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Canadian Journal of Cardiology

Pathophysiology, Diagnosis, and New Therapeutic Approaches for Ischemic Mitral Regurgitation

Published:December 18, 2020DOI:https://doi.org/10.1016/j.cjca.2020.12.011

      Abstract

      Ischemic mitral regurgitation (MR) is a valvular complication frequently seen in patients with coronary artery disease and is associated with increased mortality and morbidity. Ischemic mitral regurgitation has a complex, heterogeneous, and still incompletely understood pathophysiology involving both the mitral valve and the left ventricle. The occurrence of valve regurgitation in patients with ischemic cardiomyopathy in return accelerates left ventricular remodelling and dysfunction, ultimately leading to irreversible heart failure. Diagnostic evaluation of ischemic MR is unique and different from the other causes of MR. The severity thresholds associated with outcomes are different from primary MR, and specific imaging characteristics are potentially useful to guide therapy. The use of imaging modalities such as 3-dimensional echocardiography and cardiac magnetic resonance imaging can refine the diagnostic evaluation and help in choosing the correct management. Although multiple treatments are available to improve ischemic MR, each therapeutic option is associated with limitations and incomplete success. Therapy has therefore to be individualised for each patient. Current options include optimal medical therapy, cardiac resynchronisation therapy, percutaneous or surgical revascularisation, surgical mitral repair or replacement, and new percutaneous interventions. This review aims to discuss the latest insights regarding the pathophysiology, diagnosis, and treatment of ischemic MR.

      Résumé

      L'insuffisance mitrale (IM) ischémique est une complication valvulaire fréquemment observée en cas de coronaropathie; elle est associée à une augmentation de la mortalité et de la morbidité. L'IM ischémique a une physiopathologie complexe, hétérogène et encore mal comprise qui implique à la fois la valve mitrale et le ventricule gauche. La survenue d’une insuffisance valvulaire chez un patient présentant une cardiomyopathie ischémique accélère en retour le remodelage et la dysfonction ventriculaire gauche, ce qui peut mener éventuellement à une insuffisance cardiaque irréversible. L’évaluation diagnostique de l'IM ischémique est unique et diffère de celle de l'IM attribuable à d’autres causes. Les seuils de sévérité associés aux issues cliniques ne sont pas les mêmes qu’en cas d'IM primaire, et certaines caractéristiques particulières observées à l’imagerie peuvent être utiles pour orienter le traitement. Le recours à des modalités d’imagerie comme l’échocardiographie tridimensionnelle et l’imagerie par résonance magnétique cardiaque peut aider à préciser l’évaluation diagnostique et à choisir la bonne stratégie de prise en charge. Bien qu’il existe plusieurs traitements pour améliorer l'IM ischémique, toutes les options thérapeutiques ont des limites et ne sont pas pleinement efficaces. Le traitement doit donc être personnalisé pour chaque patient. À l’heure actuelle, les options comprennent un traitement médical optimal, la resynchronisation cardiaque, la revascularisation par voie percutanée ou chirurgicale, la réparation ou le remplacement de la valve mitrale par voie chirurgicale, et de nouvelles interventions percutanées. Nous passons ici en revue les dernières connaissances acquises en matière de physiopathologie, de diagnostic et de traitement de l'IM ischémique.
      Mitral regurgitation (MR) is a frequent disease with significant morbidity.
      • Nkomo V.T.
      • Gardin J.M.
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      • Enriquez-Sarano M.
      Burden of valvular heart diseases: a population-based study.
      There are multiple causes to MR, each with its own management strategies. Secondary (or functional) MR occurs in response to a primary left ventricle (LV) disease and currently represents a formidable therapeutic challenge. Although it is clearly associated with adverse prognosis, few treatments have been shown to influence clinical outcomes. Most data for secondary MR are derived from patients with ischemic heart disease, in which case the term ischemic MR is used. Ischemic MR has a complex physiology involving both the LV and the mitral leaflets. Multiple characteristics make the diagnostic evaluation and treatment of ischemic MR unique and distinct from the other causes of MR.

      Pathophysiology of Ischemic MR

      Ischemic MR has a heterogeneous pathophysiology, involving LV dysfunction in addition to intrinsic mitral leaflet changes. Adding to this complexity, the presence of MR in patients with ischemic disease accelerates LV remodelling and transition to heart failure. Several experimental and clinical data have improved our understanding of this disease in the last years.

