The most frequently used tool for mitral regurgitation (MR) quantification in clinical practice is “eyeballing” of the colour flow jet area to differentiate between mild and severe MR [1]. This practice is primarily explained by its ease of use. However, it seems inadequate to solely use a qualitative diagnostic parameter to distinguish between mild, moderate, and severe MR [2‐5]. As mentioned in recent recommendations, “eyeballing” of the MR jet area is misleading [3, 5, 6]. This is caused by its variations depending on ultrasound settings (Fig. 1), the different display of the jet area in respective sectional planes, and the haemodynamic variations influencing MR dynamics. In consequence, recent papers had eliminated this method in the respective tables [6, 7]. The key point statements—“The colour flow area of regurgitant jet is not recommended to quantify the severity of MR. The colour flow imaging should only be used for diagnosing MR. A more quantitative approach is required when more than a small central MR jet is observed” [3]—emphasize the necessity of a definite quantitative approach for grading MR severity.

At the same time, semi-quantitative and/or quantitative parameters, such as the 2D-PISA (proximal isovelocity surface area) method, are used by a minority of primary care physicians and cardiologists [1], whereas in clinical trials, it is the most frequently used method for MR quantification [8‐11].

Although recent recommendations describe the numerous limitations of the 2D-PISA method, making its use difficult, one key point message remains, namely “When feasible, the PISA method is highly recommended to quantify the severity of MR” [3]. However, the exact way of measuring of the 2D-PISA radius is unclear, as illustrated in Fig. 2. In the recent guidelines [5] “The radius of PISA is measured from the point of color Doppler aliasing to the VC (vena contracta)”. However, the 2D-PISA radius is illustrated in this recommendation [5], in the first description of the method [12], and in several other references [13] from the proximal convergence area to the ostium of the regurgitant orifice. This discrepancy is not clearly analysed in the literature [5, 13‐15]—especially using modern colour Doppler technologies. Also, the impact of MR jet orientation is being debated controversially when using the 2D-PISA method. While some recommendations advise the use of the 2D-PISA in both central and eccentric jets [3, 16], others advise caution [15].

These two mainly used diagnostic features—the colour flow jet area and the 2D-PISA method—are complemented by additional semi-quantitative parameters, which eventuate in the “integrated approach” of MR quantification [3, 5, 6, 16]. However, all these semi-quantitative parameters have their limitations and can only be used in certain circumstances [13, 17‐19]. A summary of the strengths and limitations of semi-quantitative parameters for grading of MR severity and the conditions when to apply or not to apply the respective parameters is particularized in Table 1. Considering the methodological challenges of the integrated approach, several concerns of semi-quantitative grading of MR severity should be considered to reduce the inter-observer variability to characterize more precisely and objectively MR severity. The dynamic nature of MR—especially with respect to loading conditions—cause a variability of MR quantification in clinical practice [20‐22]. Thus, especially in secondary MR (SMR) recommendations favour the approach of MR assessment at compensated stage [16].

The assessment of MR and the grading of its severity remain challenging today. It is the objective of this work to present tools for an in-depth analysis of the MR, taking practical, methodological, and pathophysiological aspects into consideration. To improve diagnostic conclusiveness the quantitative approach of MR assessment by determining left ventricular (LV) total and effective stroke volume (LVSV_tot, LVSV_eff), regurgitant volume at the mitral valve level (MV_RegVol) and regurgitant fraction (RF) is highlighted.

A standardized workflow during the echocardiographic examination and the patient`s visit is necessary to ensure a reproducible and verifiable MR assessment as well as documentation of treatment effects in MR patients. Patient`s characteristics and clinical parameters must be considered for therapeutic decision-making. Indexing of several echocardiographic parameters is based on body height, body weight, and surface area. Systemic blood pressure enables estimation of LV afterload. Clinical symptoms and their progression as well as alterations of echocardiographic parameters with disease progression are important to decide the necessity of therapeutic interventions. At last, age and comorbidities are not influencing MR severity, but are important to estimate the individual patients’ risk. Multiple factors cause differences in MR severity in the same patient at different time points, e.g., cardioversion of atrial fibrillation (AF) into sinus rhythm, resynchronisation therapy in patients with left bundle branch block (LBBB), optimized medical treatment (OMT) in heart failure, or revascularization in myocardial ischemia. To ensure comparability of echocardiographic investigations MR assessment should be performed according to recent recommendations at compensated stage [16].

The echocardiographic examination should consider and interpret the clinical symptoms, and the individual patient`s factors in relation to the presumed valvular defect (Figs. 3, 4). After qualitative MR detection by Doppler techniques, the next diagnostic steps by echocardiography should be the assessment of mitral valve (MV) morphology, LV wall thickness, left atrial (LA), and LV volume as well as LV shape and remodelling, prior to grading MR severity (Figs. 3, 4). Thereafter, a semi-quantitative MR assessment is advised, which should be followed by a quantification of MR severity, if moderate or severe MR is being suspected, or if severity of MR remains unclear (Fig. 4). Every changes of MR severity documented by repetitive standardized echocardiography should be noted to enable reliable conclusions about the respective treatment effects. Figure 5 depicts a recommended timeline for performing echocardiographic examinations in patients with significant MR who are considered for interventional/surgical treatment of MR.

Identifying a causal relationship between clinical symptoms and MR might facilitate the interpretation of echocardiographic results in MR patients. However, symptoms as well as echocardiographic findings depend on chronicity of the disease progress. Acute MR is normally linked to severe symptoms, smaller LA and LV cavities, and severe PH, whereas chronic MR is linked to mild symptoms, larger LA and LV cavities, and different secondary PH severity. Due to this pathophysiological complexity, all possible morphologic variations of LA and LV size can be observed in clinically relevant MR.

If MR is qualitatively detected by Doppler techniques—e.g., colour flow Doppler—MV morphology should help differentiating between primary MR (PMR) and secondary MR (SMR) [29]. This classification focusses on morphological defects of the MV apparatus (PMR) and on secondary MV alterations induced by underlying LV diseases. Thus, structural involvement of the MV apparatus characterizes PMR and LV dilatation and/or LV dysfunction SMR. Pathologies of the leaflets or alterations of the intricate anatomy of the MV apparatus are causes of PMR, failure of MV leaflet coaptation due to MV annulus dilatation, increased leaflet tethering, and/or papillary muscle (PM) restriction are causes of SMR [3‐6, 30, 31]. Furthermore, Carpentier’s classification scheme according to leaflets mobility [32] considers functional aspects of the MV leaflets.

The pathophysiological understanding of cardiac alterations in MR requires a morphological characterization of the cardiac cavities [3‐6, 16]. Both, PMR and SMR, impose a volume load on the left ventricle and the left atrium. LV dilatation increases MV tethering forces, while LV dysfunction reduces MV closing forces, both driving factors of SMR [33]. SMR resulting from predominant mitral annular dilatation is increasingly being recognized as SMR induced by atrial remodelling [34]. The volume load in chronic PMR and SMR further aggravates LV dilatation to accommodate for the MV_RegVol and to maintain LVSV_eff. LV function is preserved in the compensated state in PMR, but declines in a decompensated condition. In the decompensated state, MV_RegVol itself is a pathophysiological driver that contributes to the disease progress with concomitant increase of LV end-diastolic pressure (LVEDP) and secondary pulmonary hypertension (PH) [35, 36]. LV ejection fraction (LVEF) overestimates LV function in MR. Forward LVEF = LVSV_eff/LV end-diastolic volume (LVEDV) seems to represent more reliably LV function than global LVEF in MR [37, 38]. Hence, MR severity relative to LV remodeling has been proposed [16, 39, 40]. In consequence, LV function, LV remodelling, and global haemodynamics often differ between PMR and SMR. Thus, LV wall thickness, LV mass, LV mass index, LV diameter, LV volume, LVEF, as well as LA volume and LA volume should be measured by echocardiography to characterize LV geometry, e.g., concentric remodelling, and concentric and eccentric LV hypertrophy [41]. Relative wall thickness (RWT) and LV mass should be measured using the posterior wall. Considering clinical symptoms and chronicity of the underlying diseases in relation to the specific echocardiographic findings, an extended MR classification is proposed for PMR and SMR patients. Five subtypes can be differentiated in PMR (Table 2). Furthermore, seven subtypes can be differentiated in SMR (Table 3) with respect to symmetric LV remodelling, asynchrony of LV contraction, regional myocardial injury, asymmetric LV hypertrophy, LV stiffening, and LA remodelling [3, 5].

