Deceleration capacity of heart rate predicts 1‐year mortality in patients undergoing transcatheter edge‐to‐edge mitral valve repair

Abstract Background Risk stratification for transcatheter procedures in patients with severe mitral regurgitation is challenging. Deceleration capacity (DC) has already proven to be a reliable risk predictor in patients undergoing transcatheter aortic valve implantation. We hypothesized, that DC provides prognostic value in patients undergoing transcatheter edge‐to‐edge mitral valve repair (TEER). Methods We retrospectively analyzed electrocardiogram signals from 106 patients undergoing TEER at the University Hospital of Tübingen. All patients received continuous heart‐rate monitoring to assess DC following the procedure. One‐year all‐cause mortality was defined as the primary end point. Results Sixteen patients (15.1%) died within 1 year. The DC in nonsurvivors was significantly reduced compared to survivors (5.1 ± 3.0 vs. 3.0 ± 1.6 ms, p = 0.002). A higher EuroSCORE II and impaired left ventricular function were furthermore associated with poor outcome. In Cox regression analyses, a DC < 4.5 ms was found a strong predictor of 1‐year mortality (hazard ratio: 0.10, 95% confidence interval: 0.13–0.79, p = 0.029). Finally, a significant negative correlation was found between DC and residual mitral regurgitation after TEER (r = −0.41, p < 0.001). Conclusion In patients with severe mitral regurgitation undergoing TEER, DC may serve as a new predictor of follow‐up mortality.


| BACKGROUND
Mitral regurgitation (MR) is the most common valve condition in industrialized countries in people aged >65 years. 1 According to the 2021 ESC/EACTS Guidelines for the management of valvular heart disease, transcatheter edge-to-edge mitral valve repair (TEER) using edge-to-edge devices represents an efficacious treatment option for patients with chronic heart failure, severe functional mitral regurgitation (FMR) and prohibitive perioperative risk. 2,3 Both beneficial effects on patients' symptoms reflected in improved New York Heart Association (NYHA) functional class as well as a significant reduction in rehospitalizations could be attributed to TEER. [4][5][6] Reichart et al. demonstrated a correlation of residual MR after TEER with long-term outcome in patients with FMR. 7 However, according to the COAPT trial and MITRA-FR, the impact of TEER on mortality yielded opposite results, emphasizing the importance of selection of appropriate candidates for this procedure. 5,8 Thus, reliable and validated risk stratification tools for predicting mortality in patients undergoing TEER are urgently needed. Deceleration capacity (DC) has already been proven to be an independent predictor of 1-year mortality in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). 9 This parameter provides indirect insight into the balance of the autonomic nervous system and can be determined noninvasively and objectively by heart rate variability analysis. Autonomic impairment and reduced DC are already established as markers of cardiovascular risk and outcome. [10][11][12][13] This study aimed to evaluate the prognostic value of DC on mortality in patients with severe MR undergoing TEER.

| Study design and participants
In this study, we retrospectively enrolled 106 consecutive symptomatic patients with severe MR who underwent TEER at the University Hospital of Tübingen, Germany, between May 2010 and December 2015. Transthoracic (TTE) and transesophageal (TEE) echocardiography were performed to evaluate mitral valve morphology and MR severity before and at the end of the procedure. The assessment of MR severity followed the current European Association of Echocardiography guidelines. 14 All patients were qualified for TEER by an interdisciplinary heart team. Written informed consent was obtained wherever possible.
History of atrial fibrillation (AF) was evaluated upon study inclusion. Patient, cardiac, and operation-related factors of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) II were assessed. 15 In addition, hemoglobin (Hgb) and creatinine (Cr) levels were recorded at baseline. Patients previously treated with TEER were not included. In addition, the presence of sinus rhythm was mandatory for inclusion in the study.
The study was approved by the institutional ethics committee (260/2015R).  16 Briefly, "anchor points" were defined on the RR interval series and processed by a mathematical algorithm called phase-rectified signal averaging (PRSA). DC as central amplitude of the PRSA signal is subject to the influence of sympathetic and parasympathetic modulation. 17 Sinus rhythm is mandatory in the calculation of DC.

| Assessment of DC
In previous studies, Bauer et al. postulated that an impaired DC ≤ 4.5 ms is associated with a higher risk of mortality. 10

| Outcome
All patients were followed-up for 1 year after study enrollment. The primary endpoint was defined as all-cause mortality 1 year after TEER. Follow-up was conducted via our outpatient clinic and telephone interviews.

| Statistical analysis
The entire statistical analyses were conducted using SPSS Version 26 (SPSS Inc.). Data were analyzed by paired Student t-test and presented as mean ± standard deviation. Analyses included crosstabulation and Pearson's χ² tests, with p < 0.05 defined as statistically significant. Associations between nonnormally distributed data were evaluated with Spearman's rank correlation coefficient (rho). Cox regression analyses were applied to analyze independent associations between all-cause mortality and EuroSCORE II, left ventricular ejection fraction (LVEF), and DC. Furthermore, the prognostic significance of DC was analyzed by using Kaplan-Meier curves and log-rank tests. independently associated with all-cause follow-up mortality (Table 3).

| RESULTS
In addition, our data revealed an inverse correlation between DC and residual MR (r = −0.41, p < 0.001) as shown in Figure 2.

| DISCUSSION
The major findings of the current study of 106 patients with sinus rhythm and severe MR undergoing TEER may be summarized as follows: (1) Low DC was associated with 1-year mortality. (2) In addition to well-known predictive markers such as impaired LVEF or EuroSCORE II, DC was predictive of adverse outcomes and also reliably identified low-risk patients. (3) Residual MR severity was inversely correlated with DC.
Among patients with chronic heart failure and FMR, the overall prognosis is poor and risk prediction in this multimorbid patient cohort with high surgical risk remains challenging. 18 Our cohort represents the typical patient collective for interventional procedures with old age, impaired LVEF, and a high burden of comorbidities such as ischemic cardiomyopathy and pulmonary hypertension. Our findings confirm the predictive value of conventional risk predictors such as the ES II, LVEF, and renal failure 1 year after TEER. 19,20 Several studies found that TEER did not appear to alter disease progression regardless of the magnitude of reduction in MR severity, 20-22 especially patients with NYHA functional class IV, biventricular failure, or coexisting severe tricuspid regurgitation at baseline. In patients undergoing TAVI, it has already been shown that DC might be a valid parameter to optimize patient selection before intervention. 9 Accordingly, our findings are consistent with current studies indicating that DC provides prognostic value in patients with valvular heart disease. 9 DC of heart rate reflects autonomic nervous system function. Reduced DC mirrors compromised cardiac vagal modulation and may be correlated with disease severity, regardless of the underlying cause. 13   There is also evidence that LA and LV remodeling is reversible when MR severity reduced to at least 2+ by TEER. 26 An interaction of the sympathetic and vagus activity in the heart after TEER is therefore conceivable and could support our observation regarding the inverse correlation between the severity of the residual MR and DC. This assumption is supported by the correlation of cardiac distress markers such as atrial natriuretic peptide (ANP) and high-sensitivity cardiac troponin-I (hs-cTnI) with cardiovascular death after TEER. 27 Our study is limited due to the small sample size and the single center retrospective assessment. Furthermore, only patients with sinus rhythm were enrolled in this study. Due to the frequent presence of AF in patients with valvular heart disease, numerus patients were excluded at baseline.

| CONCLUSION
In summary, DC of heart rate is associated with 1-year mortality after Drafting of the manuscript, data collection, statistical analysis. All authors critically revised the manuscript and approved the manuscript.

ACKNOWLEDGMENTS
Open Access funding enabled and organized by Projekt DEAL.
T A B L E 3 Cox-regression analysis with all-cause mortality as dependent variable and age, gender, use of beta blockers, EUROSCORE II, left ventricular function, creatinine and deceleration capacity (DC) as independent variables.