      Left ventricle disease

      Adequate mitral closure results from the balance between tethering forces (influenced by papillary muscle position and orientation) and closing forces (mediated by LV–to–left atrium gradient). Imbalance between these opposing forces leads to the apical displacement of mitral coaptation, incomplete valve closure, and MR. Ischemic MR can be seen across the spectrum of ischemic heart disease: transient MR during exercise (baseline normal LV function),
      • Fehrenbacher G.
      • Schmidt D.H.
      • Bommer W.J.
      Evaluation of transient mitral regurgitation in coronary artery disease.
      MR associated with hibernating myocardium, and MR developing after myocardial infarction (MI). Although in some cases acute MI can lead to papillary muscle rupture and acute MR,
      • Leroux É.
      • Chauvette V.
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      Clinical and echocardiographic presentation of postmyocardial infarction papillary muscle rupture.
      the present review focuses on the most common scenario of post-MI LV remodelling leading to papillary muscle displacement, leaflet tethering, and subacute or chronic MR.
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      • Rogers E.W.
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      • Weyman A.E.
      Incomplete mitral leaflet closure in patients with papillary muscle dysfunction.
      While ischemic LV damage causing MR is most often localised in the posterior LV wall, it can also be global or apical.
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      Mitral regurgitation after anteroapical myocardial infarction: new mechanistic insights.
      The location and distribution of LV anomalies will determine the mitral tethering pattern (symmetric or asymmetric) and regurgitant jet orientation. Ischemic MR is typically dynamic and influenced by loading conditions and exercise, as these factors can affect the delicate balance needed for normal valve closure.
      • Lancellotti P.
      • Lebrun F.
      • Piérard L.A.
      Determinants of exercise-induced changes in mitral regurgitation in patients with coronary artery disease and left ventricular dysfunction.
      LV dyssynchrony can also contribute to ischemic MR by impairing LV function and directly interfering with valve closure.
      • Solis J.
      • McCarty D.
      • Levine R.A.
      • et al.
      Mechanism of decrease in mitral regurgitation after cardiac resynchronization therapy: optimization of the force-balance relationship.
      Both mechanisms can potentially be addressed by cardiac resynchronisation therapy (CRT). Acute MR response to CRT has been described, especially for patients having the latest mechanical LV activation near the posterior papillary muscle. A more progressive improvement can also occur in the months following CRT in response to LV reverse remodelling.
      • Ypenburg C.
      • Lancellotti P.
      • Tops L.F.
      • et al.
      Mechanism of improvement in mitral regurgitation after cardiac resynchronization therapy.
      Mitral annulus is another important component of the mitral valve apparatus. Normal mitral annulus has a typical nonplanar saddle shape, and its contraction contributes to leaflet coaptation. While isolated annulus dilation has been inconsistently associated with significant MR, mitral annulus deformation (loss of the normal saddle shape) and altered contractile function have been associated with ischemic MR.
      • Watanabe N.
      • Ogasawara Y.
      • Yamaura Y.
      • et al.
      Mitral annulus flattens in ischemic mitral regurgitation: geometric differences between inferior and anterior myocardial infarction: a real-time 3-dimensional echocardiographic study.