Thus, one target of paramount importance is to characterize cardiac remodelling due to MR effects, which implies the specific assessment of LV [43‐45] and LA geometry by echocardiography [46]—especially in SMR patients [3, 5, 6]. Despite recent technical improvements in echocardiography and automated features to analyze LA and LV volumes and function, conventional 2D echocardiography remains the current standard and enables the assessment of relevant cardiac parameters as illustrated in Table 4. Linear internal 2D measurements of LV diameters and LV wall thickness as well as LV volume measurements by 2D planimetry are still used in clinical practice [5, 41, 47]—especially for calculation of LV mass [41]. 3D approaches for LV mass determination are preferably recommended [48]. The sphericity ratio and sphericity index, interpapillary muscle distance, the anterior–posterior and medial–lateral PM displacement, and the length between the PM bulges and the respective contralateral MV annulus should be considered for characterization of LV remodelling [3, 49‐51]. Furthermore, LV remodelling with disease progression or reverse LV remodeling during treatment can be assessed by monitoring LV geometry [3, 51]. LA volume measurement by 2D planimetry of the maximum LA area in the 2- and 4-chamber view (2-ChV, 4-ChV) or using 3D echocardiography is preferred [48]. The progression of LA and LV volumes and reduction of LVEF during follow-up examinations are helpful to determine haemodynamically significant deterioration even in MR patients classified as clinically not severe.

The second target is the analysis of MV morphology by echocardiography. Due to the complexity of the MV apparatus, 3D image acquisition has become an indispensable tool of echocardiographic MV assessment [48, 52‐55]. However, conventional 2D echocardiography enables the measurement of specific parameters characterizing pathologies of MV morphology. MV degeneration can be identified by the presence of intensified echo-densities due to thickening and calcification of the MV annulus [42]. MV prolapse is characterized by systolic displacement of a leaflet by ≥ 2 mm overriding the annular plane into the LA [3, 52]. Rupture of the primary chordae, or ultimately of a PM, causes flail of the leaflet into the LA and is usually associated with severe MR. Analysis of MV involvement in endocarditis should include size of vegetations, presence of abscesses, aneurysms, or perforations [56]. Congenital MV defects, e.g., clefts, can be uncovered in the 3D TOE, favouring definitively this modern technology [55]. MV deformation due to LV remodelling in SMR should be assessed by measurement of MV annulus, coaptation distance/gap, coaptation length/height, as well as coaptation depth and tenting height (Table 5) [3, 5, 57]. The tenting area (area between the MA and the leaflets during systole) of ≥ 2.1 cm² is a pathologic finding due to tethering in SMR [3‐5]. MV analysis in SMR should be completed by the assessment of the anterior/medial and posterior/posterolateral tethering angle (Table 5) [3, 5]. As pathophysiology of MR is a constant and complex interplay between initial pathology and further propagation of the disease by volume overload, coexistence between PMR and SMR can be observed and should be labeled as mixed origin.

The echocardiographic workflow of grading MR severity (Figs. 3, 4) starts with a semi-quantitative MR assessment and serves two goals. First, all non-severe MR should be detected, preventing unnecessary and time-consuming further evaluation. For example, when sinus rhythm is present, an a-wave dominant inflow pattern into the LV using Doppler interrogation above the MV excludes severe MR. Also, a dominant inflow during systole from the pulmonary veins into the LA cannot be observed in severe MR. Finally, a normal LA volume is not found in chronic severe MR. These and other semi-quantitative parameters, along with their strengths, limitations, and appropriateness are listed in Table 1. In-depth quantitative evaluation should be initiated in cases if MR classification remains unclear.

The quantitative approach is based on the determination of the individual RF. This parameter is included in all current recommendations [3, 5, 6]. RF relies on the determination of LVSV_tot and LVSV_eff. The absolute value of MV_RegVol should always be interpreted with respect to LVEDV. It is obvious that the amount of MV_RegVol is much more important in small hearts than in larger hearts, which can be impressively illustrated by interspecies comparisons (Fig. 6). In consequence, haemodynamic conditions can be characterized by plausible LVEDV, LVEF, and LV forward stroke volume (= LVSV_eff). Determination of MV_RegVol by the 2D-PISA method alone was associated with significant overestimation of MR_RegVol as documented in recent transcatheter MV repair (TMVR) trials [10, 58, 59] and further MR outcome trials [60].

