mortality after TAVR. We advise heart team that RV function assessment should be more considered for TAVR and as a predictor of survival after TAVR based on our results in this meta-analysis.
This negative effect could be attributed to the following pathophysiological mechanisms. TR is considered to be caused by dilation of the tricuspid annulus and tethering of the tricuspid leaflets in an enlarged right ventricle. 10,27,28 The right ventricle enlargement and RV dysfunction in severe AS patients is assigned to the chronicity and severity of pressure overload as a consequence of left-side valve disease, AS, MR and pulmonary artery hypertension, and volume overload from fluid retention or the preexisting TR. TAVR can reduce LV hypertrophy but the degree of diffuse interstitial myocardial fibrosis is not changed. Diffuse interstitial myocardial fibrosis results in diastolic dysfunction and LV end-diastolic over-pressure, a possible cause of  What is more, the improved stroke volume after TAVR increases systemic venous return, which could accelerate the dilation and failure of the right heart when combined with pulmonary hypertension. 11,32,33 According to the ASE guideline, 22  ing in increased all-cause mortality. 16,35,36 Some studies 8,9 demonstrate that RV size is also evaluated as one of the independent predictors of outcomes after TAVR. First, RV dilation reflects chronic and severe pressure and volume overload, 6 thus can be considered to be an advanced performance of RV dysfunction.
Significant RV dilation could even be regarded as an advanced stage of right heart failure. Second, since the right ventricle shares the same septum with the left ventricle, RV dilation possibly causes left FIGURE 2 All-cause mortality outcomes after TAVR. Forest plot showing the individual and pooled analysis for hazard ratio of (A) tricuspid regurgitation (B) right ventricular dysfunction (C) right ventricular dilation on all-cause mortality ventricular volume change. 9 Third, patients with RV dilation are more likely to have AF, low LVEF, and chronic lung disease. This is in accordance with our meta-analysis, RV dilation is an independent predictor of outcomes after TAVR. 9

| Study limitation
Our study has several limitations: (a) this was a meta-analysis of nine studies, and there may be some bias; (b) our meta-analysis only assessed the impact of preoperative TR and RV dysfunction on outcomes after TAVR, without taking consideration of evolution of TR and RV function post-TAVR; (c) there was a moderate-to-high heterogeneity in the study for RV size, meta-regression could be performed if there were more relevant studies. 37 Taking into consideration the small group of studies and moderate-to-high heterogeneity, the result should be explained cautiously however, the following sensitivity analysis showed exactly the same result. Despite these limitations, our analysis provided valuable insights into the effect of right heart function on outcomes after TAVR.

| CONCLUSION
Both baseline moderate or severe TR and RV dysfunction worsen prognosis after TAVR. RV dilation is additionally related to increased all-cause mortality after TAVR. Careful assessment of right heart function should be done for clinical decision by the heart team before the TAVR procedure. More scientific studies and attention on right heart function is warranted in TAVR era.

CONFLICTS OF INTEREST
The authors declare no potential conflict of interests.