https://orcid.org/0000-0002-0412-1083
Abstract
Secondary mitral regurgitation (MR) is the most common and undertreated form of MR, whose contribution to poor prognosis and indications to correction remains under discussion. MR has been characterized into ‘proportionate’ or ‘disproportionate’, based on left ventricle (LV) and regurgitant volumes, whereas ‘tertiary’ MR identifies conditions, in which regurgitation is pathologic per se and actively contributes to LV dysfunction. Echocardiographic and anatomo-pathological studies revealed that secondary MR prompts subtle leaflet maladaptive changes, actively contributing to the dynamic progression of secondary MR. We critically discuss the paradigm shift from secondary to tertiary MR and question the notion that MV leaflets play a passive role in secondary MR. We also review the role of standard transthoracic echocardiography for appraising and quantifying maladaptive MV leaflet changes and LV volumes and call for a more sophisticated and comprehensive imaging framework for classifying MR in future interventional studies.
Introduction
Mitral regurgitation (MR) is the most common valvular heart disease in the developed countries, affecting nearly 200 million of individuals worldwide with a prevalence of 19–22% in patients aged >65 years.1,2 Traditionally, it may be classified as primary (or organic) and secondary (or functional). The mechanism of regurgitation is well-established in primary MR, relying on anatomical abnormalities of the mitral valve (MV) apparatus itself, including leaflets and chordae tendineae. On the contrary, in secondary MR, the mechanism does not depend primarily on leaflets malfunction (which are assumed to be ‘structurally’ normal) but is ‘secondary’ to multiple causes, such as left ventricle (LV) regional wall motion abnormalities following myocardial infarction (MI), global LV dysfunction (due to idiopathic or ischemic cardiomyopathy), and annulus enlargement (secondary to atrial dilatation in patients with chronic atrial fibrillation), which ultimately affect the fine balance between closing and tethering forces.
In primary MR, ‘early’ surgical correction (i.e. before symptoms onset or LV dilatation) improves clinical outcomes, LV remodelling, and life expectancy.3 In secondary MR, valve regurgitation is ‘the tip of the iceberg’ of a complex disease, whereas symptoms and prognosis largely depend on the degree of underlying LV dysfunction.4 In this setting, it is questioned whether reduction of MR severity by surgical or percutaneous procedures reverses (or at least ameliorates) LV dysfunction and may favourably impact on clinical outcomes. In this review, we aim at examining the multiform aspects of secondary MR, discussing its pathophysiological mechanisms and the actual challenges in its evaluation by current imaging techniques. We also discuss the evolving role of mitral leaflets, the current limitations of LV volume assessment and semiquantitative methods for the staging of MR severity, in order to provide a new framework for further interpreting the controversial results of recent trials on transcatheter edge-to-edge MV repair.
Secondary mitral regurgitation: what are the drivers?
Chronic secondary MR includes a range of pathophysiological conditions, of which asymmetric and/or symmetric tethering patterns are the typically recognized pathological substrates,5 representing the end-spectrums of a variety of intermediate phenotypes.
Asymmetric tethering pattern
At one end of the spectrum, there are patients with ischaemic regional wall motion abnormalities, mostly localized in inferior-posterior segments of LV involving the posterior-medial papillary muscle (PM) (Figure 1A). In these patients, LV ejection fraction (EF) is normal or only mild-moderately reduced and the annulus is still normal or only slightly dilated. The systolic outwards displacement of the infarcted wall with the contiguous PM leads to traction of chordae tendineae on the medial half of both anterior and posterior leaflets limiting their motion in systole, with consequent leakage.5
Cardiac MRI findings of asymmetric (A) and symmetric tethering pattern (B). MRI, magnetic resonance imaging; WMA, wall motion abnormalities.
Symmetric tethering pattern
At the other end of the spectrum, there are patients with ischaemic or idiopathic cardiomyopathy, in whom the LV positively remodels and dilates becoming more spherical and hypokinetic (Figure 1B).6 In this clinical scenario, the mechanism of regurgitation is typically multifactorial:
PMs are outwards and downwards dislocated and the traction of chordae on mitral leaflets induces a gap of apposition along with the entire coaptation line.
The mitral anulus dilates and therefore contributes to the regurgitation.
During progressive worsening of LV dysfunction, the intraventricular pressure forces acting on the ventricular surface of leaflets contributing to the closure (closing forces) are reduced. As a consequence, the time needed for the leaflets to reach their apposition is lengthened leading to a significant increase in the pre-coaptation regurgitation.