      Valve changes in ischemic MR

      Mitral valve leaflets undergo multiple changes in response to myocardial ischemia and the mechanical stretch imposed by LV remodelling (Fig. 1). The mitral valve has the possibility of increasing its surface to match LV dilation and prevent MR.
      • Chaput M.
      • Handschumacher M.D.
      • Tournoux F.
      • et al.
      Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation.
      ,
      • Dal-Bianco J.P.
      • Aikawa E.
      • Bischoff J.
      • et al.
      Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation.
      Current knowledge suggests embryonic growth process reactivation in response to mechanical stretch, increasing extracellular matrix production and resulting in larger mitral leaflets. However, mitral leaflet enlargement is often unable to keep the leaflets proportional to the dilated LV. In ovine models of MI, it was shown that infarction can modify the leaflet response to mechanical stretch by inducing significant remodelling including active leaflet thickening, excessive presence of myofibroblasts, and profibrotic signalling, such as transforming growth factor (TGF) β with subsequent collagen production.
      • Dal-Bianco J.P.
      • Aikawa E.
      • Bischoff J.
      • et al.
      Myocardial infarction alters adaptation of the tethered mitral valve.
      In a recent experimental study in which mitral valve growth was induced by aortic regurgitation, the presence of MI was associated with attenuated increase in mitral valve area, with subsequent development of MR.
      • Marsit O.
      • Clavel M.A.
      • Côté-Laroche C.
      • et al.
      Attenuated mitral leaflet enlargement contributes to functional mitral regurgitation after myocardial infarction.
      While precise mechanisms for those changes have yet to be elucidated, the hypothesis of angiotensin II triggering TGF-β–mediated remodelling has been explored. Interestingly, models of MI with controlled LV dilation suggest that losartan can potentially prevent post-MI adverse changes in the leaflets.
      • Bartko P.E.
      • Dal-Bianco J.P.
      • Guerrero J.L.
      • et al.
      Effect of losartan on mitral valve changes after myocardial infarction.
      Those experimental studies are parallelled with clinical observations. Abnormal valve biology and biomechanics have been observed in patients with advanced heart failure, suggesting an organic contribution to secondary MR.
      • Grande-Allen K.J.
      • Barber J.E.
      • Klatka K.M.
      • et al.
      Mitral valve stiffening in end-stage heart failure: evidence of an organic contribution to functional mitral regurgitation.
      In patients followed sequentially after MI, progressive leaflet thickening as determined with the use of echocardiography was correlated with the presence of MR, independently from LV function or size.
      • Beaudoin J.
      • Dal-Bianco J.P.
      • Aikawa E.
      • et al.
      Mitral leaflet changes following myocardial infarction: clinical evidence for maladaptive valvular remodeling.
      Thus, in addition to the primary LV changes, ischemic heart disease is associated with abnormal mitral leaflet biology, limiting valve adaptation to the remodelling ventricle and impairing the biomechanical properties of the valve and its normal coaptation.
      Figure thumbnail gr1
      Figure 1Current pathophysiologic concepts for ischemic mitral regurgitation (MR). (Left) Illustration of tethering and closing forces after myocardial infarction. This process results in an apical displacement of the coaptation. (Right) Illustration of a normal mitral valve leaflet (top) and thickened post–myocardial infarction leaflet (bottom). GAG, glycosaminoglycan; LV, left ventricular.

      Impact of ischemic MR on LV function and survival

      Ischemic MR has the specificity of self-aggravating in a vicious circle as it promotes the dilation of the LV which, in turn, leads to additional LV remodelling and exacerbated MR (Fig. 2). This phenomenon is facilitated by the fact that ischemic LV seems more vulnerable to MR.
      • Beeri R.
      • Yosefy C.
      • Guerrero J.L.
      • et al.
      Mitral regurgitation augments post-myocardial infarction remodeling failure of hypertrophic compensation.
      Adverse prognosis and survival are proportionally related to increasing MR severity after MI, but in contrast to primary MR, even mild ischemic MR is associated with adverse events. The presence of nonsevere MR after MI markedly increases the occurrence of congestive heart failure at 5 years, including in patients without symptoms at baseline (rates more than doubled, despite adjustments for age and LV ejection fraction). The presence of any degree of MR has been consistently associated with reduced survival at 30 days, 1 year, and 5 years.
      • Grigioni F.
      • Enriquez-Sarano M.
      • Zehr K.J.
      • Bailey K.R.
      • Tajik A.J.
      Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment.
      Figure thumbnail gr2
      Figure 2Interplay between ischemic mitral regurgitation (MR) and left ventricular (LV) remodelling, eventually leading to irreversible heart failure without treatment option.
      At the molecular level, combination of myocardial ischemia and volume overload is characterised by a biphasic response: transient rise in intramyocardial molecular signals promoting compensatory LV hypertrophy, followed by their decline as heart failure progresses.
      • Beeri R.
      • Yosefy C.
      • Guerrero J.L.
      • et al.
      Mitral regurgitation augments post-myocardial infarction remodeling failure of hypertrophic compensation.
      Those dynamic changes in LV biology in ischemic MR are highlighted by further animal experimentations showing that early MR correction can reverse LV remodelling and improve LV function, whereas the same intervention performed at a later time point has less or no effect.
      • Beaudoin J.
      • Levine R.A.
      • Guerrero J.L.
      • et al.
      Late repair of ischemic mitral regurgitation does not prevent left ventricular remodeling: importance of timing for beneficial repair.
      ,
      • Beeri R.
      • Yosefy C.
      • Guerrero J.L.
      • et al.
      Early repair of moderate ischemic mitral regurgitation reverses left ventricular remodeling: a functional and molecular study.
      While the timing of MR correction after MI in clinical studies remains largely unexplored, recent data from percutaneous mitral repair also suggest that patients with more advanced heart failure are less likely to benefit from these procedures.
      • Obadia J.F.
      • Messika-Zeitoun D.
      • Leurent G.
      • et al.
      Percutaneous repair or medical treatment for secondary mitral regurgitation.
      ,
      • Stone G.W.
      • Lindenfeld J.
      • Abraham W.T.
      • et al.
      Transcatheter mitral-valve repair in patients with heart failure.
      In summary, multiple studies with different approaches and design consistently indicate that 1) ischemic MR, even if not severe, is independently associated with adverse LV remodelling and poor clinical outcomes; and 2) the level of LV remodelling and dysfunction is an important moving target to assess in order to estimate the benefits of intervention.

