Does left atrial deformation impact on symptoms and prognosis in functional mitral regurgitation patients with poor left ventricular function?

This article refers to ‘Quantified mitral regurgitation and left atrial function in heart failure with reduced ejection fraction: interplay and outcome implications’ by A. Malagoli et al., published in this issue on pages 694–702. It is a long-standing accepted notion that the presence of some degree of mitral incompetence is going to impact negatively and significantly on symptoms and prognosis of patients with functional mitral regurgitation (FMR) associated with a poor left ventricular ejection fraction (EF) due to ischaemic heart disease.1 The background pathophysiological explanation would be that, in heart failure patients with reduced ejection fraction (HFrEF), even a minor degree of regurgitation will cause a considerable increase in pressure if the atrium is non-compliant.2 Such reasoning fits the more recent acquisition that, when EF is severely depressed, the effective regurgitant orifice area (EROA) is skewed towards a smaller size, and that such smaller EROA, if routinely measured, appears as the strongest independent mitral incompetence determinant of survival after diagnosis.3 Excess mortality, in fact, has been reported to increase exponentially above a certain threshold area (0.10 cm2), with a much steeper slope, for any EROA increment, than in degenerative mitral insufficiency.3 In this issue of the Journal, Malagoli and colleagues move further their investigation addressing the complex interaction between peak atrial longitudinal strain (PALS), taken as an estimate of atrial compliance, and FMR reporting on a prospective study performed in 286 HFrEF patients with a complete follow-up of 4.1 ± 1.5 years.4 During this time period, the primary endpoint (defined as a composite of congestive heart failure hospitalization or cardiovascular [CV] death) occurred in 99 patients (35%). Using a sophisticated spline modelling of the risk by FMR severity, they showed a remarkable graded association between EROA and the risk of CV events (hazard ratio [HR] for EROA per 0.10 cm2 increase: 1.42, 95% confidence interval [CI] 1.19–1.68, p < 0.0001), with EROA ≥0.30 cm2 seemingly associated with CV events regardless of left atrial function (HR 2.34, 95% CI 1.29–4.19, p = 0.005). Interestingly, however, less severe FMR (EROA ≥0.10 cm2) was associated with a dismal outcome only in patients with reduced left atrial function (PALS <14%: 5-year CV event rate 51 ± 4%). Conversely, the risk of events was less when FMR coexisted with a preserved global PALS (5-year CV event rate 38 ± 6%). This different outcome for FMR patients with a comparable, less severe EROA but different PALS should underline, according to the authors, the role of left atrial properties in modulating prognosis in these patients.4 It should be noted that this is not the only study exploring the FMR–left atrial function interaction with respect to CV outcome. Palmiero et al.,5 few years ago, did analyze, in a population of 97 HFrEF patients dichotomized into a mild-to-moderate versus severe regurgitation group, the possible interplay between severity of FRM and the reservoir function, quantified using the atrial total emptying fraction, and the effect of their various combinations on survival. In that study, they showed that survival was significantly lower when FMR was severe and associated with a depressed cavity emptying fraction.5 Relative to that study, the authors of the current paper provide a differently quantified echocardiographic evaluation of left atrial function (PALS), mitral regurgitation (EROA), and heart failure biomarker (B-type natriuretic peptide) encompassing a much larger HFrEF population followed for more than 5 years, coming to aligned conclusions.4 Their findings underline the role of atrial mechanical characteristics in modulating symptoms and prognosis in these patients and suggest that atrial function should be considered in order to improve the selection of those to be proposed for more-than-mild degree percutaneous FMR correction.6 Some perplexities, however, for the authors' interpretation of the results do exist. As also they recognize (see reference #24 of their work), a strong, inverse relation has been described between ventricular global longitudinal shortening (GLS) and PALS,7 due to the fact that atrial volume, in systole, is increasing while ventricular volume is decreasing because of descent of the mitral plane. Thus, such reservoir function can be markedly affected by the inotropic status of the underlying ventricle, not fully reflecting the mechanical characteristics of the atrial cavity. It is true that the authors corrected data for the magnitude of ventricular EF in their patients, but it is well-known that such pump function parameter does not necessarily reflect an equivalent GLS value.8 Thus, it is tempting to speculate that the interaction between PALS and EROA on CV events may rather be a reflection of different ventricular, rather than, atrial properties. Similar reasoning could be applied to the finding that any FMR grade associated with reduced left atrial function portends severe clinical features and dismal outcomes. The atrial reservoir phase takes place during ventricular systole, with