Diagnosis and Management of Ischemic Mitral Regurgitation: Evidence-Based Clinical Decision Making at the Point of Care

Abstract

Anatomical, functional, and pathophysiologic mechanisms of ischemic mitral regurgitation (IMR) are markedly different from the primary mitral regurgitation. The older and ubiquitous cutoff of EROA (effective regurgitant orifice area) and Rvol (regurgitant volume) for IMR has been reinstated in the new guideline after a brief hiatus. There had always been a lack of good-quality evidence for its introduction for guiding IMR severity in the previous guideline, and we still do not have quality evidences that could justify its reintroduction. Unlike primary MR, IMR is usually associated with reduced ejection fraction. Therefore, it appears unrealistic to keep the similar cutoff for primary MR and IMR. The cutoff of severity can be modified according to projected values of Rvol normalized to ejection fraction and EROA normalized to Rvol. In addition, the treatment outcome in these patients is determined by factors (left ventricular dyssynchrony, annular dilatation, tenting area, tenting height, tenting volume, and myocardial viability) other than the simple grading. In this review article, a series of graph have been constructed from the numerical data derived from the literatures on IMR to depict the relationship between EROA, Rvol, left ventricular end diastolic volume, and ejection fraction in order to obtain a reasonable projection formula for EROA and Rvol. Furthermore, a management algorithm has been proposed for patients with IMR undergoing coronary artery bypass grafting based on echocardiographic predictors that influence the postoperative outcome.

Keywords

coronary artery bypass grafting ischemic mitral regurgitation intraoperative transesophageal echocardiography cardiac surgery cardiac anesthesia

Introduction

Ischemic mitral regurgitation (IMR) is a type of secondary MR due to coronary artery disease. The incidence of moderate to severe IMR is found in around 17% of patients after myocardial infarction.^1-3 Chronic reduction in blood supply to the myocardium in coronary artery disease induces functional and structural changes in the mitral valve apparatus and the left ventricular (LV) geometry. An inadequate coaptation of the mitral leaflets despite normal leaflets and chordal morphology results in mitral regurgitation. The position of mitral leaflet during systole is decided by the dynamic relationship between the 2 opposite forces.⁴ Tethering force is exerted by the chordae and the papillary muscles while closing force is exerted by increasing the LV pressure. The equilibrium between these 2 forces decides coaptation and the leaflet position. The apical displacement of the leaflets is due to increased tethering force and/or reduced closing force. Similarly, the atrial displacement of the leaflet is due to increased closing force and/or decreased tethering force.⁵ The outward or inward displacement of the papillary muscles is responsible for augmentation or reduction in tethering force. Tethering of the leaflet is modulated by papillary muscle dysfunction, LV dilatation, and infarction site. Dilatation and remodeling of the LV at the site of papillary muscle attachment is the major determinant of tethering as compared with the global dilatation. Papillary muscle dysfunction tries to attenuate the severity of tethering and thus reduces the severity of MR. The change in shape of mitral annulus and annular dilatation may contribute to MR. A normal saddle-shaped mitral annulus becomes circular in ischemic heart disease and thus contributes to the development of MR. The role of annular dilatation is less clear. It coexists with LV dilatation and by itself rarely causes MR.⁶ However, in the presence of the leaflet tethering, annular dilatation augments the severity of MR. A synchronous increase in the LV contractility increases the closing force and, thus, decreases the severity of MR. The simultaneous arrival of action potentials to both the anterolateral and posteromedial papillary muscles is essential for initiation of simultaneous contraction of both muscles for perfect coaptation. Whenever QRS is prolonged due to left bundle branch block or ventricular dilatation, there is papillary muscles dyscoordination.⁷ Subsequently, the leaflets do not move together during the coaptation process resulting in MR. Furthermore, there is loss of sphincteric contraction of the posterior mitral annulus due to the poorly coordinated contraction of the basal LV musculature. Finally, the rate of rise in LV pressure (dp/dt) is also affected by dyssynchronous LV contraction, which reduces the closing force and aggravates the MR.

