Can mild to moderate secondary mitral regurgitation be a therapeutic target for symptomatic patients with heart failure with reduced ejection fraction?

This article refers to ‘Treating symptoms and reversing remodelling: clinical and echocardiographic 1-year outcomes with percutaneous mitral annuloplasty for mild to moderate secondary mitral regurgitation’ by K.K. Witte et al., published in this issue on pages 1971–1978. The prognostic value of secondary mitral regurgitation (SMR) in patients with heart failure (HF) is well known.1-3 It increases with increasing SMR severity and long-term survival can be extremely low (<60% at 8 years) even in patients with moderate SMR.2 The prevalence of moderate SMR in patients with HF with reduced ejection fraction (HFrEF) is relevant (43% in a recent series by Bartko et al.).3 However, current guidelines recommend treatment of SMR only in selected patients with HFrEF, symptomatic despite optimal medical therapy and with an effective regurgitant orifice area (EROA) ≥30 mm2.4 Indeed, we have a wealth of data regarding treatment of moderate-to severe and severe SMR5-9 while data on correction of mild to moderate SMR are still limited. Surgical correction of moderate SMR on top of coronary artery bypass grafting (CABG) did not improve left ventricular (LV) reverse remodelling at 2 years and did not improve survival or reduce overall adverse events or readmissions compared with CABG alone.10 On the other hand, the proportion of patients who experience a significant reduction in SMR after percutaneous or surgical coronary revascularization ranges from 40% to 50%.11, 12 However, there is a huge number of patients with mild to moderate SMR who do not need coronary revascularization and who have exertion symptoms despite optimal medical therapy. These patients may represent an unmet need, which has to be fulfilled in the near future. In this context, the dynamic nature of SMR is well known and the role of exercise echocardiography may be crucial. Almost one-third of patients were reclassified from non-severe to severe SMR after exercise and an increase of at least 13 mm2 of EROA with exercise was associated with poor prognosis.13 Papillary muscle dyssynchrony and LV sphericity at rest are the main predictors of worsening SMR during exercise.14 In this issue of the Journal, Witte et al.15 reported echocardiographic and functional outcomes of 68 patients with mild or moderate SMR and LV dysfunction treated by percutaneous indirect annuloplasty with the Carillon device. At 1-year follow-up, a significant reduction in SMR degree, assessed by qualitative methods, was observed compared with baseline. Moreover, there was a significant improvement in symptoms, assessed by New York Heart Association (NYHA) class; functional capacity, assessed by 6-min walking test; and quality of life, evaluated by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Finally, HF hospitalizations were significantly reduced during the year after the procedure compared with the year before. The study is limited by the small sample size and the lack of a control arm. Moreover, SMR was evaluated only at rest without performing any exercise test. However, the hypothesis generated is extremely interesting and may pave the way to future studies. The authors should also be congratulated for the wealth of data on quality of life and functional status, which strengthen their results. Recently, Izumo et al.16 reported their results in a series of 200 consecutive patients with SMR who underwent exercise stress echocardiography. Among them, 46 (23%) had exercise-induced secondary MR and 19 (41%) underwent percutaneous edge-to-edge mitral valve repair. Compared with the other 27 patient receiving medical therapy alone, those undergoing percutaneous correction had a higher event-free survival rate and an improvement in symptoms, although assessed only by the NYHA class. Compared with the study by Witte et al., the sample size of this study was smaller (n = 19) and there were no data regarding quality of life and 6-min walking test. However, the data consistently show the value of exercise echocardiography and the impact of percutaneous correction of exercise-induced SMR on symptoms and outcomes. The effects of percutaneous repair of SMR on symptoms are consistent also with previous data showing a clear association between the improvement in exercise haemodynamics, with a higher cardiac output at lower pulmonary pressures, and symptom relief after percutaneous SMR correction.17 Witte et al. also showed a non-significant improvement in LV ejection fraction and volumes after percutaneous mitral annuloplasty. Indeed, even moderate SMR may contribute to the LV afterload increase leading to LV remodelling. This is also indirectly reported in observational studies showing a worse outcome in patients with moderate vs. none/mild SMR after percutaneous mitral valve repair.8, 18, 19 Treatment of mild to moderate SMR in patients with LV dysfunction may seemingly be in contrast with the hypothesis that only disproportionate SMR may benefit from intervention.20 However, on the other side of the spectrum of the relation between SMR and LV dysfunction severity, observational data showed that also a very large EROA may be associated with worse outcome due to the inability to achieve optimal procedural results.19 In conclusion, patients with HF, limiting symptoms during exercise and mild to moderate SMR at rest, need a careful evaluation including exercise echocardiography in addition to optimization of medical therapy. This may unmask exercise-induced moderate to severe SMR and this may benefit from percutaneous treatment of SMR. Future studies on large populations are urgently needed to clarify the role of exercise echocardiography in identifying patients who may benefit from intervention and the effect of percutaneous therapies in this setting. Conflict of interest: M.A. received speaker fees from Abbott Vascular outside the submitted work. M.M. received consultation and speaker fees from Abbott Vascular and Edwards Lifesciences outside the submitted work.