Prediction of long-term survival in patients with concomitant pulmonary hypertension and its subtypes after successful transcatheter edge-to-edge mitral valve repair

Introduction

Mitral valve regurgitation (MR) represents the most common valvular heart disease in patients aged over 75 years in Western industrialized nations (1). Transcatheter edge-to-edge mitral valve repair (M-TEER) has become an efficacious treatment modality for patients who have an increased perioperative risk and present with refractory congestive heart failure symptoms (2). Owing to the increasing age and morbidity of patients, careful selection of appropriate patients remains a crucial matter of debate to improve treatment outcomes and diminish the socioeconomic burden on public health.

Pulmonary hypertension (PH) remains a closely linked pathophysiological comorbidity among patients with high-grade MR (3) and is known to significantly worsen morbidity and mortality (4-7). Among the etiological subtypes of PH, precapillary PH and isolated postcapillary PH (Ipc-PH) are caused by increased resistance in front of or behind the pulmonary capillary vascular pathway due to, e.g., vascular, pulmonary, or cardiac disorders. In contrast, combined post- and precapillary PH (Cpc-PH) arises from a combined increased resistance in both pulmonary capillary vascular pathways (8). However, owing to the inconsistent definition of PH between various clinical trials and the further modified definition of PH within the international guidelines throughout the ongoing period of clinical care (8), the results regarding the influence of concomitant PH on treatment outcomes in patients receiving M-TEER remain contradictory. There is also a paucity of data regarding the impact of the respective PH subtypes on long-term mortality after successful M-TEER (9), as hemodynamic and clinical characteristics may differ substantially between these distinct subcohorts.

Therefore, the aim of this study was to investigate the prevalence of concomitant PH and its respective subtypes according to the latest guideline definition (8) and its impact on long-term survival in a group of patients receiving current “real-world” M-TEER care. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-654/rc).

Methods

In this monocentric retrospective cohort study, all patients who underwent M-TEER between May 2014 and May 2023 at the Department of Cardiology, University Hospital Marburg were enrolled for further analysis. If the intervention had to be terminated before clip application, the patient was excluded from the analysis. Patients without detailed echocardiographic and right heart catheterization (RHC) data were also excluded from further analysis. The documented treatment course was used for the analysis of the follow-up period. In the case of loss to follow-up—defined as a lack of follow-up after discharge from the index hospitalization—the patient was also excluded from the analysis.

Prior to the performance of the M-TEER procedure, all patients were considered unsuitable candidates for surgical mitral valve repair by the interdisciplinary cardiac conference consisting of interventional cardiologists and cardiac surgeons. The feasibility and anatomical suitability of M-TEER intervention were likewise confirmed by transesophageal echocardiography (TOE). For the M-TEER procedure, either the MitraClip^© (Abbott Vascular, Chicago, IL, USA) or the PASCAL™ (Edwards Lifesciences, Irvine, CA, USA) system was applied during analgosedation or general anesthesia. The devices and the implantation technique have already been described in detail (10-12). Major adverse cardiac and cerebrovascular events (MACCEs) were reported according to the definitions of the Mitral Valve Academic Research Consortium (MVARC) classification (13).

Patients were allocated to the respective cohorts on the basis of the presence of PH at the time of index hospitalization, which was determined by RHC without general anesthesia. In accordance with current guidelines (8), the diagnosis of PH was defined by a mean pulmonary artery pressure of >20 mmHg measured invasively via RHC. Precapillary PH was present in the case of increased pulmonary vascular resistance (PVR) of >2 Wood units (WU) at a normal pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg. Ipc-PH was present at elevated PCWP >15 mmHg with a normal PVR (≤2 WU). If both the PCWP and PVR were above their respective normal values, the patient was categorized as presenting Cpc-PH. During index hospitalization, cardiac output was also calculated using the thermodilution or Fick method in line with current recommendations (14,15). In addition to the invasive measurements acquired from RHC, Doppler echocardiographic determination of pulmonary arterial systolic pressure (D-PASP) across the tricuspid valve was also performed before and after the M-TEER procedure.