The recent guideline opines that the lower cutoff would bring more patients in severe MR category and they would end up in getting unnecessary treatment.⁸ If we continue to follow the current existing cutoff to define the severity of severe IMR, we would never ever get patients who could be clubbed in the severe IMR category. There is a high probability that we would deny adequate treatment to a large number of patients with severe IMR. Though guideline has opined to lower the cutoff of EROA (effective regurgitant orifice area) and Rvol (regurgitant volume) in low flow states, it has not provided the definition of low flow state in terms of cardiac index and LV ejection fraction. Furthermore, the low flow state cannot be quantified accurately in MR. This confusion needs to be addressed to facilitate prudent perioperative clinical decision making. Surgical treatment of severe IMR along with coronary revascularization is inextricably linked with the prognosis of the patients. If prognosis remains poor in all grades of MR, then surgical treatment should not be offered in severe IMR also. Integrative approach may not be ideal in the intraoperative period, where quick decision making is the need of the hour. In this review, we have synthesized and summarized the evidences related to MR correction with concomitant coronary artery bypass grafting (CABG) to facilitate the perioperative decision makers.

Diagnosis and Quantification of Ischemic Mitral Regurgitation

Traditionally, mitral regurgitation has been graded as mild, moderate, and severe, both qualitatively and quantitatively, irrespective of etiologies.^9,10 However, this classification is an oversimplification, especially when etiologies and ejection fraction have been kept out of its ambit. Genesis of IMR is strikingly different from the genesis of primary MR.^11-15 Primary MR results from structural deformation in the mitral valvular apparatus and usually begins with a normal LV ejection fraction and internal dimension. In contrast, IMR usually begin with a reduced LV ejection fraction and larger LV inner dimension.¹⁶ Additionally, MR is a dynamic entity and severity may vary with change in systemic vascular resistance, systemic blood pressure, and heart rate that can be modulated by drugs, anesthesia, and exercise.^17-19 IMR usually progresses in a vicious circle.^20,21 Rvol induced increase in left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) leads to further LV dilatation, annular dilatation, and papillary muscles displacement. Additionally, higher filling pressure in the presence of reduced LV ejection fraction leads to a smaller regurgitant volume. Furthermore, in the presence of the crescent-shaped regurgitant orifice in secondary MR, there is always a possibility of underestimation of EROA by Doppler-derived flow convergence method. The grade of MR may vary with changing hemodynamic, especially in patients at the threshold of mild MR to moderate MR and moderate MR to severe MR.²² Intraoperative decision making gets further complicated in presence of anesthetic agents. A reduction in systemic vascular resistance and cardiac contractility alters the grade of MR.

We searched PubMed using keywords functional/secondary/ischemic MR and selected only those studies for construction of graphs that provided numerical values of EROA, Rvol, EF, LVEDV, and LVESV. If the Rvol numerical value was not mentioned in severe IMR category, then we derived it by using numerical values of LVEDV and LVESV and assuming 50% regurgitant fraction. For moderate IMR, we extracted data from those studies that reported Rvol along with EROA, EF, and LVEDV. Data were extracted from 12 studies that included 2754 patients. We compared the quoted value of Rvol with a derived value of Rvol ([LVEDV − LVESV] × regurgitant fraction).