      Diagnosis and Evaluation

      Anatomic and functional mechanisms of ischemic MR are markedly different from primary MR. The differences between etiologies and between different guidelines can lead to misdiagnosis or incorrect grading of ischemic MR, as highlighted by a study in which only a minority of cardiologists were able to correctly recognise and grade severe secondary MR.
      • Iung B.
      • Delgado V.
      • Lazure P.
      • et al.
      Educational needs and application of guidelines in the management of patients with mitral regurgitation. A European mixed-methods study.
      Although a complete review of every diagnostic and MR quantification parameters is beyond the scope of this manuscript, a few elements specific for ischemic MR are worth discussing. Transthoracic echocardiography (TTE) is the first-line modality used to determine MR mechanism and severity because numerous quantitative and qualitative parameters can be gathered. However, TTE can sometimes be suboptimal because of poor patient echogenicity. In that case, other modalities, such as transesophageal echocardiography (TEE) or cardiac magnetic resonance imaging (CMR), can be helpful.

      Evaluation of mitral valve morphology and deformation

      A careful description of mitral and LV geometry in ischemic MR is as important as grading MR severity: in addition to confirming the underlying mechanism, these geometric changes can help to predict the success of surgical repair and are critical to assess when planning mitral intervention (Table 1).
      • Utsunomiya H.
      • Itabashi Y.
      • Kobayashi S.
      • et al.
      Comparison of mitral valve geometrical effect of percutaneous edge-to-edge repair between central and eccentric functional mitral regurgitation: clinical implications.
      With the exception of noninfarcted but ischemic LV, in which MR can be revealed only during exercise, most TTE examinations at rest show either local or global wall motion abnormalities along with a variable increase in LV size and sphericity. The apical shift of the coaptation point increases tenting height, tenting area, anterior and posterior leaflet angles, and decreases coaptation length (Fig. 3). TTE can also reveal mitral leaflet anomalies in ischemic MR. Post-MI leaflet thickening is not uncommon and has been previously described with the use of TTE and related to MR.
      • Beaudoin J.
      • Dal-Bianco J.P.
      • Aikawa E.
      • et al.
      Mitral leaflet changes following myocardial infarction: clinical evidence for maladaptive valvular remodeling.
      Patients with ischemic heart disease have increased incidence of mitral annulus calcifications, which can interfere with valve function.
      • Movva R.
      • Murthy K.
      • Romero-Corral A.
      • et al.
      Calcification of the mitral valve and annulus: systematic evaluation of effects on valve anatomy and function.
      Both excessive leaflet thickening and calcifications can represent technical limitations when considering surgical or percutaneous mitral repair. Although most of these parameters can be assessed with the use of 2-dimensional (2D) TTE, the use of 3-dimensional (3D) TEE will yield the most comprehensive assessment, reducing the risk of foreshortened views and off-axis planes.
      • Fattouch K.
      • Castrovinci S.
      • Murana G.
      • et al.
      Multiplane two-dimensional versus real time three-dimensional transesophageal echocardiography in ischemic mitral regurgitation.
      Three-dimensional imaging and cardiac computed tomography also are frequently used to plan emerging transcatheter therapies for MR.
      Table 1Anatomic and physiologic parameters associated with procedural outcomes
      Type of procedureParameters predicting the impact on mitral regurgitation
      Cardiac resynchronisation therapyFactors predicting failure to improve mitral regurgitation:

