Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence that approaches that of bicuspid aortic valve and is estimated to occur in between 0.6 and 2.4% of the population (1, 2). MVP has been the leading cause for severe primary mitral regurgitation (MR) requiring surgery in western countries for five decades (3). Mitral valve repair can be achieved in most patients, improving symptoms and restoring life expectancy when surgery is performed before left ventricular (LV) systolic dysfunction, which remains the ultimate complication of organic MR (4), the first cause of post-operative mortality (5) and the hinge point of the highly debated optimal timing for surgical correction. Severe degenerative MR (DMR) management is a controversial topic between defenders of a traditional symptom waiting approach (6) and supporters of earlier surgical strategies (7, 8). The latter note the challenge of early detection of LV impairment in the presence of severe MR-related altered loading conditions (9, 10), the high incidence of unexpected post-operative LV dysfunction despite normal preoperative LV parameters and observational data reporting restoration of outcome after early repair (11–13). In this context, both US and European guidelines rely on clinical and echo triggers to determine the timing for surgery (14, 15), noting that the post-operative outcome of symptomatic patients (16) and of those with preoperative decreased LV ejection fraction (EF) (10) or increased LV end-systolic diameters (LVESD) (9) might not be optimal. Therefore, the aforementioned guidelines open the door for earlier surgical strategies as class IIa indications in patients with no symptoms and normal LV echocardiographic parameters (14, 15) provided that repair is feasible in a high volume Heart Valve Center. However, European guidelines mention left atrial (LA) dilation as an additional condition (15), underlining the current ambiguity surrounding primary MR management. This controversy has prompted cardiologists to search for new indicators of earlier evidence of LV systolic dysfunction in patients with severe DMR to refine surgical timing in asymptomatic patients with normal classic LV echographic markers (17–20). Among those, we tested the hypothesis that in the presence of severe DMR, alterations in forward LV ejection markers, specifically LV outflow tract velocity-time integral (LVOT_TVI) and stroke volume index (SVi), could represent simple and reproducible indicators of early LV systolic dysfunction, helping risk stratification and decision-making.

Our study including 198 patients with MV repair for severe DMR due to MVP showed that (1) post-operative LV systolic dysfunction occurred in 11% of all patients and in 5% of asymptomatic patients despite normal preoperative classic echocardiographic LV parameters; (2) LVOT_TVI and forward SVI were identified as independent risk factors for post-operative LV dysfunction and appeared to be stronger predictors than classic clinical and echocardiographic markers, particularly LVEF; and (3) thresholds of 15 cm for LVOT_TVI and 31 ml/m² for forward SVI could be early indicators of latent LV dysfunction, helping risk stratification and decision-making.

In the absence of randomized trials, DMR due to MVP has nourished a passionate controversy around the optimal timing of surgical indication in asymptomatic patients without signs of overt LV dysfunction for more than two decades. In this debate, supporters of early strategies (13, 23, 28–31) are facing guardians of the historical conservative approach (6, 32). The so-called watchful waiting approach argues that close follow-up until the occurrence of overt symptoms or patent LV dysfunction is not associated with outcome penalty based on two observational studies including small populations with likely moderate MR attested by low LV volumes (6, 32). In contrast, early surgical correction of DMR is supported by profuse observational studies, which reported a strong association between preoperative severe symptoms, decreased LVEF (16), increased LVESD (27), occurrence of AF (33) or pulmonary hypertension, and adverse outcomes both under conservative management and post-operatively (8). In addition, early repair has been associated with LA and LV function preservation (7, 8, 12, 18, 34), better post-operative outcomes than the conservative approach after propensity score matching (13, 29, 30), and restoration of normal life expectancy (35).

LV systolic dysfunction is the ultimate adverse consequence of primary MR and the first cause of post-operative mortality (5, 34). As such, its prevention remains the primary target of DMR treatment. In the compensated stage of chronic MR, LV remodeling is indeed the compensatory response to volume overload, which promotes extracellular matrix disturbances, including dissolution of collagen fibers and rearrangement of myocardial fibers. The transition to the decompensated stage of chronic MR is promoted by a reduction of the sarco-endoplasmic reticulum Ca²⁺ATPase2, which is also referred to as SERCA 2, and an increase in the secretion of matrix metalloproteinases that initiates matrix proteolytic activity, cell apoptosis and ultimately impaired myocardial contractility (4). Preservation of LV systolic properties by eliminating volume overload “on time” therefore appears to represent the challenge in DMR management. However, assessment of LV systolic function by traditional echocardiographic indices is obscured by the modified loading conditions induced by MR. Classic markers, such as LVEF and LVESD, are pertinent indicators of patent LV dysfunction when altered (9, 10). However, these markers suffer from low sensitivity in the detection of early LV systolic impairment, which might already be present despite normal preoperative values and is subsequently unmasked post-operatively. This phenomenon is referred to as the so-called unexpected post-operative LV dysfunction (27).

