Disproportionate Functional Mitral Regurgitation: A New Therapeutic Target in Patients with Heart Failure and a Reduced Ejection Fraction

Patients with chronic heart failure and a reduced ejection fraction commonly show evidence of functional mitral regurgitation (MR), which may result from two distinct pathophysiological mechanisms.1 First, MR can occur primarily as a result of enlargement of the left ventricle, which leads to mitral annular dilatation and the tethering of the valve leaflets by displaced papillary muscles. Second, MR can be caused by left ventricular (LV) dyssynchrony due to a localized electrical or mechanical disturbance that leads to uncoordinated support of the valve leaflets during systole. Although the degree of MR may be mild and of little consequence, one-third of patients with chronic heart failure manifest severe MR, which is related to either LV enlargement or LV dyssynchony.2 The two mechanisms leading to functional MR can be distinguished in the clinical setting.3 When the principal reason for MR is LV enlargement, there is a predictable relationship between LV end-diastolic volume (LVEDV) and the effective regurgitant orifice area (EROA), assessed by Doppler echocardiography. An EROA of 0.1–0.2 cm2 can be expected when the LVEDV is 150–200 mL, whereas an LVEDV of 250–300 mL generally leads to EROA of 0.3–0.4 cm2 (i.e. severe MR). A patient who has severe MR in association with an LVEDV of 250–300 mL has a regurgitant lesion that is proportionate to the LVEDV, i.e. the MR can be explained entirely by LV enlargement. In contrast, when the EROA is of 0.3–0.4 cm2 but the LVEDV is only 150–200 mL, the degree of MR is much greater than expected from the LV chamber size; i.e. the MR is disproportionate to LV dilatation, typically because it is related to LV dyssynchrony. Thus, distinguishing between proportionate and disproportionate MR allows for the identification of the pathophysiological pathways leading to MR. Since proportionate MR is related to LV dilatation, this type of functional MR responds favorably to interventions that act to reduce LV cavity size. Many well-established pharmacological treatments for chronic heart failure and a reduced ejection fraction can cause reverse LV remodelling, and thereby ameliorate proportionate MR. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors and beta-blockers have been shown to reduce functional MR in randomized placebo-controlled trials.4, 5 These agents can greatly minimize regurgitant flow, even when the MR is severe (EROA of 0.3–0.4 cm2). However, intensive medical therapy is not sufficient to alleviate MR if there is meaningful ventricular dyssynchrony2 (e.g. as reflected by the presence of left bundle branch block), which is strongly associated with disproportionate MR. Should severe and disproportionate MR be a therapeutic target independent of pharmacological efforts directed to the left ventricle? If the increased morbidity and mortality of these patients is related to the presence of MR, interventions that act directly to reduce MR should lead to a reduction in the risk of major adverse cardiovascular outcomes. Severe and disproportionate functional MR is clinically important, and it responds poorly to neurohormonal antagonists. So, how should this type of MR be treated? In patients with important electrical conduction delay (i.e. QRS ≥ 150 ms or left bundle branch block), the initial treatment strategy for disproportionate MR should be cardiac resynchronization therapy (CRT). Initiation of CRT leads to an immediate reduction in MR without any change in LV volumes6; however, LV volumes are meaningfully decreased during prolonged CRT if the MR is alleviated.7 Yet, even when the left ventricle has favourably remodelled, interruption of CRT leads to an immediate recurrence of MR, indicating that dyssynchrony (rather than LV volumes) is critical to the pathogenesis of severe and disproportionate MR.6 Restoration of synchronized papillary muscle contraction following CRT has dramatic effects on MR in 40–50% of patients.8, 9 A prediction model to identify patients most likely to respond to CRT includes radial dyssynchrony, the absence of meaningful LV enlargement and evidence for viable myocardium at the papillary insertion site (all indicative of disproportionate MR due to electrical delay). In one report, if all three determinants were present, 75% of patients treated with CRT showed a reduction of severe MR to non-significant levels. Similar results have been reported by others.8 Therefore, it seems likely that much of the haemodynamic and clinical benefit that patients with LV dysfunction, QRS prolongation and severe MR derive from long-term CRT is due to amelioration of functional MR.7 What can be done for severe and disproportionate MR if patients are not eligible for or show no improvement in MR following cardiac resynchronization? Transcatheter edge-to-edge mitral valve repair involves the percutaneous