      Large tenting area

      Severely dilated left ventricle

      Scar in papillary muscle region

      LV dyssynchrony according to strain analysis

      High levels of fibrotic biomarkers (galectin)
      Revascularisation aloneFactors predicting failure to improve mitral regurgitation:

      Low myocardial viability

      Ventricular dyssynchrony > 60 ms

      Flattened annular saddle shape

      High tethering angle
      Restrictive annuloplastyFactors predicting failure to improve mitral regurgitation:

      Larger LV size

      Increased annulus diameter

      High mitral tethering angle

      High tenting area/coaptation height

      Significant LV dyssynchrony

      Increased sphericity index

      Increased interpapillary muscle distance

      Restrictive ventricular filling

      Small annuloplasty size
      Percutaneous edge-to-edge repairMore likely to positively influence outcome if:

      Significant MR (EROA > 30 mm2)

      LVEF > 20%

      LV not severely dilated (< 70 mm)
      Anatomic considerations:

      Level of leaflet tethering (coaptation depth/length)

      Mitral valve area > 4 cm2, no elevated gradients

      Absence of severe leaflet calcification

      Adequate leaflet length for grasping

      Absence of commissural jet
      EROA, effective regurgitant orifice area; LV, left ventricle; LVEF, left ventricular ejection fraction; MR, mitral regurgitation.
      Figure thumbnail gr3
      Figure 3Example of mitral geometry modification in ischemic mitral regurgitation. (A) Transoesophageal echocardiography showing apical valve displacement. White arrow: annulus diameter; red arrow: coaptation depth; green lines: anterior and posterior leaflet closure angles. (B) Bicommissural view showing a relatively symmetric tethering in this case, resulting in (C) a central jet.