A similar forward stroke volume can be obtained at a normal ejection fraction and severely reduced ejection fraction depending on the LVEDV. Similarly, an equal Rvol can be obtained at a low ejection fraction with higher LVEDV. In addition, EROA is approximately 10% to 15% of aortic valve area; therefore, EROA is a major determinant of retrograde flow in contrast to the forward flow, which is determined by systemic vascular resistance. At a lower EROA, Rvol remains constant irrespective of ejection fraction and LVEDV (Figure 1). However, at a higher EROA, Rvol increases with increase in ejection fraction and LVEDV (Figures 2 -4).^16,23-34 Furthermore, the Rvol increases with increase in EROA at constant ejection fraction. The measured value of EROA and Rvol influences each other. Therefore, the low Rvol in a low ejection fraction could be responsible for low measured EROA. The actual EROA in patients with poor ejection fraction reflects a relative quantitative reduction in Rvol and VTIreg (velocity time integral of regurgitant volume). If EROA remains constant, regurgitant fraction (RF) would remain constant or may increase with a reduction in ejection fraction. Therefore, the RF cutoff value should be retained in low flow state and its value exceeding 50% should be considered as severe IMR irrespective of flow state and ejection fraction. Low Rvol has always been observed in low flow state and low ejection fraction. The Rvol increases with increase in EROA at constant ejection fraction and flow rate. Therefore, it seems reasonable to get projected EROA value at 60 mL of Rvol to obtain cutoff to define severity. Similarly, the projected value of Rvol at normal ejection fraction can be obtained to define the severity.

\begin{array}{l} Projected EROA = measured EROA \times 60 ml / \\ measured Rvol \end{array}

\begin{array}{l} Projected Rvol = measured Rvol \times 60 % / \\ measured ejection fraction \end{array}

The projected value of EROA and Rvol based on indexing may not be the actual value of EROA and Rvol. Nevertheless, it appears mathematically sound based on our interpretation of dependent relationship between EROA, Rvol, ejection fraction, and LVEDV. Unlike primary MR, IMR is usually associated with reduced ejection fraction. Therefore, it appears unrealistic to keep the similar cutoff for primary MR and IMR. The cutoff of severity can be retained if we classify according to projected values of EROA and Rvol and thus would ensure uniformity across all types of MR. We have not come across studies reporting Rvol and EROA beyond their respective cutoff (EROA ≥ 0.4 cm² and Rvol ≥ 60 mL) for severe IMR even in patients with ejection fraction more than 40%. However, the Rvol and EROA values can exceed the cutoff for severe IMR, if LVEDV is very high (>400-500 mL). The largest randomized controlled trials on severe IMR reported maximum mean EROA of 0.4 cm² at an ejection fraction of >40%.²⁹ Furthermore, the Rvol would not have exceeded the cutoff of 60 mL in their study unless we assume a RF of more than 80%.

Though the prognosis remains poor in all grades of IMR, the increase in grade or severity definitely worsen the prognosis further. Patients with EROA ≥ 0.2 cm² and Rvol ≥ 30 mL have been associated with higher 5-year mortality than patients with EROA< 0.2 cm² and Rvol < 30 mL.²⁴ Pulmonary hypertension is commonly associated with EROA ≥ 0.2 cm² in patients with LV dysfunction.³⁵