The primary endpoint of the study was long-term mortality, which was analyzed between patients with and without PH and within the denoted PH subtypes. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was authorized by the local Ethics Committee of the Department of Medicine of Philipps University of Marburg (protocol code: RS 23-163). Informed consent was waived because of the retrospective design of the study.

Statistical analysis

Categorical variables are presented as absolute and relative frequencies (%). Continuous variables are presented as the means and standard deviations (SDs) for normally distributed variables and as medians and interquartile ranges (IQRs) for nonnormally distributed variables. For categorial variables, differences between the compared groups were tested for significance via Fisher’s exact test when the expected cell size was <20 and the chi-squared test when the expected cell size was ≥20. For continuous variables, Student’s t-tests were performed for normally distributed variables, and the Wilcoxon test was used for nonnormally distributed variables. The existence of a normal distribution was confirmed via the Shapiro-Wilk test. The strength of the correlation between D-PASP and RHC-PASP before M-TEER was tested via linear regression analysis and Pearson’s correlation coefficients. The comparison of the peri-interventional changes in the D-PASP measurements was tested for significance by paired t-test. Long-term mortality following M-TEER was analyzed by Kaplan-Meier method, whereby differences between groups were compared by log-rank test. Independent predictors of mortality were identified using univariable Cox regression analysis (16). Based on an event-to-variable ratio of 10:1, the seven strongest predictors of mortality according to univariable Cox regression analysis were incorporated into the multivariate model to avoid overfitting of the model. A two-sided P value of ≤0.05 was considered statistically significant. All the statistical analyses were performed utilizing R Studio V4.4.2 (R Foundation for Statistical Computing, Vienna, Austria) with the following packages: “survival”, “survminer”, “dplyr”, “Rcmdr”, “TableOne” and “My.stepwise”. The graphics were designed with BioRender.com (Science Suite Inc., Toronto, ON, Canada).

Results

A total of 183 patients underwent M-TEER during the observation period. Due to insufficient data records, 58 patients were excluded from further analysis. No patient was lost to follow-up. Among the remaining patients that were enrolled for further analysis, PH was diagnosed in 77.6% of the patients (97/125), but the presence of PH did not affect procedural success [odds ratio (OR) 2.2, 95% confidence interval (CI): 0.6–14.5, P=0.32]. A comparison of the clinical and procedural data between the included and excluded patients is presented in Table S1.

Clinical cohort characteristics and short-term outcomes

Patients with concomitant PH had a significantly lower incidence of functional MR etiology, while further clinical and procedural data were equally distributed between both cohorts. The analysis of MACCEs revealed the occurrence of minor bleeding events as the most common procedure-associated complication, with no significant differences between the cohorts. The clinical and procedural data of the patients with and without PH are presented in Table 1, and the MACCE rates of the entire study cohort are reported in Table 2.

Within the cohort of patients with concomitant PH, Cpc-PH was the most common phenotype, observed in 56.7% (55/97) of patients, followed by Ipc-PH, observed in 39.2% (38/97) of patients. The remaining four patients (4.1%, 4/97) presented with precapillary PH and were excluded from subsequent analyses due to the consequent low statistical power.

Patients with Cpc-PH had higher prevalences of coronary artery disease (CAD) and arterial hypertension than Ipc-PH patients did. Consequently, significantly higher values of the EuroSCORE II and STS risk scores were observed in Cpc-PH patients, both of which still represent established scores for mortality prediction after cardiac interventions (17).

In terms of echocardiographic and hemodynamic parameters, compared with patients with Ipc-PH, those with Cpc-PH presented significantly increased pulmonary artery pressures in both invasive and noninvasive measurements before M-TEER. While a significant correlation between D-PASP and RHC-PASP was observed in Cpc-PH patients (r=0.57, P<0.001), RHC-PASP was considerably underestimated in Ipc-PH patients when noninvasive measurements were used (r=0.18, P=0.90). In contrast, Ipc-PH patients presented a significant reduction in D-PASP during the follow-up period [−6±10 mmHg + central venous pressure (CVP), P=0.02], which was not observed in Cpc-PH patients (−3±14 mmHg + CVP, P=0.20).

The clinical, echocardiographic and hemodynamic cohort characteristics of the Ipc-PH- and Cpc-PH patients are presented in Table 3. The linear regression analysis of RHC-PASP and D-PASP as well as the comparison of pre- and postinterventional D-PASP values of the PH subcohorts, can be found in Figure 1 and Figure 2, respectively.

