Functional mitral regurgitation: a proportionate or disproportionate focus of attention?

This article refers to ‘Impact of mitral regurgitation in patients with worsening heart failure: insights from BIOSTAT-CHF’ by M. Pagnesi et al., published in this issue on pages 1750–1758. Functional mitral regurgitation (FMR) is defined by the presence of regurgitation in the context of structurally normal leaflets.1 We prefer the term ‘functional’ to the label of ‘secondary’ regurgitation as all mitral regurgitations are secondary to a mitral alteration, organic (e.g. rheumatic, endocarditis, degenerative) or functional (deformed ‘normal’ leaflets due to papillary muscle displacement or insufficient mitral leaflet coverage with mitral annular dilatation). FMR, diagnosed in the early days of angiography,2 was generally considered a seldom treatable and peculiar manifestation of ventricular dysfunction and has remained controversial in many aspects. The fundamental troubling fact leading to controversy is that FMR is a low-volume regurgitation,3-5 even when it is labelled ‘severe’, raising the issue of the causal link to clinical consequences. Are we certain that FMR is a low-volume regurgitation? Quantitative FMR assessment has generally measured a low regurgitant volume, much lower than in organic mitral regurgitation (MR).3-7 While some have decried these quantitative methods,8 this low regurgitant volume is confirmed by the low total stroke volume of the left ventricle.2, 9 As blood is incompressible, both forward stroke volume and regurgitant volume have to be ejected by the left ventricle in systole. With reduced ventricular function and low total left ventricular (LV) stroke volume, a low regurgitant volume is obligatory, confirming the observations of quantitative Doppler echocardiographic studies. Reports that suggested a disproportionate regurgitant volume to the LV size10, 11 have been plagued by severe underestimation of ventricular volumes and should be discounted.12 Hence, we come back to the fundamental question of how it is possible for a truly low-volume FMR to affect clinical outcomes. We know that degenerative MR of small volume is relatively benign.13 In patients with heart failure the serious FMR clinical consequences despite the small regurgitant volume are considered secondary to several processes, secondary to LV dysfunction and summarized in Figure 1. First, a small regurgitant volume in the context of a diseased ventricle may be highly harmful and induce further ventricular remodelling than it would on a ‘healthy’ left ventricle. Thus, FMR despite its volume may be linked to a vicious circle of progressive LV remodelling.14 Second, for any given effective regurgitant orifice (ERO) the regurgitant volume is determined by the driving force of the regurgitation, i.e. the LV to left atrial (LA) gradient in systole. Low compliance atria seen in heart failure will cause rapid LA pressure elevation in systole (the V-wave)15 with equalization of pressure, limiting the regurgitant volume entering the left atrium but yielding elevated pulmonary pressure and propensity for recurrent heart failure.16 In turn, LA overload is a cause of LA dysfunction that may contribute to heart failure and is an independent determinant of mortality.17 Finally, with FMR ejection of forward stroke volume may not be sustained2 leading to circulatory failure and excess mortality. Hence, we understand how FMR, despite its low regurgitant volume, has important pathophysiologic consequences and may be associated with poor outcomes. However, the question remains whether FMR is independently responsible for the outcomes and in all circumstances. Several cohort publications were negative,18, 19 stating that FMR was not independently responsible for the poor outcomes observed, suggesting that FMR is a surrogate for another cause of poor outcome, such as comorbidity or worse ventricular alterations not fully captured by the ejection fraction. Also, the contradictory results of COAPT20 and MITRA-FR9 raised further doubts on the link FMR–outcomes. Contradictory survival rates from cohorts originating from the same centre6, 21 and discrepant interaction analyses suggesting that FMR only affects outcome in certain subsets of ventricular size or function or in certain strata of biomarkers11, 22 led to a profound confusion regarding FMR, its assessment, grading, interpretation and impact on outcome. In turn, this confusion leads to considerable FMR undertreatment and to pervasive excess mortality.23 In this context, resolving the FMR conundrum requires new data, to define the risk associated with FMR presence, that clinical trials cannot resolve, and to determine its independent association with outcome in very large cohorts comprehensively characterized. Three such large cohorts5, 24, 25 were reported this year, including that by Pagnesi et al. in the current issue of the Journal. The authors conducted a post-hoc analysis of the BIOSTAT-CHF cohorts which involve worsening or acute heart failure collected in 69 European centres for the 2516 patients enrolled in the index cohort and 1738 patients enrolled in Scotland for the validation cohort. All ranges of ejection fraction were enrolled and MR was marked as moderate–severe (present or absent) without more details and the mechanism and cause of MR were not specified. As usual patients with MR had more frequent symptoms and atrial fibrillation, had lower ejection fractions and larger left ventricles but were more intensely treated. Patients with moderate–severe MR had during follow-up more frequent composite endpoint of death or heart failure hospitalization and also more total and cardiac mortality. Various adjustments including for the BIOSTAT-CHF risk score showed that moderate–severe MR remained independently associated with more frequent composite endpoint events. Although directionally similar, for overall survival, the presence of moderate–severe MR did not reach statistical significance with full adjustment, but cardiac mortality did. Therefore, the study strongly supports the independent link FMR–outcome in the context of worsening heart failure. This observation is fully coherent with the role of FMR in acute pulmonary oedema.26 Conflict of interest: none declared.

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