The current diagnostic criteria are based on limited evidences. Furthermore, EROA and Rvol are dynamic entities; therefore, our projected estimation of EROA and Rvol seems a reasonable alternative for further studies. Considering the unique pathophysiology of IMR, several other echocardiographic variables should be included to quantify it adequately and clearly. For that, large volume of normative data needs to be generated. The diagnostic criteria, management protocol, and prognosis cannot be segregated in patients with IMR. The diagnostic cutoff needs to be redefined and there should be a clear segregation between different grades of IMR with an addition of a score index. The score index should comprise already existing echocardiographic variables such as EROA, regurgitation volume, regurgitant fraction, vena contracta, jet area ratio, and angiographies grade. An addition of echocardiographic variables such as ejection fraction, annular diameter, end systolic volume, end diastolic volume, end systolic diameter, end diastolic diameter, tenting area, coaption depth, tenting volume, posterior leaflet angle, septal-lateral delay, wall motion score index, sphericity index, number of viable segments, and systolic dyssynchrony index would make the score index more comprehensive. These echocardiograpic variables have been noted as independent predictors of postoperative outcome in each grade of IMR. Low ejection fraction (<35%) has been consistently associated with poor prognosis—adverse remodeling in patients with IMR.²⁴ A higher LV end diastolic and systolic volume and area have been uniformly noticed in patients with MR recurrence. The end diastolic LV dimension with cutoff value of 65 mm (sensitivity and specificity 89%; area under the curve [AUC] 0.92) has been identified as single best factor in predicting the occurrence of reverse remodeling.³⁶ The mitral annular diameter, interpapillary muscle distance, and leaflet tethering increases with increase in the LV volume and thus influence the prognosis irrespective of grade of IMR. The anterior tethering angle of ≥39.5° has been found to be strong independent predictor of MR recurrence with sensitivity of 98% and specificity of 97% with AUC of 0.99 and odds ratio (OR) of 5.4.³⁷ Similarly, the higher degree of posterior leaflet tethering was also observed with MR recurrence (P = .0362, r² = 0.2463).³⁸ The degree of anterior and posterior leaflet tethering, mitral annular dimension, and the position of leaflet coaption represent coaption depth, and its value exceeding 1 cm predicts MR recurrence after repair.^39,40 A large extent (≥5 segments) of viable myocardium (OR = 1.45; 95% confidence interval [CI] = 1.22-1.89; P = .001) and an absence (≤60 ms) of anterior papillary muscle-posterior papillary muscles dyssynchrony (OR = 1.49; 95% CI = 1.29-1.72; P = .001) have been independently associated with improvement in IMR.⁴¹ The prognosis becomes poorer with increase in nonviable myocardial segment and dyssynchrony. Impairment of LV diastolic filling progresses with an increase in the severity of coronary artery disease. The restrictive LV filling pattern has been observed as an important marker of progression of MR after surgical repair.³¹ In another study, systolic sphericity index (OR = 4.918) was noted as the most important predictor of LV reverse remodeling followed by myocardial performance index (OR = 4.753) and wall motion score index (OR = 2.612).²⁸

The score index would help in creating uniformity across the globe for all future randomized trials on IMR with better predefined inclusion criteria. A management decision based on these prospective trials would create a consensus among all stakeholders. The quantification of myocardial viable segments, septal-lateral delay, wall motion score index, and systolic dyssynchrony index becomes crucial in the perioperative clinical decision making, as these indices would determine the regression in IMR after an isolated CABG and/or CRT.

Management of Ischemic Mitral Regurgitation

Coexistence of MR with coronary artery disease predisposes the patients to increased perioperative morbidity and mortality irrespective of management strategy.^42-44 There is a general consensus to repair or replace the mitral valve in severe IMR with CABG.^9,45-47 However, ambiguity still exists in prioritizing the repair over replacement.^29,48,49 Repair or replacement of the mitral valve has been shown to reduce LV end systolic volume index and, therefore, improves prognosis.^50-52 Meta-analyses and clinical studies have quoted lower operative mortality and higher long-term survival in the repair group.^29,53-57 Similar survival rate between mitral repair and replacement groups has also been noted in the literature.^49,58 Additionally, improvement in the LV function has been found to be similar or superior in the repair group.^29,57 However, the higher risk of recurrence in the repair group predisposes to atrial fibrillation and heart failure with long term negative outcomes.²⁹

In moderate IMR with concomitant CABG, ideal approaches to treatment strategies are lacking.^26,59-64 In these patients, the safety and efficacy of mitral valve intervention have always been controversial (Table 1).^{26,27,59-61,65-68} Randomized studies on moderate IMR have failed to demonstrate a reduction in LV end systolic volume index, survival benefit, and improvement in quality of life after mitral valve intervention.^59,64,69,70 Meta-analyses have also observed similar survival benefit and relief of heart failure symptom at follow-up in mitral valve repair group and isolated CABG group.^71-74 Isolated CABG in moderate to severe IMR had maximum adjusted survival at 10 years and there was no significant association between severity of MR and overall survival.⁴³ Furthermore, isolated CABG has shown to reduce the severity of MR.^61,63,75 In addition, many believe that coronary revascularization may improve the LV systolic function and, therefore, reduces the LV dimension and restore the functional relationship of the mitral valvular apparatus.^41,76,77

Table 1.