Importantly, between the symmetric and asymmetric tethering patterns, there is a ‘continuum’ of intermediate stages which are strictly related to the dynamic evolution of LV dysfunction/remodelling and to the impact of medical therapy on MV apparatus geometry.
What is the role played by surgical or percutaneous mitral valve repair?
Patients with secondary MR typically suffer from severe LV dysfunction, multiple comorbidities, and dismal long-term prognosis despite optimized medical therapy.7 Actually, the role of cardiac surgery (MV repair or replacement) in isolated secondary MR remains controversial, typically due to concomitant high surgical risk features and lack of supportive evidence. In a randomized trial enrolling 251 patients with secondary MR, no significant differences in mortality and LV remodelling have been observed between repair or replacement at 2 years, albeit replacement was associated with a lower incidence of recurrent MR.8 Therefore, the surgical correction of secondary MR remains an option in highly selected patient subsets (i.e. those undergoing coronary artery bypass grafting), without overt heart failure (HF) after careful evaluation by the Heart Team.9
Recently, percutaneous edge-to-edge MV repair has been assessed as new treatment option in isolated secondary MR. The Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR)10 and the Cardiovascular Outcomes Assessment of the MitraClip (COAPT) trials11 investigated the role of MitraClip on top of guidelines-directed medical therapy (GDMT) vs. medical therapy alone. While these two trials apparently included the same patient populations with the same disease (secondary MR, not suitable for MV surgery) using the same device (MitraClip), results largely differed, in that only COAPT was able to demonstrate a mortality advantage with the percutaneous treatment. Reconciling these strikingly different results is of paramount importance since it may help unravelling the complex selection process of patients who may prognostically benefit from intervention from those who may only potentially derive symptom mitigation.
May the so-called secondary MR become disproportionate or tertiary?
Severity grading of MR includes both qualitative and quantitative methods, such as EROA and RVol, but does not consider the variability of LV volumes (left ventricular end-diastolic volume, LVEDV) and the degree of LV dysfunction in patients with HF with reduced EF (HFrEF). Thus, Grayburn et al.12 has recently proposed a novel classification of secondary MR according to the relationship between MR severity and LV dilation as ‘proportionate’ (when LV volumes are appropriate to the severity of regurgitation) and ‘disproportionate’ (when LV volumes are smaller than expected to the degree of regurgitation). When MR is truly secondary (being a consequence of LV dysfunction), the magnitude of MR flow is ‘proportionate’ to the LV volumes. Conversely, whether MR is the predominant pathophysiological mechanism, the magnitude of MR is ‘disproportionate’, by exceeding what would be predicted by LV volumes. This innovative framework, though subjected to some criticisms13 and not validated yet on patient-level pooled data of MITRA-FR and COAPT trials, paves the way for a potentially refined selection process for treatment: ‘proportionate’ MR may respond to pharmacological therapies or cardiac resynchronization therapy (CRT) aimed at reducing LVEDV, while patients with ‘disproportionate’ pattern may benefit from interventions (e.g. edge-to-edge MV repair) that reduce regurgitation. In other words, EROA/LVEDV ratio may help to predict the extent of LV reverse remodelling after MV intervention.14
Using this framework, the authors revisited MITRA-FR and COAPT trials and observed that these two trials enrolled different patient populations. Those enrolled in the COAPT trial had a mean EROA of 41 mm2 and mean LVEDV of 192 mL (LVEDV index 101 mL/m2), as shown in Figure 2. Thus, most of the COAPT patients were likely to have a disproportionately larger MR in relation to LV dimensions, therefore, better responding to targeted MV intervention. On the contrary, in patients enrolled in the MITRA-FR, mean EROA and LVEDV were 31 mm2 and 252 mL (LVEDV index 135 mL/m2), respectively. Though an EROA >20 mm2 should be considered severe, the severity of secondary MR was ‘proportionate’ to LV enlargement. Therefore, these patients may better respond to GDMT and/or CRT (aimed at reducing LVEDV) rather than MV repair.
Proportionate vs. disproportionate MR and EROA/LVEDV ratio in MITRA-FR and COAPT trials. EROA, effective regurgitant orifice area; LVEDVI, left ventricular end-diastolic volume index; MR, mitral regurgitation.