placement of mechanical clips on the valve leaflets to directly reduce the EROA. The COAPT trial10 evaluated the efficacy of transcatheter mitral valve repair in patients with heart failure and severe MR. The trial excluded patients with an EROA of 0.2 cm2 and those with marked LV enlargement; furthermore, patients who responded favourably to maximally tolerated therapy with neurohormonal antagonists (typically with proportionate MR) were not enrolled. For all these reasons, the trial selected patients with severe and disproportionate MR. Indeed, while the mean EROA was 0.41 cm2, the mean LVEDV was only 192 mL. After 2 years, transcatheter mitral valve repair improved symptoms and exercise tolerance and reduced the risk of death and of hospitalization for heart failure. Thus, transcatheter mitral valve repair has important benefits in patients with heart failure, LV dysfunction and disproportionate MR. Interestingly, the procedure may be particularly helpful (≈70% response rate) in patients who have persistent disproportionate MR following cardiac resynchronization.11 It should be noted that another trial of transcatheter mitral valve repair — the MITRA-FR trial12 — found no benefit of the procedure on functional status or on the risk of death or hospitalization for heart failure. However, the MITRA-FR trial focused on the enrolment of patients with proportionate, rather than disproportionate, MR.3 The protocol allowed the participation of patients with an EROA of 0.2 cm2 as well as those with marked LV dilatation. Consequently, at baseline, the mean EROA was 0.31 cm2, but the mean LVEDV was 252 mL. Thus, when compared with those in COAPT, the patients in MITRA-FR had an EROA that was 30% smaller but LV volumes that were 30% larger.3 In such patients (who have proportionate MR), the main driver to functional MR is not ventricular dyssynchrony but LV enlargement. When the left ventricle is markedly dilated, a procedure directed solely at the mitral valve cannot address the primary pathophysiological derangement in these individuals. Given the discordant results of the MITRA-FR and COAPT trials, some might believe that the issues surrounding the efficacy of transcatheter mitral valve repair remain unsettled and that a third ‘tie-breaker’ trial is needed to resolve the controversy. However, it should be noted that the hypothesis that was confirmed in COAPT was first proposed in an earlier trial (EVEREST II),13 which also focused on patients with severe and disproportionate MR. Given this direct confirmation and the totality of evidence, it is difficult to understand why a tie-breaker trial is needed or how carrying it out would even be possible. In patients with multivessel coronary artery disease and meaningful LV remodelling, coronary revascularization does not restore the contractility of viable papillary muscle segments, and thus, does not reduce functional MR in ischaemic cardiomyopathy.14 What then should be done if patients with severe functional MR undergo coronary artery bypass graft surgery? The MR can be surgically ameliorated with a downsized annuloplasty ring or the valve can replaced by a prosthesis using a chordal-sparing procedure. Both surgical options can yield symptomatic benefits in severe and disproportionate MR. Unfortunately, neither mitral annuloplasty nor prosthetic valve replacement produces optimal results. Mitral valve replacement is accompanied by an increased risk of death, primarily related to the mortality risks of the operative procedure. At the same time, patients who have a restrictive annuloplasty have a high recurrence of MR and an increased risk of adverse heart failure events and cardiovascular hospitalizations. The high failure rate of ring annuloplasty in patients with severe MR appears to be related to a mismatch between LV end-systolic dimension and the mitral ring size,15 causing lateral displacement of the posterior papillary muscles and tethering of the posterior mitral valve leaflet. Patients with chronic heart failure and a reduced ejection fraction who have severe and disproportionate MR are likely to experience important clinical consequences resulting from the haemodynamic stresses imposed by the regurgitant lesion, and the severity of MR is not likely to be reduced by conventional therapy with neurohormonal antagonists, even when administered in maximally tolerated doses.2 Such patients should first be treated with cardiac resynchronization (if they qualify for the procedure), and non-candidates and non-responders should be seriously considered for transcatheter mitral valve repair (Table 1). Therefore, when treating heart failure with a reduced ejection fraction, it is now time for physicians to identify patients who also have severe and disproportionate MR, because they require specialized procedures beyond optimal pharmacological therapy. Conflict of interest: M.P. has recently consulted for Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance.