Ventricular functional mitral regurgitation: also a tale of the left atrium

This editorial refers to ‘Prognostic impact of regurgitant volume to left atrial volume ratio on ventricular functional mitral regurgitation’, by M. Yoshikawa et al., https://doi.org/10.1093/ehjci/jeaf304. Patients with heart failure may present with significant mitral regurgitation (MR) in the absence of structural mitral valve disease. This condition, known as functional mitral regurgitation, is associated with a major increase in morbidity and mortality.1 In heart failure with reduced ejection fraction (EF), the development of MR is often assumed to be due to left ventricular (LV) dilatation and dysfunction, leading to the displacement and dysfunction of the papillary muscles and subsequently tethering of the mitral leaflets. This type of MR is commonly referred to as ventricular functional MR (VFMR).2 In recent years, a second type of functional MR due to left atrial (LA) dysfunction has been increasingly recognized in patients with atrial fibrillation and/or heart failure with preserved EF. In these patients, increased LA size and reduced LA compliance are accompanied by the dilatation, flattening, and altered mechanics of the mitral annulus, resulting in reduced mitral leaflet coaptation and atrial functional MR (AFMR).3 The distinction between these two entities, seemingly simple, is not always straightforward in clinical practice and has been clouded by a lack of a uniform definition of AFMR. As such, VFMR is common in patients with dilated cardiomyopathy or ischaemic heart disease, while AFMR is, by definition, present in ventricles that are not or only slightly dilated and that have normal EF.2 However, persistent tachyarrhythmias in patients with AFMR can cause both LV dilatation and a reduction in LV EF. Moreover, longstanding LV failure with reduced EF is accompanied by a gradual increase in intra-atrial pressures, leading to a certain degree of LA and mitral annular dilatation. Interestingly, the LA size has been suggested to be a more important contributor to mitral annular remodelling than LV size in patients with VFMR, but this needs confirmation in larger studies.4 The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial was the first large, prospective study to provide evidence of a mixed VFMR-AFMR phenotype in a subgroup of patients with heart failure with reduced EF.5 Among 624 patients with heart failure, moderate-to-severe or severe MR, and a mean EF of 31%, 53% had a history of atrial fibrillation. The atrial fibrillation group exhibited larger LA volumes and mitral valve orifice areas despite similar MR severity and less dilated LVs.5 In a further COAPT subanalysis, the investigators assessed the prognostic impact of the ratio between the MR regurgitant volume and the LA maximum volume (RVol/LAV), a surrogate for the MR’s contribution to the total LA overload, in 567 patients with available data.6 They found that patients on guideline-directed medical treatment with lower MR volume relative to the LA size (RVol/LAV < 0.67) fared worse and had a higher rate of heart failure hospitalization (HFH) during follow-up. However, this did not hold true for patients treated with mitral transcatheter edge-to-edge repair (M-TEER). In this issue, Yoshikawa et al further explore the potential utility of the RVol/LAV ratio as a discriminator of VFMR with poorer outcomes after M-TEER using data from 1830 patients treated at 21 centres across Japan, enrolled in the OCEAN (Optimized CathEter vAlvular iNtervention) Mitral registry.7 Contrary to the COAPT findings, they report that a low RVol/LAV (below the median of 0.40) was associated with a significantly higher risk of HFH even after M-TEER. This finding remained consistent after adjusting for possible confounders and competing risks, and in sensitivity analyses applying the 0.40 threshold only to patients with COAPT-like profile. On the other hand, RVol/LAV was not related to the risk of cardiovascular death after M-TEER. Several interesting parallels can be draw between the OCEAN analysis and earlier COAPT results. First, the phenotype of patients with low RVol/LAV is comparable, characterized by a higher age, a larger proportion of male patients, and a notably greater burden of atrial fibrillation or flutter in both studies. Moreover, these patients had much larger atria and smaller LVs indexed for body size, both features suggestive of an important atrial contribution to MR- indicating a mixed functional MR aetiology (Figure 1). Several distinctions are also noteworthy. The Japanese patients with low RVol/LAV were on average older and had lower renal function than their COAPT counterparts, both recognized risk factors of atrial myopathy. They used less beta-blockers, but more mineralocorticoid receptor antagonists, suggesting more congested LAs and pulmonary circulation. Their LAVs adjusted for body size were much larger than average values in COAPT, aligning with more advanced atrial disease. These differences, along with the markedly larger cohort size, likely explain the discrepancies in median RVol/LAV values and the significance of this ratio regarding the risk of HFH post-M-TEER between the two studies. The OCEAN analysis has several limitations, some of which are acknowledged by Yoshikawa et al. One key limitation is the absence of an echo core lab and the mixed methodology used to quantify the severity of MR. Although none of the commonly used echocardiographic methods to grade MR severity are perfect -especially in assessing functional MR- a uniform methodology helps mitigate measurement variability and errors and is always desirable in a research setting. The maximum LA volume is a convenient and widely used measure of LA remodelling. However, impaired LA reservoir function and reduced LA compliance have been shown to be stronger determinants of adverse outcomes than LA volume in both VFMR and AFMR.8,9 In AFMR in particular, not the largest atria, but those with most impaired reservoir function had the highest mortality.9 Whether a ratio of MR severity to LA function or stiffness might better identify patients with VFMR who could benefit from M-TEER or, conversely, who are most in need of intensified care requires investigation in future studies. Finally, the OCEAN analysis was conducted on patients with heart failure and more than moderate functional MR who underwent M-TEER. The value of RVol/LAV in less selected populations and in MR of other aetiologies remains at the moment unknown. How should we implement these findings in clinical practice and further research? From COAPT, we learned that M-TEER improves outcomes irrespective of RVol/LAV, emphasizing that patients with mixed ventricular-atrial functional MR also benefit from percutaneous mitral valve treatment.5,6 However, the Yoshikawa study suggests that M-TEER may be less effective in preventing worsening heart failure within this mixed functional group, possibly due to their larger mitral annular areas, which may respond less effectively to this type of valve repair. Therefore, close post-interventional monitoring and diligent adjustment of medical treatment are prudent recommendations for patients with low RVol/LAV based on current evidence. More importantly, the findings of Yoshikawa et al emphasize that not all patients with heart failure with reduced EF have a pure VFMR phenotype, and that a non-negligible proportion of them have prognostically important atrial disease. So, do look above the LV, also in VFMR! Dana Cramariuc (M.D. Ph.D. (Conceptualization [lead]; Project administration [equal]; Resources [equal]; Writing—original draft [lead]; Writing—review & editing [equal])) and Judy Hung (MD (Conceptualization [supporting]; Resources [equal]; Writing—review & editing [equal])) No new data were generated or analysed in support of this research.