Figure 1 Linear regression analysis between RHC-PASP and D-PASP before M-TEER among Ipc-PH (A) and Cpc-PH patients (B). Cpc-PH, combined post- and precapillary pulmonary hypertension; CVP, central venous pressure; D-PASP, Doppler-echocardiography measured pulmonary artery systolic pressure; Ipc-PH, isolated postcapillary pulmonary hypertension; M-TEER, transcatheter edge-to-edge mitral valve repair; RHC-PASP, right heart catheterization measured pulmonary artery systolic pressure.

Figure 2 Variation of D-PASP in the course of M-TEER procedure in patients with concomitant Ipc-PH and Cpc-PH. Cpc-PH, combined post- and precapillary pulmonary hypertension; CVP, central venous pressure; D-PASP, Doppler-echocardiography measured pulmonary artery systolic pressure; Ipc-PH, isolated postcapillary pulmonary hypertension; M-TEER, transcatheter edge-to-edge mitral valve repair.

Analysis of long-term survival

The median follow-up time was 484 days (IQR: 131–959). There was a significantly lower survival rate among patients with concomitant PH at three years after M-TEER than among patients without PH [ 47.4% (46/97) vs. 75.0% (21/28), P=0.02]. Among the PH cohort, there was a trend towards improved survival in Ipc-PH patients compared with that in Cpc-PH patients; however, this trend did not reach significance three years after M-TEER [52.6% (20/38) vs. 40.0% (22/55), P=0.20]. However, patients with Cpc-PH had significantly poorer survival at three years after M-TEER compared with patients without PH [40.5% (22/55) vs. 73.6% (21/28), P=0.009], which could not be confirmed for Ipc-PH patients compared with patients without PH [53.4% (20/38) vs. 73.6% (21/28), P=0.10].

Concomitant PH was identified as an independent predictor of long-term mortality in the univariable Cox regression analysis [hazard ratio (HR) 2.8, 95% CI: 1.1–7.1, P=0.03]. However, in the multivariable analysis, PH failed to reach statistical significance (HR 2.5, 95% CI: 0.95–6.6, P=0.06). Male sex, peripheral arterial disease (PAD) and coexistent high-grade tricuspid regurgitation (TR) emerged as independent predictors of mortality in the multivariable Cox regression analysis (HR 2.0, 95% CI: 1.04–3.9, P=0.04; HR 2.1, 95% CI: 1.1–4.5, P=0.04; HR 3.0, 95% CI: 1.6–5.7, P<0.001, respectively).

The course of postinterventional survival of the overall cohort after M-TEER is shown in Figure 3, and the course of survival of the respective PH subtypes compared to patients without concomitant PH is presented in Figure 4. The results of the uni- and multivariable Cox regression analyses can be found in Table S2 and Table 4.

Figure 3 Long-term survival of patients with versus without concomitant PH after successful M-TEER. M-TEER, transcatheter edge-to-edge mitral valve repair; PH, pulmonary hypertension.

Figure 4 Long-term survival of patients with concomitant Ipc-PH and Cpc-PH versus patients without concomitant PH after successful M-TEER. Cpc-PH, combined post- and precapillary pulmonary hypertension; Ipc-PH, isolated postcapillary pulmonary hypertension; M-TEER, transcatheter edge-to-edge mitral valve repair; PH, pulmonary hypertension.

Discussion

Owing to ongoing demographic changes in Western industrialized nations, M-TEER intervention is becoming increasingly important, leading to continuously rising implantation rates among the elderly along with favourable safety profiles and treatment outcomes (18). However, concomitant PH is responsible for a significantly greater morbidity and mortality in patients suffering from congestive heart failure and high-grade MR (19). Additionally, conflicting data exist regarding the influence of PH on mortality after M-TEER due to diverging PH definitions and a lack of analyses on PH subgroups.

