From forgotten to rediscovered: shifting focus to the right ventricle in primary mitral regurgitation

This article refers to ‘Right ventricular dysfunction predicts outcome after transcatheter mitral valve repair for primary mitral valve regurgitation’ by P.M. Doldi et al., published in this issue on pages 2162–2171. Mitral regurgitation (MR) is one of the most common valve heart diseases worldwide and is associated with increased morbidity and mortality.1 In primary or degenerative MR, primary abnormalities of the leaflets and/or of the sub-valvular apparatus including the chordae tendineae, papillary muscles and mitral annulus are responsible for the mal-coaptation of the leaflets and the resulting regurgitation.1 According to current guidelines, first-line treatment to restore coaptation in primary MR is surgery, with mitral valve repair being preferred over replacement when a successful and durable repair is expected, due to better long-term outcomes.2 In patients with high or prohibitive surgical risk, mitral transcatheter edge-to-edge repair (M-TEER) has been proven safe and effective in reducing MR severity and improving patient-centred outcomes.3-10 In this patient population, advanced age, heart failure (HF) symptoms, coronary artery disease and functional class, together with left ventricular dysfunction, atrial fibrillation and pulmonary hypertension (PH) are considered as major prognostic determinants.4 Historically considered as a ‘conduit’, the right ventricle has on the contrary emerged as a crucial determinant of prognosis in multiple clinical scenarios.11-13 Nonetheless, if the presence of PH in patients with primary MR has considerable prognostic implications, little is known about the impact of right ventricular dysfunction (RVD) on outcomes in primary MR patients treated with M-TEER. In this issue of the Journal, in the multicentre German study by Doldi et al.,14 648 patients undergoing M-TEER for symptomatic primary MR at nine centres, were evaluated with the aim of defining, validating, and assessing RVD and its effects on procedural and 2-year clinical outcomes. By means of right ventricular–pulmonary artery (RV-PA) coupling, measured as the ratio of the tricuspid annular plane systolic excursion (TAPSE) over the pulmonary arterial systolic pressure (PASP), the study population was divided into a derivation and validation cohort for calculation and validation of the best discriminatory value for RVD. Primary MR patients with RVD showed a 2.2-fold increase in 2-year all-cause mortality as well as less symptomatic improvement after M-TEER. Despite a consistent efficacy of M-TEER in the overall population, the presence of RVD was associated with reduced procedural success rate, less reduction of symptoms and higher mortality at follow-up. Based on these results, the authors highlight the importance of a focused RV function assessment to be included into pre-procedural evaluation of primary MR patients. Right ventricular function evaluation has recently gained momentum due to the central and rediscovered prognostic implications of RVD in many cardiovascular conditions.15 Advances in imaging techniques have made it feasible to better diagnose and characterize RV anatomy and function. If cardiac magnetic resonance (CMR) is still considered the gold standard for quantification of RV volumes and ejection fraction, due to its high accuracy and reproducibility,16 three-dimensional (3D) echocardiography and strain techniques have emerged as important alternatives and have improved our understanding of RV anatomy and function by providing important data on the particular anatomical and physiological characteristics of the right ventricle. Notwithstanding the tremendous advances in the assessment of the right ventricle, however, there still remains a relevant level of uncertainty around the most appropriate echocardiographic parameter to define RVD. Moreover, although the presence of allegedly ‘severe’ RVD has been considered as a major exclusion criterion from all previous and ongoing clinical trials in various clinical settings, the scientific community is still struggling with achieving a definition for severe RVD, and whether this should be based on a prognostic relevance. What is then severe RVD? How do we define it? Which parameter or group thereof should we rely on? As of today, these remain open questions (Table 1). If on the one hand, we know what constitutes normal RV function, and could consequently derive what is abnormal, we are still far from understanding what indeed constitutes severe RVD. Recent research has emphasized the importance of assessing RV systolic function in relation to its afterload, as a relation of the efficiency with which RV stroke work is transferred into the pulmonary artery. Lower ratios indicate an inadequate RV contractile response to increased afterload.17 To accomplish this, RV ejection fraction, TAPSE and/or RV longitudinal strain divided by the estimated PASP have been proposed as measurements of RV-PA coupling. Studies have shown that RVD assessment by RV-PA coupling is an important outcome predictor in different scenarios including aortic stenosis, PH and HF with preserved ejection fraction.18-20 Additionally, in patients with severe tricuspid regurgitation (TR), a TAPSE/PASP ratio ≤0.41 was associated with increased all-cause death after transcatheter tricuspid valve intervention.21 In the COAPT trial, which included patients with HF and severe secondary MR, advanced RVD assessed as RV-PA coupling was a powerful predictor of adverse events at 2-year follow-up.22 The superiority of RV-PA coupling over other methods lays in the concept of accounting for RV afterload; indeed, the relationship TAPSE versus PASP, taken as an index of in vivo RV length versus developed force, provides a more comprehensive non-invasive assay of RV contractile state that adds to the information offered by either variable considered separately.17 Functional measurements by two-dimensional echocardiography have some technical limitations, due to the intrinsic limitation of TAPSE, as an expression of mere longitudinal function, together with the echocardiographic estimation of PASP, which is not exact when compared with right heart catheterization, and not always doable. It would be appropriate to evaluate RV function by measuring ejection fraction by 3D echo or CMR, when possible, due to its accuracy and established prognostic value. To overcome the issues related to TAPSE, other investigators have been assessing RV-PA coupling by either RV free-wall longitudinal strain (RVFWLS) or RV fractional area change (RVFAC), whereas RVFWLS may provide a more accurate picture of RV function, as shown in a recent CMR study demonstrating stronger correlations between CMR-derived RV ejection fraction and echocardiographic RVFWLS than with echocardiographic RVFAC.22 In addition, RVFWLS may have advantages relative to TAPSE, as proposed by Prihadi et al. showing that in patients with significant functional tricuspid regurgitation, RVFWLS identified the highest percentage of patients with RVD, in comparison with RVFAC and TAPSE, and was independently associated with all-cause mortality and incremental to RVFAC and TAPSE.23, 24 Overall, RV-PA coupling provides a more sophisticated assessment of RV performance, and might thus provide greater prognostic utility. In conclusion, when RVD is present in patients with severe primary MR, the prognosis following M-TEER is worse. Therapeutic decision-making should therefore be preceded by a careful evaluation of RV function criteria. The multicentre study by Doldi et al. lays the foundation for further investigations. If these data were to be confirmed, the cardiologic community should consider RV evaluation in the baseline assessment of primary MR patients. In this setting, RVD might, thus, be crucial for decision-making, giving physicians the option to take early action before interventional treatment is no longer beneficial. Conflict of interest: M.M. has nothing to disclose. A.S. receives research grant support from Cardiovalve, Edwards Lifesciences and W. L. Gore.