Echocardiographic Characteristics and Outcomes After Isolated CABG Versus CABG + MVR in Patients With Moderate Ischemic Mitral Regurgitation.

Studies	Echocardiographic Variables	CABG	CABG + MVR	Outcome	Comments
Smith et al⁵⁹ (2014)	EROA (cm²)	0.2 ± 0.1	0.2 ± 0.1	No significant difference (similar reduction 8.7 mL/m² vs 10 mL/m²) in LVESVI at 1 year	Had lower LVESVI—54.8 mL/m² vs 59.6 mL/m². Similar reverse remodeling
Diken et al⁶⁵ (2014)	EROA (mm²)	21 ± 0.2	22 ± 0.3	Significant reduction in severity of MR in CABG + Repair group
Bouchard et al²⁷(2014)	EROA (mm²)	22.7 ± 5.2	19.5 ± 3.2	Similar reduction in left ventricular volume and dimension	CABG + Repair group had a higher preoperative LVEDV (133.9 mL vs 118.4 mL) and LVESV (76.6 mL vs 58.4 mL)
	Jet area/LA area (%)	34.1 ± 7.0	39.0 ± 5.9
	Rvol (mL)	36.9 ± 8.6	35.0 ± 10.7
	RF (%)	21.9 ± 10.0	25.0 ± 11.7
Chan et al²⁶ (2012)	EROA (cm²)	0.18 ± 0.10	0.21 ± 0.09	Significant reduction in LVESVI (22.2 mL/m²) and improved peak oxygen consumption	Had higher LVESVI than Smith et al Study CABG + repair group (71.8 mL/m² vs 78.4 mL/m²). Better reverse remodeling in CABG + repair group
	Rvol (mL)	30.3 ± 13.8	35.5 ± 13.3
	VC (cm)	0.4 ± 0.1	0.4 ± 0.1
Fattouch et al⁶⁰ (2009)	MR grade	2 (PISA radius 5-8 mm)	2 (PISA radius 5-8 mm)	Significant improvement in reverse remodeling and no MR recurrent during follow up in CABG + Repair group	LVEDD (58 mm and 59 mm), LVESD (44 mm and 45 mm), tenting area (1.7 cm² and 1.8 cm²), respectively, in CABG alone vs CABG + Repair group
Fattouch et al⁶⁰ (2009)	Tenting area (cm²)	1.7 ± 0.7	1.8 ± 0.6
Goland et al⁶⁶ (2009)	MR grade (MR jet/LA area 20% to 40%)	3	3	Significant reduction in MR grade in Repair group	More patients were in NYHA III and NYHA IV grade in CABG + Repair group preoperatively
Wong et al⁶¹ (2005)	Mean MR grade (qualitative)	2.3 ± 0.7	3.1 ± 0.3	Repair group had significantly lower grade of MR during follow-up	Left ventricular size (55.1 mm and 52.2 mm) and ejection fraction (39% vs 42%) in Repair group vs CABG alone, respectively
Di Donato et al⁶⁷ (2003)	Mean MR grade (qualitative)	2	2	Better improvement in heart failure symptoms in CABG + Repair group
Harris et al⁶⁸ (2002)	Mean MR grade (qualitative)	2.6 ± 0.5	2.1 ± 0.3	Similar survival in both groups	Better survival in poor functional class after repair

Abbreviations: CABG, coronary artery bypass grafting; EROA, effective regurgitant orifice area; LA, left atrium; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVESD, left ventricular end systolic diameter; LVEDD, left ventricular end diastolic diameter; LVEDVI, left ventricular end diastolic volume index; LVESVI, left ventricular end systolic volume index; MR, mitral regurgitation; MVR, mitral valve repair; NYHA, New York Heart Association; PISA, proximal isovelocity surface area; RF, regurgitant fraction; Rvol, regurgitant volume; VC, vena contracta.