Subgroup analyses of the COAPT trial may offer the opportunity to speculate on the potential impact of this new framework on clinical outcomes (Figure 3). The MitraClip procedure in COAPT was associated with lower composite endpoint of 1-year death and HF hospitalization compared to GDMT only among patients with significant LV dilation (LVEDV index >96 mL/m2) and EROA 30–40 mm2 or >40 mm2. Interestingly, in MITRA-FR-like patients (i.e. LVEDV index >96 mL/m2 and EROA ≤30 mm2), the rates of 1-year death or HF hospitalization were similar with MitraClip and GDMT or GDMT alone (27.8% vs. 33.1%, hazard ratio 0.90, confidence interval 0.33–0.43). Therefore, COAPT trial subgroup analyses suggest that there are no beneficial effects of MitraClip on top of GDMT in the MITRA-FR-like subgroup of patients and that EROA/LVEDV ratio may represent a useful tool to select patients who may benefit or not from intervention. Nonetheless, several additional analyses from MITRA-FR and COAPT trials raised the need of further validation of this novel framework.15,16
COAPT subgroups analysis according to LVEDV index >96 mL/m2 and different EROA (≤30 mm2, 30–40 mm2, and >40 mm2). EROA, effective regurgitant orifice area; HF, heart failure; LVEDVI, left ventricular end-diastolic volume index; MR, mitral regurgitation.
In the same year, Carabello coined the term ‘tertiary’ MR to identify a subtype of functional MR which is too severe to be considered only a consequence of LV remodelling, but instead, it actively contributes to LV dysfunction.17 The author hypothesized that most patients enrolled in the MITRA-FR trial may have had pure ‘secondary’ MR, while most COAPT patients were affected by a ‘tertiary’ MR, whose correction would have been beneficial. Both Grayburn and Carabello have to be commended for having defined a novel conceptual framework in the setting of functional MR (nor primary, neither secondary or proportionate but ‘tertiary’ or disproportionate MR). Clinicians may argue that these two entities may simply encapsulate two different stages of the same disease, whereas a severe and more advanced reduction of the systolic LV function results in progressive LV dilatation with lower anterograde (i.e. cardiac output) and retrograde (i.e. regurgitant volume) outputs. However, the intrinsic value of this new framework lies on the need to thoroughly quantify not only regurgitant but also LV volumes and their internal coherence for staging the disease.
Are echocardiography and cardiac magnetic resonance imaging suitable imaging techniques for LV volumes assessment?
Accurate quantification of LV volumes and EF is of paramount importance in the selection of patients who may benefit most from MV intervention. Although transthoracic echocardiography (TEE) is the recommended first-line investigation for valvular heart disease, quantifying LV volumes, and function may be challenging. Indeed, poor acoustic window, need of geometric modelling, and errors caused by foreshortened views or inaccurate border detection represent notable limitations of this imaging technique. One of the main determinants of interobserver variability is operator’s perception of the blood–tissue interface, and the principal discordance regards the presence of trabeculation. The 2015 ‘Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults’ states that volumetric measurements are based on tracings of the interface between the compacted myocardium and the LV cavity.18 However, in the same document, the blood–tissue interface is also recommended.18 There are significant differences in volume assessment whether operator traces the border of LV according to blood tissue interface (i.e. at the tip of trabeculation), or on compact myocardium (Figure 4). Moreover, trabeculations are well visible in diastole while they almost disappear in systole. We noted that the mean value of LV volume using the blood–tissue interface is 95 ± 24 mL, while this value increases up to 145 ± 52 mL when traced on compact myocardium (unpublished data). The latter value is closer to the mean value assessed by cardiac magnetic resonance imaging (MRI), currently considered the gold-standard for the measurement of LV volumes.
The importance of accurate borders detection in 2D echocardiography. LV volumetric measurements based on tracings of borders according to blood/tissue interface (upper panels) or on compact myocardium (lower panels) may differ significantly, as outlined in this case. ED, end-diastolic; ES, end-systolic; LV, left ventricle; LA, left atrium.