Calculation of RF is based on the measurement of LVEDV and LV endsystolic volume (LVESV) as well as LVSV_eff and MV_RegVol to estimate cardiac output (CO) and cardiac index (CI) by echocardiography. Practical tips to avoid pitfalls when determining cardiac volumes—especially LVSV_tot, LVSV_eff, and right-ventricular (RV) stroke volume (RVSV_eff), are listed in Table 6. The practical approach to check Doppler measurements of RVSV_eff by a plausibility cross-check is illustrated in Fig. 7. However, this concept is still not validated by prognostic data [2, 3, 5]. Compared to cardiac magnetic resonance (CMR) tomography, a significant underestimation of LV volumes by echocardiography has been reported [63]. Furthermore, over- and underestimation of LV volumes in humans [64] and phantoms [65, 66] have been described comparing different imaging methods, e.g., native 2D- and 3D echocardiography, contrast echocardiography, CMR, and computed tomography. Recently, conclusive LV volume assessment by 2D echocardiography was illustrated if image quality is adequate [67‐70]. The differences in LV volumes between 2D echocardiography and CMR can be minimized by triplane, 3D-, and contrast echocardiography [71, 72]. A Doppler echocardiographic approach to calculate LVSV_tot by the LV filling volume has been proposed in recent recommendations using MV diameter in the 4-chamber view and the transmitral velocity time integral (VTI) at the level of the mitral annulus [2, 3, 5]. However, this approach seems to be error-prone due to the non-circular shape of the MV annulus.

LVSV_eff in “pure” MR can be determined by Doppler calculations using cross-sectional area (CSA) or diameters of the LV outflow tract (LVOT) and the corresponding pulsed wave (pw) Doppler velocity time integral (VTI) [2, 3, 5]. In patients with combined aortic valve disease, LVSV_eff assessment is more complex, because Doppler calculations of LVSV_eff should be performed using the CSA or diameter of the RV outflow tract (RVOT) and the respective pw-Doppler VTI to assess RVSV_eff, which corresponds to LVSV_eff, if no or only mild pulmonary regurgitation is present. However, RVSV_eff measurement is challenging due to the variable anatomy of the RVOT and the additional time needed for precise measurements.

The problem of incongruent haemodynamic measurements in MR patients is highlighted by the recently introduced terms “proportionate” and “disproportionate” MR [40, 73‐75]. The concept of proportionality between blood flow and orifice areas can be illustrated by the continuity equation determining effective orifice area in patients with aortic valve stenosis (AS) [36, 76]. The same principle of proportionality can only theoretically be applied to the calculation of the MV_RegVol (Fig. 8), because MV_RegVol cannot be practically measured by pw-Doppler techniques due to methodological limitations. However, a plausibility cross-check of LVSV_tot, LVSV_eff, MV_RegVol,CO, and CI can be performed independently of the method used for determination of these parameters, because proportionality is a prerequisite between EROA and MV_RegVol. The usage of the continuity equation for MV_RegVol determination is impossible due to the high transmitral velocities of regurgitant flow at the level of the mitral annulus, the EROA changes of the valve during the systolic time interval, and the deceleration of flow velocities between EROA and the mitral annulus level. Because of the rheological need of proportionality between EROA and retrograde volume flow or flow velocities, the term “disproportionateness” [40, 73‐75] can only be interpreted as a characterization of SMR severity in relation to the impaired LV function. However, the potential therapeutical benefit of MR treatment in relation to heart failure cannot be described by the disproportionality between LVEDV and EROA, because these parameters are proportionally interrelated at a defined LVEF (Fig. 9).

MR severity can be assessed as mild or moderate in heart failure patients at rest during compensated stage with OMT. However, this MR characterization at rest might not describe the individual risk of re-decompensation. Thus, in these cases, haemodynamic impairment should predominantly be documented by increase in SMR severity during mild-to-moderate dynamic stress testing to support this hypothesis [77, 78]. Early treatment of SMR is comprehensible during these conditions because of the potential for reverse LV remodeling and prevention of further deterioration of LV function, which should be documented by prospective trials.

The analysis of MR severity has become more and more important with respect to therapeutic options for MR treatment. The grading of MR severity by “eyeballing” and the 2D-PISA method is common in clinical practice, but it often leads to incongruent results with a high inter-observer variability. In addition, the dynamics of MR due to volume conditions, heart rhythm, and respective medical treatment require a high level of standardization in echocardiography. However, echocardiography allows for reliable assessment of LVSV_tot, LVSV_eff, MV_RegVol, and RF in MR patients. Prerequisites are verifiable documentations, respective technical skill, and plausible measurements. The present proposal provides a “new” haemodynamically oriented workflow, which integrates a detailed MR classification scheme, considering the clinical complaints, the chronicity of the disease process, the MV morphology, and the echocardiographic parameters characterizing LA and LV remodelling. The essential point to note is the integration of a quantitative assessment of MR severity into the recent “integrated approach” to provide haemodynamic plausibility and to avoid inconsistencies of echocardiographic measurements.