Consequently, efforts have been focused on defining new surgical signals with the common objective of preserving LV function, but none have been fully validated to date. Myocardial deformation has been investigated (36), and patients with post-operative LV dysfunction have been shown to have alterations in preoperative global longitudinal strain (GLS). Although GLS seems to be more sensitive than LVEF to detect patients with LV dysfunction in severe MR, it is limited by the need for high-quality images, imperfect sensitivity and variability of GLS thresholds from one echo manufacturer to another. The detection of diffuse myocardial fibrosis by T1 mapping in MRI is currently the subject of active ongoing research and seems promising (37, 38). However, MRI suffers from its lower accessibility than TTE in routine practice. Upstream of LV parameters and mitral valve, LAVI was reported as an independent risk factor for events in patients under conservative treatment (39). However, preoperative LA remodeling is physiologically connected to the occurrence of AF and its dismal consequences both under conservative management and post-operatively (31, 40, 41). In the absence of new effective markers, current guidelines still rely on classic parameters but acknowledge their limitations and open the door for early strategies in asymptomatic patients without Class I signals as reasonable Class IIa indications (14, 15). It is however conceivable that within this subset of asymptomatic patients with normal LVEF and without extreme cavity remodeling, some could benefit from watchful waiting, whereas others should promptly undergo surgery. In this context and in an attempt to refine risk stratifications, we investigated the impact of forward flow indices in predicting the risk of post-operative LV dysfunction in DMR. Indeed, in the presence of MR and despite volume overload, global LV afterload does not increase at variance with aortic regurgitation (AR) due to the double outlet (42), and LV ejection is distributed between forward and backward flow. Forward flow in the setting of MR partly reflects the ability of myocardium to eject forward against arterial afterload instead of regurgitating backward in the low-resistance LA. As such, one can assume that markers of forward flow better reflect LV intrinsic systolic performance than LVEF and LVESD, which implicitly integrate both antegrade and retrograde streams and may overestimate LV systolic function in case of severe MR. In our study population of patients who all benefited from surgical mitral repair, the traditional impact of LVEF and LVESD in predicting post-operative LV dysfunction were actually supplanted by two forward flow indices which, decreased values could be pertinent indicators of systolic dysfunction at an early stage. LVOT_TVI and forward SVi were thus strong determinants of post-operative LV systolic dysfunction independent of all known risk factors for outcome. Importantly, all cases of unexpected LV dysfunction could have been detected by alteration of either one of these factors. These data are congruent with a previously published index of LV performance using LVOT_TVI in combination with LVESD, which suffered from mixing forward and backward markers (20). Forward LVEF did not reach significance when considered as a continuous variable but did so when the threshold of 30% was considered, which is more restrictive than the previously reported value of 50% (26). Forward LVEF has been identified as predictive of a composite criterion combining MV surgery and post-operative LV systolic dysfunction among patients with severe primary MR and normal ejection fraction (26). This parameter appeared less robust in our data for unclear reasons but might be related to a lack of power or technical issues. LVOT_TVI is indeed a surrogate for stroke volume (SV) that is easy to obtain in routine practice with low skill requirements in contrast to forward SVI and forward LVEF. Both of these parameters indeed require the tricky measurement of LV outflow tract diameter, the squared value of which magnifies any inaccuracy in its recording. In addition, forward LVEF requires LV tracing and perfect apical views. Despite reflecting the same physiologic concept, the increased robustness of LVOT_TVI observed in our study population could be the consequence of such methodological matters.

In patients with severe DMR, forward flow parameters could represent pertinent indicators of intrinsic LV performance, and alterations in these parameters could serve as earlier markers of latent LV dysfunction compared with conventional echocardiographic indices. Among these parameters, LVOT_TVI appears to be the most robust and could be used as an easy recording tool in routine practice for risk stratification, thereby refining surgical indications in patients with no Class I or IIa indications.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by APHM Assistance publique des Hopitaux de Marseille, RGPD: 2019-48 (please see Supplementary files). The patients/participants provided their written informed consent to participate in this study.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.