Our study demonstrated that 77.6% (97/125) of current “real-world” patients who underwent M-TEER revealed concomitant PH. The M-TEER procedure was equally feasible in patients with and without PH, resulting in the absence of any significant differences in short-term complication rates. The prevalence of PH among M-TEER patients was comparable to that reported in previous studies, which reported a prevalence of 31.5–87.6% (4-6,20-22). In general, the clinical characteristics of the present cohort were comparable to those of previous clinical studies (4,20-22) and registries (23) investigating M-TEER patients.

This study contributes to the existing literature by providing an in-depth analysis of the respective PH subtypes. Cpc-PH was the most represented PH subtype, and patients with this subtype had the greatest morbidity and PASP values, whereas precapillary PH was only encountered in a minority of cases. Previous research has shown that increased PASP levels have a significant impact on mortality among M-TEER patients (22-24). Additionally, determining the most precise PASP value at the time of intervention is particularly important, with RHC measurement representing the gold standard for this metric. However, this method also has disadvantages due to its invasiveness, thus a noninvasive measurement would be equally valuable in predicting outcomes, assuming it provides a comparable level of accuracy. According to our data, this suggestion cannot be given for Ipc-PH patients, as no significant correlation was found between D-PASP and RHC-PASP values in this particular subcohort of patients. In this respect, the Ipc-PH component might be associated with a lower incidence of right-sided heart valve regurgitation, resulting in a systematic underestimation of PASP by noninvasive measurement. To date, no conclusive data have been published to elucidate this phenomenon. Even though there was a significant correlation in Cpc-PH patients, the RHC-PASP was also underestimated in these patients by an average of 25 mmHg, so the prediction of outcomes via noninvasive measurements could also be misguided in these patients. However, it should also be considered that the noninvasive measurement of D-PASP may have been systematically underestimated due to method-specific factors, which could have subsequently affected the correlation analysis to RHC-PASP.

In addition to the higher mortality associated with increasing PASP values (22-24), previous studies have also demonstrated a reduction in PASP values as a result of M-TEER intervention (20,23). In the present cohort, however, this was only significant for Ipc-PH patients for whom the D-PASP values were already insufficiently correlated with the RHC-PASP values. A dynamic reduction in PASP may nevertheless be present, but the absolute amount of the reduction was low in both Ipc-PH and Cpc-PH patients. Furthermore, method-specific variation in the measurement as well as interobserver bias cannot be excluded as possible explanations. Nevertheless, the significant decrease in the PASP values reported in previous studies was also limited. A study by Tigges et al. (23) revealed an average reduction in PASP of 7 mmHg, whereas an average reduction of 14 mmHg was recorded only among patients with severe PH in the study by Rashi et al. (20). A comparison of RHC-PASP values before M-TEER and during the follow-up period in the present PH subcohorts would have been desirable to explore this aspect more precisely; however, this was not possible with the acquired data. In this respect, a study by Mandurino-Mirizzi et al. on M-TEER patients with functional MR was able to demonstrate that patients with Ipc-PH particularly revealed the greatest benefit in those hemodynamic parameters (25). These findings should be further explored among the remaining MR etiologies by future studies.

With respect to the follow-up period, concomitant PH was responsible for significantly worse long-term survival, as shown by the corresponding Kaplan-Meier and univariable Cox regression analyses. The borderline significance in the multivariable Cox regression analysis can most likely be attributed to the comparatively low sample size of this monocentric study cohort. As long-term survival results are consistent with those of previous studies (4,5,7,22-24), an independent influence on mortality by concomitant PH could be assumed in total. Nevertheless, these findings of the present study should be regarded in an exploratory manner and should be further investigated by ongoing clinical trials. However, data on the long-term outcomes of entire “real-world” M-TEER cohorts stratified by PH subtypes have not been reported to date. Our analysis revealed that patients with concomitant Cpc-PH had a significant diminished survival compared with patients without concomitant PH. Moreover, a trend towards improved survival in Ipc-PH patients compared with that in Cpc-PH patients was observed; however, this difference was not significant. The comparatively poorer survival of Cpc-PH patients could be explained by the significantly greater morbidity and higher PASP values, for which an influence on mortality was demonstrated (17,22-24). The failure to reach the significance level in the comparison to Ipc-PH patients could also be due to the smaller sample size of this monocentric study; thus, this aspect should also be regarded in an exploratory manner and should be further investigated in future multicenter studies. Another study by Mandurino-Mirizzi et al. represents the only study to date that investigated the influence of PH subtypes on survival after M-TEER, although this study again focused on patients with heart failure with reduced ejection fraction and functional MR etiology (9). Cpc-PH proved a significant predictor of mortality in this subcohort (9), potentially indicating that the significantly diminished survival of patients with PH seems primarily attributable to patients with Cpc-PH. However, due to the relevant differences in cohort characteristics, the findings of Mandurino-Mirizzi et al. are not completely transferable to the present study. Future studies should therefore further investigate the impact of PH subtypes on survival among patients of the respective MR etiologies. Furthermore, the small sample sizes of the PH subgroups and the failure to reach statistical significance in survival between the subgroups should be considered in the interpretation of the results. Based on the available data, it was also not possible to draw any conclusions about residual PH and its influence on survival after successful M-TEER. In this regard, previous research by Tsubata et al. demonstrated a negative impact on survival due to residual PH after M-TEER in patients with functional MR (26). Moreover, advanced parameters of right ventricular function, right ventricular to pulmonary artery coupling, pulmonary vascular load and compliance (27,28) should be investigated with regard to their impact on long-term outcomes.

Nonetheless, the present results may indicate potential approaches for improving the prognosis in patients with PH. Although Ipc-PH patients did not constitute the majority of PH patients, PH in this cohort appears to be primarily attributable to valvular heart disease due to high-grade MR, which underscores the importance of dedicated interventional MR treatment and guideline-directed optimal medical therapy for congestive heart failure. Conversely, the systematic treatment of complicating comorbidities among Cpc-PH patients, the majority of whom were PH patients in this cohort, could be a potential therapeutic approach to reduce morbidity and mortality in addition to the early identification of such patients and subsequent referral for M-TEER intervention.

Limitations

Owing to the nature of a retrospective cohort study, no conclusions can be drawn regarding any causalities. The monocentric study design may have limited the generalizability of the results. Due to the exclusion of patients with precapillary PH, who were nevertheless underrepresented, the results cannot be applied to this PH subcohort. A distortion of the mortality analysis due to unknown and unsurveyed cofactors cannot be completely ruled out. Furthermore, a limitation arises from the lack of cause-specific mortality analyses and competing risk analyses. Owing to insufficient RHC data, a relevant proportion of patients had to be excluded from the analysis. On the one hand, this led to a reduction in the study population with a consecutive reduction in statistical power; on the other hand, this may have led to a relevant selection bias that has to be considered in the interpretation of the results. With regard to the external validity of the presented data, patients who were previously not considered for RHC prior to M-TEER may therefore be underrepresented. Furthermore, stratification according to the respective MR etiologies would have been desirable, but this was not feasible given the small subcohort sizes. The relatively small sample size of the PH subcohorts may limit the interpretation of the results due to underpowered statistical analyses, meaning that the presented results concerning long-term outcomes between the PH subcohorts should be regarded in an exploratory manner. In addition, it would have been desirable to examine longitudinal noninvasive as well as invasive data with respect to right heart function, residual PH and tricuspid valve regurgitation after M-TEER. However, this was unfortunately not possible to a sufficient extent based on the available data. The same applied to changes in medical treatment for heart failure and PH, New York Heart Association (NYHA) classes, PASP values and N-terminal pro-B-type natriuretic peptide (NT-proBNP) values after M-TEER. Nevertheless, clinically relevant approaches towards an improvement of outcomes were addressed within this analysis.

Conclusions

Concomitant PH was associated with a diminished long-term survival among M-TEER patients. Cpc-PH represented the most common PH phenotype, and patients in this subgroup presented the highest morbidity and PASP values. The invasive RHC measurement is still recommended for the referral of patients for M-TEER, as PASP was significantly underestimated by noninvasive measurements. Early differentiation of PH subtypes and their complicating comorbidities could represent a potential approach for improving long-term outcomes in this vulnerable cohort of patients. Nevertheless, prospective multicenter studies are needed for further investigation.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-654/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-654/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-654/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-1-654/coif). The 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was authorized by the local Ethics Committee of the Department of Medicine of Philipps University of Marburg (protocol code: RS 23-163). Informed consent was waived because of the retrospective design 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/.

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