Even using 3D echocardiography (3DE), volumes assessment is less accurate and reproducible compared to MRI. Three-DE-derived volumes are underestimated in most patients, because it cannot differentiate between compact myocardium and trabeculae.19 Recently, a new-generation fully automated software based on an adaptive analytics algorithm has been developed for left-heart chamber quantification (HeartModelA.I.; Philips Healthcare, Andover, MA, USA).20 This novel technology appears feasible, fast, and reproducible. Of note, automated default border detection based on the compact myocardium with operator’s adjustments has shown an excellent agreement with cardiac MRI among patients with HF and secondary MR.20
Although universally considered the gold-standard imaging technique for LV volumes assessment, cardiac MRI also suffers from significant limitations. Current guidelines suggest that LV volumes and mass should be quantified according to the same protocol as used for reference range.21 However, PMs and major trabeculations had been excluded by the blood pool and included in the LV mass in pivotal MRI studies detailing normal reference values, while in current clinical practice their inclusion in the blood pool has become the standard approach. Of note, PMs may account for ∼9% of LV mass,22 affecting the final precise volume assessment in some cases.
Recent advancements have shown how the importance of LV volume relies not only on its volume but also on its ‘composition’, as the extent of replacement fibrosis (scar burden) measured by late gadolinium enhancement is emerging as a key factor for proper risk stratification and selection of patients eligible for MV repair.23 Moreover, myocardial scar is a marker of LV contractile reserve and viability and, therefore, a potential predictor of afterload mismatch following MV repair. Even if the exact threshold for clinical decision-making remains unclear, scar burden is independently associated with clinical outcomes24 and should be taken into consideration in the multidisciplinary heart team discussion.
Are echocardiography and cardiac MRI suitable imaging techniques for grading the severity of MR?
Accurate quantification of MR severity is key for the appropriate selection of patients eligible for MV repair. Although 2D colour Doppler echocardiography is usually the first-line test, a more quantitative approach is always needed. However, quantitative parameters (such as EROA and PISA method) holding promises of a more objective and reliable assessment are subjected to interobserver variability, patient’s haemodynamics, leaflet geometry, acoustic window, and applications in elliptical shapes of the regurgitant orifice. The ‘internal coherence’ of the various echocardiographic parameters is of paramount importance in the assessment of LV volume measures and quantitative parameters for MR grading. For instance, the forward stroke volume calculated as the difference between LVEDV and end-systolic volume minus the RVol should correspond to that measured by Pulsed wave (PW) Doppler through the LV outflow tract. In routine echocardiographic practice, the occurrence of these discrepancies is not rare, as demonstrated in Figure 5. Importantly, the lack of echocardiographic consistency has been also pointed out in the COAPT trial.25 Some of 2D echocardiography limitations have been overcome by the introduction of 3D technology, as the 3D vena contracta area method.26 However, no study has implemented the assessment of the internal coherence and consistency of the investigator-reported or centrally appraised 3D parameters for the selection or characterization of the study population.
An example of internal ‘incoherence’ of echocardiographic parameters. The borders of LV cavity are traced in-between the blood–tissue interface and the compact myocardium (A). Despite a good quality of two-dimensional images, the accurate assessment of the hemisphere shell (where aliasing occurs), and the continuous wave Doppler spectrum through the mitral regurgitant jet (PISA method, B), some relevant discrepancies could be noted. Indeed, the difference between end-diastolic and end-systolic volume corresponds to a total stroke volume of 51 mL; the regurgitant volume is calculated equal to 47 mL, which would lead to the unacceptable forward stroke volume of 4 mL. However, the forward stroke volume measured by pulsed wave (PW) Doppler through the left ventricular outflow tract (LVOT) is 36 mL (C), demonstrating the lack of internal coherence of such data. CO, cardiac output; EDV, end-diastolic volume; EF, ejection fraction; ERO, effective regurgitant orifice; ESV, end-systolic volume; HR, heart rate; PG, pressure gradient; PISA, proximal isovelocity surface area; SV, stroke volume; VTI, velocity time integral.
Cardiac MRI may overcome some limitations, quantifying MR with high accuracy and reproducibility through a combination of LV volumetric measurements and aortic flow quantification with phase-contrast velocity mapping. Moreover, advanced applications of MRI as 4D flow cardiac MRI with retrospective valve-tracking method allows to quantify directly the regurgitation at the valve level, though at the cost of higher acquisition time and possible artefacts linked to respiratory motion. Therefore, a self-gated free-running whole-heart 5D flow MRI has been recently developed and tested in healthy volunteers, proving to be a promising time efficient technique and less respiratory motion dependent.27 Despite the growing interest and higher accuracy of cardiac MRI in assessing MR severity and LV volumes, its use is still limited in clinical practice.
Are mitral leaflets truly normal in secondary MR?
