‘Finding the Biomarker’ for Transcatheter Mitral Valve Repair

This article refers to ‘Predictors of rehospitalization after percutaneous edge-to-edge mitral valve repair by MitraClip implantation’ by M. Keßler et al., published in this issue on pages xxx. Percutaneous mitral valve repair with the MitraClip System (Abbott Vascular, Santa Clara, CA, USA) has emerged as a viable alternative to surgery for the treatment of selected patients with symptomatic severe mitral regurgitation (MR).1 The evidence basis supporting MitraClip therapy is currently limited to one relatively small randomized trial2 and several single-arm registries.3-6 On the other hand, potential benefits of the MitraClip procedure are the reduction of MR, improvement in New York Heart Association (NYHA) functional class, quality of life and echocardiographic parameters demonstrating left ventricular remodelling.3-7 These effects lead to a significant reduction in rehospitalization for heart failure (HF) and corresponding costs.8 Nevertheless, in-hospital readmission in patients treated with MitraClip is a critical issue after the procedure, with a significant impact by the clinical and economical point of view. Rehospitalization is not uncommon after MitraClip implantation, due to critically ill population with multiple cardiac and non-cardiac co-morbidities. In this issue of the Journal, Keßler et al.9 report a rate of rehospitalization for HF decompensation of 18% in the first year after MitraClip procedure and that rehospitalization correlates significantly with all-cause mortality (odds ratio 2.3, 95% confidence interval 1.3–4.1; P = 0.004) and cardiovascular mortality (odds ratio 3.3, 95% confidence interval 1.7–6.1; P = 0.0003). Patients in the rehospitalization group had higher levels of troponin T and creatinine, higher EuroSCORE II and high previous implantable cardioverter-defibrillator implantation rate. Pre-procedural echocardiography revealed a more severe reduction of left ventricular ejection fraction (LVEF) in the rehospitalization group, mainly in patients with functional MR. The most significant risk factors for rehospitalization during the first year after MitraClip implantation were found to be baseline troponin T, LVEF and NYHA class. In particular, a LVEF ≤ 44% and a baseline troponin T > 21 ng/mL correlated with a high rate of 1-year rehospitalization. Conversely, in this study, pulmonary artery pressures and high-grade tricuspid regurgitation did not predict rehospitalization. Data from the TRAMI registry established a 1-year mortality of 20.3% with a rehospitalization rate during the first year of 64.3%, of which 14.1% secondary to cardiac decompensation and 17.8% to other cardiovascular reasons.10 Predictors of 1-year mortality were NYHA class IV, anaemia, previous aortic valve intervention, serum creatinine ≥ 1.5 mg/dL, peripheral artery disease, LVEF < 30%, severe tricuspid regurgitation, and procedural failure.9 The GRASP registry reported that hospital readmission after MitraClip occurred within 12 months in about one patient out of four, mostly related to cardiovascular causes (66.3%), particularly for primary HF due to impaired LVEF.3 Anaemia and gastrointestinal bleeding were the most frequent non-cardiovascular causes. Rehospitalization at 30 days occurred in 27% of cases and was associated with higher mortality than late readmission. Independent predictors of early rehospitalization were length of stay ≥ 3 days, LVEF reduction ≥ 5% after MitraClip implantation and systolic pulmonary artery pressure ≥ 60 mmHg at discharge. The independent predictors of late rehospitalization between 30 days and 12 months were device failure and pulmonary hypertension at discharge.3 In the study of Keßler et al.,9 the strongest predictive factors for rehospitalization and mortality were impaired LVEF and troponin T, reflecting the most compromised clinical status of the patients undergoing MitraClip procedure. Troponin is not routinely determined in clinical practice, even if in HF its release is promoted by several mechanisms, namely myocardial ischaemia attributable to coronary artery disease or microcirculatory dysfunction, damage elicited by neurohormonal overactivation, inflammatory or infiltrative processes, myocardial apoptosis or autophagy, and increased protein turnover.11 A recent meta-analysis of Aimo et al.12 concluded that in chronic HF, high-sensitivity troponin T (hs-TnT) is independently associated with all-cause mortality, cardiovascular mortality and cardiovascular hospitalization. The use of hs-TnT in the clinical practice can assist the clinician in diagnosis and risk stratification of HF patients, complementary to the routine use of B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP). Gohar et al.13 demonstrated also a potential role for of hs-TnT in predicting outcomes in men and women with HF with preserved ejection fraction. A study of Jungbauer et al.14 found that hs-TnT was significantly elevated in patients with chronic HF compared to healthy controls and positively correlated with NT-proBNP. The hs-TnT increase correlated with NYHA class severity, low LVEF and fluid retention. Additionally, hs-TnT was a significant predictor of all-cause mortality or rehospitalization for HF. Upon consideration of both hs-TnT and NT-proBNP, the combination of elevated hs-TnT (≥ 0.014 ng/mL) and NT-proBNP (≥ 900 pg/mL) was the strongest predictor for all-cause mortality and the combined endpoint of all-cause mortality and rehospitalization for HF. When only one marker was elevated, patients with elevated hs-TnT and normal NT-proBNP showed a comparable prognostic value to those patients with increased NT-proBNP and normal hs-TnT.14 The simultaneous dosage of hs-TnT and NT-proBNP can be used in a complementary way, because they reflect different biological information, i.e. the severity of ongoing myocardial damage and haemodynamic overload, respectively, which are related to yet different pathophysiological phenomena. In the study of Keßler et al.,9 higher levels of TnT but not NT-proBNP were observed in the rehospitalization group; this could be explained by the observation made by Jungbauer et al.14 that small increments of hs-TnT are more sensitive to predict a clinical compromise secondary to HF. Both patients rehospitalized and those not rehospitalized had high NT-proBNP values, and values were much higher in those rehospitalized, although this did not reach statistical significance. Finally, the higher levels of TnT in the rehospitalization group could reflect the greater renal impairment as demonstrated by higher levels of creatinine at baseline.15, 16 On the other hand, functional aetiology of MR, which is the most involved mechanism in patients treated with MitraClip in the ‘real world’, is more represented in patients with high rates of rehospitalization as well as in patients with high mid and long-term mortality. As secondary severe MR in HF patients worsens prognosis and accelerates left ventricular failure in a vicious circle, treating MR is reasonable. Patients affected by functional MR usually have more severe co-morbidities and higher procedural risk. In addition, these patients present with severely depressed left ventricular function and markedly remodelled cardiac ventricles, rendering the potential benefit of MitraClip implantation unpredictable in terms of functional and echocardiographic outcomes.17 In the future, a better patient selection and performing MitraClip repair at an earlier stage of left ventricular remodelling could avoid some ‘futile’, ‘less beneficial’ procedure, in terms of long-term clinical outcomes. Finally, trials, such as the Multicenter, Randomised, Controlled Study to Assess Mitral vAlve reconsTrucTion for advancEd Insufficiency of Functional or iscHemic ORigiN (MATTERHORN, NCT02371512), in which the percutaneous edge-to-edge repair is compared with surgical repair or replacement in patients with functional MR, and the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT, NCT01626079), and the Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR, NCT01920698) randomised trials, in which the percutaneous edge-to-edge repair is compared with optimal medical therapy in patients affected by functional MR, should help to clarify the therapeutic position of percutaneous edge-to-edge repair in these patient subsets. The discovery of reliable prognostic factors for predicting the outcome of patients undergoing MitraClip repair will be of outmost help for the optimal patient selection and for improving procedural success and long-term benefits. Conflict of interest: none declared.