Regional wall motion abnormality of the myocardium in the vicinity of the papillary muscles increases the tethering force and it initiates and/or aggravates MR.^6,11,78 The wall motion score indexes of the basal, mid-posterior, and inferior segments for the posterior papillary muscle and the basal, mid-lateral, and anterior segments for the anterior papillary provide better assessment of imbalance in closing and tethering forces. The presence of viable myocardial segments predicts reverse remodeling of the left ventricle and regression of IMR.^41,79,80 Coronary revascularization alone may not be sufficient to restore cardiac resynchronization.⁸¹ Cardiac resynchronization therapy (CRT) synchronizes papillary muscles contraction and promotes reverse LV remodeling and, thus, attenuates the severity of MR.^23,82-86 However, several studies have reported improvement in New York Hear Association functional class, heart failure symptoms, LV ejection fraction, survival benefit, increase in peak oxygen consumption, and superior reverse remodeling after CABG and mitral valve repair in moderate IMR.^{26,60,62,68,87-89} The increase in perioperative risk is associated with longer duration of cardiopulmonary bypass time and aortic cross-clamp time negates the advantages of mitral valve repair.^90,91 Furthermore, studies claiming superiority or with neutral results are characteristically silent on the role and extent of improvement in ejection fraction in both the groups. Despite these conflicting evidences, recent guidelines have opined the benefit of adding mitral valve repair with CABG in moderate IMR.

The preferred method of mitral valve intervention in IMR is restrictive mitral annuloplasty or mitral valve replacement with subvalvular preservation. Nevertheless, there are several other surgical modalities such as chordal cutting, internal direct repositioning of the displaced papillary muscles, and infarct placation using plaquating sutures.⁹² The treatment failure after mitral annuloplasty could be attributed to functional mitral stenosis, increased leaflet tethering, progressive remodeling, and progression of coronary artery disease.^93-96 In addition, echocardiographic predictors of MR recurrence after mitral annuloplasty includes central regurgitant jet, complex regurgitant jet, restrictive diastolic filling pattern, systolic sphericity index, end systolic volume, wall motion score index, large systolic tenting area (>2.5 cm²), large distance between the coaptation point and the mitral annulus plane (>1 cm), large angle (≥45°) of the posterior leaflet, very enlarged LV, or the presence of several regurgitant jets (Table 2).^{31,37-40,95,97,98} An interpapillary muscle distance >20 mm, a mid-systolic mitral valve tenting height >11 mm, and mitral annular diameter >37 mm have also been reported as predictor of MR recurrence after annuloplasty.^37,99 Three-dimensional echocardiographic estimation of tenting volume provides better assessment tethering, geometric deformation of mitral valve, and mitral valve remodeling. The EROA varies similar to the tenting volume during systole and this variation is influenced by the LV systolic function.¹⁰⁰ An increase in sphericity index indicates the progression of leaflet tethering because the more spherical the LV becomes, the greater the degree of papillary muscle displacement that exerts tethering on the leaflets.^13,78 A higher papillary muscle systolic dyssynchrony with a cutoff >58 ms has found to be a strong predictor of recurrence of IMR.¹⁰¹ Persistent LV dyssynchrony causes reduction in closing force and thus predispose to MR recurrence and LV remodeling. Several other surrogates of LV dyssynchrony have been extensively studied in the literature in patients with heart failure scheduled for CRT. A cutoff of >65 ms for septal-lateral delay and >60 ms for interventricular mechanical have been associated with continued LV remodeling in heart failure.^102-104

Table 2.

Predictors and Clinical Characteristics of Adverse Remodeling and MR Recurrence.