two periods identifiable within it: in the first, just following mitral valve closure, there is a relaxation phase that basically modulates flow from the pulmonary veins9; the second phase, with atrial volume increasing more slowly, is dominated by systolic ventricular longitudinal shortening, which causes the descent of the cardiac base, “sucking” blood into the atrium, while simultaneous right ventricular contraction “pushes” blood into the atrial cavity.10, 11 Thus, ventricular shortening is going to potentially impact significantly on atrial deformation, at least in mid-late systole. One way to definitively sort out such conundrum, the one between PALS versus the ventricular contribution to PALS and their combined impact on symptoms and survival in heart failure patients, would be to provide data on simultaneous GLS, but this information was not collected at the time of the study and thus not made available by the authors. Further, PALS is a measurement of wall deformation and not of atrial stiffness. In this scenario, further support to a potentially different data interpretation also comes from the supplementary Table S2 provided by the authors.4 In that Table, left ventricular and atrial volumes are reported for the four groups of patients depicted in Figure 4 of the manuscript. One can notice that both atrial and ventricular cavities appear to be enlarged in the PALS <14% groups, as compared with those patients who exhibit a PALS >14%. This, again, may point toward an alternative interpretation from the one above proposed, one that favours depression in left ventricular contractility, rather than an intrinsic increment in atrial stiffness, in modulating outcome. This consideration comes from the effects that an acute stiffening of the atrial cavity would exert on left ventricular volume as derived from a theoretical prediction (CircAdapt Simulator v1.0.2, available on the web at www.circadapt.org): such a change would impact on modulating atrial and particularly ventricular volume changes in a direction that is opposite to that shown in supplementary Table 2, although it should be recognized that it is always difficult to make predictions according to an acute simulation as compared to a chronic clinical condition. On the other side, we cannot ignore that PALS has recently been shown to be inversely related to peak exercise wedge pressure in a population of heart failure patients with preserved EF12 and that it can even predict exercise capacity in heart failure independently of EF.13 Further, a significant association can be shown between PALS and invasively estimated atrial stiffness in a bunch of patients suffering from atrial fibrillation, studied at rest, immediately before pulmonary vein ablation (Figure 1) (Marino P.N., unpublished data). Figure 1 shows that such relation is negative and curvilinear, with invasively estimated atrial stiffness increasing exponentially for values of atrial strain below the number Malagoli and colleagues propose (14%) as the threshold for excess risk.4 Thus, there may be much more to atrial stiffness within PALS than meets the eye. Recently, in a population of heart failure patients exhibiting a wide range of EF values, we showed that another phasic atrial parameter, linked to atrial stiffness and reciprocal to reservoir, i.e. chamber conduit, is strongly associated with prognosis.14 Conduit was quantified volumetrically as the cumulative net volume difference between three-dimensionally assessed simultaneous ventricular and atrial volumes, from end-systole to just before atrial contraction and normalized to left ventricular stroke volume.15 Such diastolic phasic atrial parameter resulted strongly associated with exercise capacity, as quantified by the 6-min walked distance, and mid-term survival. Although, in that study, the presence of more than mild mitral regurgitation was an exclusion criterion, we were able to demonstrate that a larger conduit contribution to left ventricular filling was associated with a lower pulmonary artery compliance, likely due to a greater atrial pressure pulsatility load and stiffness, suggesting outmost right ventricular haemodynamic burden at rest and, likely, during walk in the enrolled population.15 Although the selection criteria used for the present investigation are not strictly superimposable to the one used for the above study, we think that the message conveyed from Malagoli and colleagues expands further the topic, being of pathophysiological and not simply phenomenological importance. At a glance, looking upon their writing “… the introduction of ‘on-board’ left atrial strain software makes our findings easily applicable in routine practice in order to modify treatment strategies…in…the selection of candidates for surgical or percutaneous treatment of FMR…”,4 it could be contributed that, given the pivotal role of atrial stiffness in modulating symptoms and survival in heart failure patients, we, as clinicians, can no longer afford to forget it about; rather, we should take advantage of the potentials intrinsic to carefully performed atrial phasic function computations to deepen the knowledge of its role, for better prognostic stratification of heart failure patients and prediction of the results of interventions. Conflict of interest: none declared.