The long-held view that the MV leaflets are innocent bystanders in the pathophysiology of secondary MR has been challenged by Dal-Bianco et al.,28 who firstly demonstrated that mechanical stresses imposed on leaflets by PM tethering increase leaflet size and thickness of the spongiosa, with cellular changes suggestive of reactivated embryonic pathways. They called this phenomenon active ‘adaptation’ of tethered valve. Although some concerns still exist about the term ‘adaptation’ which implies a finalistic mechanism attempting at compensating LV dilation and reducing MR, the concept that tethered leaflets may increase their size and thickness over time and secondary MR may be in part ‘organic’ was per se revolutionary, disrupting the paradigm that leaflets and chordae are ‘structurally normal’. Several subsequent studies confirmed these initial observations, demonstrating that insufficient leaflet ‘adaptation’ to annular dilation is associated with greater severity of secondary MR.29,30 In 2017, Beaudoin et al.31 coined the term ‘maladaptive’, suggesting that histopathological changes of mitral leaflets after acute MI lead to an increased valve thickness and stiffness that contribute to increase MR. While leaflets rearrangement may be adaptative in the first stages, excessive leaflets remodelling can lead to fibrosis, finally worsening MR. Of note, angiotensin receptor blockers (e.g. losartan) have been shown to hinder tissue growth factor (TGF)-beta overexpression and to reduce leaflet thickening.32
These studies challenged the traditional belief that secondary MR is exclusively related to LV remodelling and that MR exclusively results from an altered balance of closing and tethering forces, whereas the leaflets are innocent bystanders. It is tempting to speculate that patients with disproportionate or tertiary MR, suffer from a ‘mixed’ MV patho-morphology, both functional and organic at the same time, explaining the ‘disproportionately’ larger MR with respect to LV enlargement and at the same potentially reconciling the concept of disproportionate MR with the tertiary form of MR, whereby mitral leaflet maladaptive changes contribute to MR severity.
Imaging the leaflets: from innocent bystanders to active players in secondary MR
The detection of morphological changes of mitral leaflets remains challenging with current 2D TEE.
Three-dimensional transoesophageal echocardiography (TOE), enhancing superior visualization of the MV complex and accurate measurements of leaflets area, may be useful in this setting. Indeed, an elegant study with 3D TOE found that coaptation area significantly decreased in patients with secondary MR related to the bilateral PMs displacement, with a corresponding increase of leaflet-to-annular area ratio compared with control patients, demonstrating that 3D TOE is able to measure the leaflet’s area.33
A new 3D rendering tool using a freely movable virtual light enhances transillumination and depth by positioning the light beyond the structure of interest.34 In such a way, thicker structures appear less transilluminated than thinner surrounding tissues (Figure 6). Conversely, although this new tool may improve our capability of distinguishing thinner or thicker areas (i.e. rough zone vs. clear zone of anterior mitral leaflets), its usefulness to detect and quantify submillimetre variation of leaflets thickness (through shade changes of transillumination) remains to be established.
![Multimodality imaging techniques for the assessment of MV leaflets changes. (A and B) The appearance of MV leaflets (white arrows) by 2D transoesophageal echocardiography and cardiac MRI. Leaflets thickness might not be accurately detected by 3D echocardiography (C), whereas a new 3D rendering tool (D) using a freely movable virtual light allows to point out thicker structures [i.e. the rough zone (RZ) of anterior mitral leaflet (AML)] as less transilluminated than the thinner clear zone (CZ).](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/ehjcimaging/22/8/10.1093_ehjci_jeab080/1/m_jeab080f6.jpeg?Expires=1747880025&Signature=Nh-lluW2NQqQRAAPtXw-xNuRP-kGYdfjUVrVa2AxD4qLJIHdpcOKQqc1qMyeCPTjMUC4iLS0FJ0hiJ2xwq714H6h5qAT2Ack9uCx2IughanYJyc8LPXLqQwL6krdX23dIWVrJmWOlh5NO9aCSGO2JkJLZaIoKRQ8GN0jiDsBDfs9C8~1UuZ7GvnOkRF7iaHEOQFrF69uhyFW6SsYS5lXdx3SiCQkBPJBmcirbcfAR-1UNh2rBikqlBhKeKGijLvq31JJHzc1mpOt0gv3xicgcsxnp1t0lJYicKAoEo6pGhkuDQSUyDyNDJoygZQ5i0NGPj3RsTJtZLValbtGAGPcfg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Multimodality imaging techniques for the assessment of MV leaflets changes. (A and B) The appearance of MV leaflets (white arrows) by 2D transoesophageal echocardiography and cardiac MRI. Leaflets thickness might not be accurately detected by 3D echocardiography (C), whereas a new 3D rendering tool (D) using a freely movable virtual light allows to point out thicker structures [i.e. the rough zone (RZ) of anterior mitral leaflet (AML)] as less transilluminated than the thinner clear zone (CZ).