Studies	MR Characteristics	Grade of MR	Procedure	Total Patients/No. or % of MR Recurrence or Treatment Failure	Predictors and Characteristics of Adverse Remodeling and MR Recurrence in Treatment Failure Group
Gelsomino et al³⁷ (2008)	EROA 37 mm², RF 46%, Rvol 57 mL/beat	Moderate	CABG + annuloplasty	230/54	TH 11 mm, APM-WMSI 1.6, anterior tethering angle >39.5°
Penicka et al⁴¹ (2009)	Ratio of jet area to LA area, 20% to 40%	Moderate	Isolated CABG	135/64	Mitral annulus diameter 39 mm, TA 2.6 cm², TH 10 mm, PLA 42°, APM-PPM dyssynchrony >60 ms, no. of viable segments <5
Gelsomino et al²⁸ (2008)	EROA 38 mm², RF 47%, Rvol 59 mL/beat	Moderate	CABG + annuloplasty	204/120	MPI >0.9, WMSI >1.5, SSI >0.7, TA 4.3 mm, TH 1.3 mm, EDD 65 mm, ESD 56 mm, LVESVI 77 mL/m², LVEDVI 107 mL/m², PMs 37 cm
Hung et al⁹⁵ (2003)	Vena contracta 0.72 cm, jet area/LA area ratio 38%	Severe to moderate	CABG + annuloplasty	30/22	EDV 151 mL, ESV 86 mL, SPI-ED 0.47, SPI-ES 0.34
Magne et al⁹⁸ (2007)	Vena contracta 0.54-0.59, jet area/LA area ratio 39% to 40%	Moderate	CABG + annuloplasty	39/10	PLA >45°, TA >2.5 cm², TH >1 cm, mitral annular diameter 39 cm, LVEDV 180 mL, LVESV 120 mL
Braun et al³⁶ (2005)	Mean MR grade +3.1	Severe	CABG + annuloplasty	87/5; in 12 patients only annuloplasty	LVESD > 51 mm, LVEDD > 65 mm
Serri et al³⁸ (2006)	Mean MR grade 2.72	Moderate	CABG + annuloplasty	73/57%	Posterior leaflet tethering distance <40 mm, sphericity index 1.35, LVEDV 147 mL, LVESV 106 mL
Bax et al⁸⁹ (2004)	Mean MR grade 3.4	Severe	CABG + annuloplasty	51/1	LVEDD 64 mm, LVESD 51 mm
Ereminiene et al³¹ (2005)	Mean MR grade 2.6-2.7, EROA 27-29 mm	Moderate	CABG + annuloplasty	Impaired relaxation group 13/31.3%, pseudonormalization group 19/47.6%, restriction group 21/85.7%	Restrictive diastolic filling pattern, LVEDDi 33.6 mm/m², LVESDi 23.6 mm/m², WMSI 2.4
Lee et al⁴⁰ (2009)	Vena contracta 0.5-0.6 cm	Moderate	Only annuloplasty	104/25	LVEDV 349 mL, LVESV 271 mL, Sphericity index 1.38, TH 10 mm, TA 3.8 cm², PLA 65°, distal anterior leaflet angle 30°

Abbreviations: APM, anterior papillary muscles; CABG, coronary artery bypass grafting; EROA, effective regurgitant orifice area; EDV, end diastolic volume; ESV, end systolic volume; LA, left atrium; LVEDV, left ventricular end diastolic volume; LVESV, left ventricular end systolic volume; LVESD, left ventricular end systolic diameter; LVEDD, left ventricular end diastolic diameter; LVEDDi, left ventricular end diastolic diameter index; LVESDi, left ventricular end systolic diameter index; LVEDVI, left ventricular end diastolic volume index; LVESVI, left ventricular end systolic volume index; MPI, myocardial performance index; MR, mitral regurgitation; PLA, posterolateral angle; PPM, posterior papillary muscles; PMs, papillary muscles separation; RF, regurgitant fraction; Rvol, regurgitant volume; SPI-ED, sphericity index-end diastole; SPI-ES, sphericity index-end systole; TA, tenting area; TH, tenting height; WMSI, wall motion score index.

The literature provides comprehensive evidences to refine the management protocol (Figure 5). The surgical intervention in severe IMR is indisputable despite the absence of well-defined randomized control trials. Several independent predictors of MR recurrence and reverse remodeling after the surgical repair have been identified in the severe IMR grade (Table 2). The largest randomized trial on the outcome of mitral valve repair versus replacement in the severe IMR has observed almost identical postoperative outcome.²⁹ However, studies are in abundance that suggest variable MR recurrence rates with a surgical mitral valve repair. Therefore, these predictors with well-defined cutoff may be incorporated into decision making. Presence of any of these predictors exceeding the defined cutoff justifies the suggestion of mitral valve replacement over repair in patients with severe IMR. Contrary to severe IMR, moderate IMR poses a different management dilemma. A definitive opinion recommending mitral valve intervention over nonintervention in moderate IMR has been overtly subjective. A clear-cut prioritization is lacking in the recently published largest randomized trial.⁷⁰ Therefore, preoperative or intraoperative identification of predictors of successful outcome after mitral valve repair is required to remove ambiguity in decision making. The presence of any of these predictors exceeding defined cutoff may guide us to suggest the superiority of mitral valve repair over no intervention. In addition, CRT proved to be beneficial in preventing reverse remodeling and MR recurrence in patients with poor ejection fraction. Furthermore, dyssynchrony, higher wall motion score index, and septal-lateral delay may not prevent MR recurrence after coronary revascularization alone. Considering the unique mechanism of IMR, mitral valve repair may not be sufficient for mitral leaflet coaption in these pathologies to prevent the recurrence of MR. Though it looks cumbersome and time consuming, nonetheless it would change the approach of perioperative clinicians and patients would certainly end up in getting appropriate evidence-based management at the point of care. Future randomized controlled trials with or without these predictors in each grade of IMR would strengthen the evidences and thus would guide us in formulating better management protocol.

Limitations

Our projected estimation of EROA and Rvol has several limitations. First, it needs prospective validation. Second, further evidences could alter the relationship between EROA, Rvol, LVEDV, and ejection fraction, and therefore, our formula would be subjected to rigorous review and modification. Third, 3-dimensional echocardiography is now increasingly used to determine EROA, and it appears more accurate and has potential to replace 2-dimensional echocardiography-based estimation. In addition, we assumed RF of 50%, while calculating Rvol in a few studies, where data were incomplete. The actual RF could have been higher or lower, and we could have underestimated or overestimated Rvol. The guidelines defined echocardiographic criteria (EROA, Rvol, and RF) and their respective cutoff have not been followed consistently while including patients in different IMR grade in literatures till now. This heterogeneity in inclusion criteria could have arisen due to inability to find patients with severe IMR grade based on cutoff suggested by the guidelines and the reasons for this have been abundantly expressed earlier. Therefore, our projected estimation of EROA and Rvol would ensure uniformity in patient selection for future studies. Furthermore, the variance in EROA and Rvol due to different ejection fraction and LVEDV across studies could be minimized and the studies would become comparable.

A predictors-based, individualized management protocol has inherent limitations too. It is time consuming and requires technical expertise. Hemodynamic conditions can change rapidly during the intraoperative period due to anesthetic agents, surgical stimulus, pharmacological agents (inotropes, vasopressors, and vasodilators), and cardiopulmonary bypass induced cardiac and vascular alterations. This hemodynamic perturbation can substantially alter the measured echocardiographic predictors. Decision making would become more challenging if measured predictor value hovers around the threshold.

Conclusions

The diagnosis and management of IMR at the point of care should be accommodative and precise. The patients would rarely fulfill the criteria of severe IMR based on the current cutoff, especially under the influence of anesthetic agents. The current diagnostic and management protocol lack objectivity. Therefore, a refinement in diagnostic criteria and management protocol is required to facilitate the prudent decision making at the point of care. Grading of IMR based on the projected value of EROA and Rvol appears a suitable alternative. In addition, evidences suggest the utility of predictors-based, individualized management protocol in patients with IMR undergoing CABG. Randomized trials based on projected estimation of EROA and Rvol and predictors-based randomization in each grade of IMR are required to arrive at definite management recommendation.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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