MRI has proven to be able to detect changes in MV leaflets, such as leaflet elongation, in hypertrophic cardiomyopathy.35 However, evidence about mitral leaflet remodelling (length and thickness) in patients with secondary MR by cardiac MRI is still lacking (Figure 6) and MRI can neither be regarded as the ideal imaging technique to detect leaflet thickness due to the high speed of closing and opening motion. In this setting, cardiac computed tomography may overcome these limitations, representing a promising imaging technique to detect MV leaflets changes over time. Further studies are warranted to better address this issue, outlining the dynamic evolution of MV leaflets in patients with secondary MR.
Appropriate patient selection and future perspective
Secondary MR is the most common and undertreated form of MR which, when moderate to severe or severe, remains associated with poor prognosis despite GDMT.7 The identification of patients who may benefit most from MV intervention remains controversial. However, the emerging paradigm shift of tertiary MR and an integrated appraisal of LV volumes and MR degree may help identifying the most suitable candidates for intervention (Figure 7). It is important to emphasize that optimization of medical therapy (titrated to the guideline-directed or maximum tolerated dose) over time remains the mainstay in the treatment of secondary MR, reversing adverse LV remodelling and reducing MR severity in up to 40% of patients with secondary MR.36
Multimodality imaging for eligibility assessment of secondary MR for MV repair. TTE, transthoracic echocardiography; TOE, transoesophageal echocardiography; MRI, magnetic resonance imaging; MR, mitral regurgitation; MV, mitral valve; LV, left ventricle.
The results from MITRA-FR and COAPT should be regarded as complementary more than contrasting. The differences in patient’s selection with ‘tertiary’ MR and less advanced LV dysfunction, the run-in period (assessed by a centralized committee) and per-protocol definition of GDMT appropriateness differed significantly between the two trials, leading to the enrolment of patients with truly severe MR despite optimized medical therapy in the COAPT trial.
Therefore, the lessons learnt from MITRA-FR and COAPT trials are multiple.
Firstly, only patients suffering from severe secondary MR despite aggressive GDMT should be considered for MV intervention. Secondly, severe MR should be not merely a consequence but rather a player of LV dysfunction (tertiary MR), being disproportionate to LV volumes. Finally, MV intervention may be still justifiable in highly symptomatic patients despite optimal GDMT as an effective measure to improve quality of life and reduce hospitalization rates.
Conclusions
Secondary MR may be either a player or an innocent bystander of poor prognosis in HFrEF and appropriate patient selection for percutaneous intervention requires a thorough assessment of the mechanisms and role of MR on top of GDMT and alternative treatment options. The relation between regurgitant and LV volumes as well as subtle MV leaflet maladaptive changes prompted by secondary MR and potentially leading to a so-called ‘tertiary’ form (whereby MR per se contributes to LV dysfunction) have received attention to increase the likelihood of identifying more precisely patients in whom a prognostic benefit from intervention can be expected. Standard TEE has well-known pitfalls and suffers from limited reproducibility in assessing LV volumes and the degree of MR. A more advanced and integrated appraisal of both LV volumes and MV leaflet morphology than the one obtained with standard TEE, including routine use of enhanced 2D and 3D echo software-based image reconstructions and/or more liberal use of MRI is warranted in future studies. The borders between secondary and tertiary MR remain undefined and only a thorough characterization of LV and MV parameters in the setting of interventional studies may pave the way forward.
Conflict of interest: F.F.F. has performed several talks supported by Philips, outside the submitted work. M.V. reports grants and personal fees from Abbott, personal fees from Chiesi, Bayer, Biotronik, Daiichi Sankyo, and Amgen, grants and personal fees from Terumo, personal fees from Alvimedica, grants from Medicure, grants and personal fees from Astrazeneca, personal fees from Biosensors, personal fees from Idorsia, outside the submitted work. The other authors have nothing to disclose.
References
Author notes
Antonio Landi and Francesco Fulvio Faletra authors contributed equally to the study.