      Evaluation of ischemic MR severity by echocardiography

      Doppler echocardiography incorporates several methods such as color-flow, continuous-wave, and pulsed Doppler in addition to being able to assess the hemodynamic consequences of MR on cardiac chambers. Significance of parameters such as LV and left atrial size, LV function, mitral inflow E-wave velocity, and right ventricle systolic pressure derived from tricuspid regurgitant jet velocity are less specific to define severe ischemic MR, because LV dysfunction by itself can interfere with those parameters. While the use of TEE can be helpful to characterise mitral valve anatomy and MR mechanism, caution should be used when grading ischemic MR severity in sedated (lower systolic pressure) and fasting (lower circulating volume) patients. Stress testing combined with TTE can be useful to confirm symptoms and evaluate the hemodynamic response to exercise in patients with MR, and variation of ischemic MR severity during exercise has been associated with adverse events.
      • Lebrun F.
      • Lancellotti P.
      • Piérard L.A.
      Quantitation of functional mitral regurgitation during bicycle exercise in patients with heart failure.
      For the purpose of valvular evaluation, supine bicycle ergometer stress is preferable to treadmill test because it allows serial measurements of MR severity and pulmonary pressure at different stress levels.
      Color-flow Doppler is the first tool used to screen for MR. Although MR jet area is an intuitive method, it is not the most reliable, because color-flow Doppler can be affected by several factors, including left atrial size, jet direction (central vs eccentric), irregular heart rate, and transmitral gradient. The latter is typically variable in ischemic MR and is affected by systolic LV pressure and volume status.
      • Zoghbi W.A.
      • Adams D.
      • Bonow R.O.
      • et al.
      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      Color Doppler also allows measuring the vena contracta (VC), the narrowest central region of the regurgitant jet. With the use of 2D echocardiography, this parameter is, however, limited to the VC width, a clear oversimplification of often geometrically complex orifices that are known to be markedly elliptical in secondary MR.
      • Kahlert P.
      • Plicht B.
      • Schenk I.M.
      • et al.
      Direct assessment of size and shape of noncircular vena contracta area in functional versus organic mitral regurgitation using real-time three-dimensional echocardiography.
      Alternatively, the VC area can be calculated by manual planimetry of the color Doppler signal with the use of 3D echocardiography. A value of 3D VC area > 0.41 cm2 has been proposed to denote severe MR of any cause and was potentially more helpful than other parameters for secondary MR.
      • Zeng X.
      • Levine R.A.
      • Hua L.
      • et al.
      Diagnostic value of vena contracta area in the quantification of mitral regurgitation severity by color Doppler 3D echocardiography.
      This method allows estimating the regurgitant orifice area (ROA) without geometric assumptions, and can be used for both central and eccentric MR.
      Continuous-wave (CW) and pulsed-wave (PW) Doppler can add useful information in ischemic MR. Typical transmitral CW Doppler shows decreased maximal MR velocity associated with lower LV systolic function and/or elevated left atrial pressure. Timing of regurgitation can be assessed as well, with a typical biphasic pattern in patients with secondary MR, showing early and late systolic peaks and midsystolic decrease,
      • Schwammenthal E.
      • Chen C.
      • Benning F.
      • et al.
      Dynamics of mitral regurgitant flow and orifice area. Physiologic application of the proximal flow convergence method: clinical data and experimental testing.
      reflecting the dynamic variations of closing forces during myocardial contraction. This implies a variability in MR flow during systole and highlights the limitation of static parameters such as effective ROA (EROA) or VC measured on a single frame (Fig. 4). PW Doppler can be used to compute regurgitant volume, but the method requires multiple measurements and is not universally recommended.
      • Lancellotti P.
      • Moura L.
      • Pierard L.A.
      • et al.
      European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease).
      Figure thumbnail gr4
      Figure 4Characteristics, complexity, and limitation of effective regurgitant orifice area calculation in ischemic mitral regurgitation. (A) Standard proximal isovelocity surface area (PISA) measurement from a zoomed 4-chamber view after color Doppler scale adjustment. (B, C) Significant leaflet tenting affects the hemispheric assumption used in calculations, leading to smaller estimated regurgitant orifice. (D) Orthogonal view from (A) showing a large, elliptical, and irregular PISA. (E) Typical ischemic mitral regurgitation in continuous-wave Doppler, with low maximal velocity and maximal jet density in early and late systole. (F) M-mode performed on the PISA, showing its variations throughout systole.
      The flow convergence (or proximal isovelocity surface area [PISA]) is a robust method for MR quantification and is based on the ability to obtain a hemispheric proximal flow convergence region at the site of a regurgitant orifice.
      • Zoghbi W.A.
      • Adams D.
      • Bonow R.O.
      • et al.
      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      From the measure of a PISA radius, an EROA can be calculated, with a threshold of 0.4 cm2 to define severe MR. However, the cutoff for severity is less than clear in ischemic MR because adverse clinical events and excess mortality have been observed with calculated EROA (mostly PISA derived) ≥ 0.2 cm2 and regurgitant volumes ≥ 30 mL.
      • Grigioni F.
      • Enriquez-Sarano M.
      • Zehr K.J.
      • Bailey K.R.
      • Tajik A.J.
      Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment.
      These findings led to some debates of whether different thresholds for MR severity should be considered for secondary MR vs primary MR, and EROA cutoffs of 0.2 cm2, 0.3 cm2, and 0.4 cm2 have been proposed in recent years.
      • Zoghbi W.A.
      • Adams D.
      • Bonow R.O.
      • et al.
      Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.
      ,
      • Baumgartner H.
      • Falk V.
      • Bax J.J.
      • et al.
      2017 ESC/EACTS Guidelines for the management of valvular heart disease.
      ,
      • Nishimura R.A.
      • Otto C.M.
      • Bonow R.O.
      • et al.
      2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
      Despite similar suggested severity thresholds for primary and secondary MR in the current American Heart Association/American College of Cardiology guidelines, some distinctions are made indicating an EROA cutoff of > 0.2 cm2 as being more sensitive to detect severe ischemic MR, whereas a threshold of > 0.4 cm2 is more specific. Physiologic and technical factors can explain in part the detrimental impact of lower EROA on prognosis in ischemic MR. First, as detailed above, ischemic myocardium could be more sensitive to MR, and adverse outcomes can be observed with lower regurgitation severity.
      • Beeri R.
      • Yosefy C.
      • Guerrero J.L.
      • et al.
      Mitral regurgitation augments post-myocardial infarction remodeling failure of hypertrophic compensation.
      Also, some geometric and temporal characteristics of ischemic MR can interfere with EROA calculation. The presence of tethered leaflets and typically noncircular regurgitant orifice in ischemic MR (Fig. 4, A-D) are factors interfering with the hemispheric mathematical assumption necessary to derive EROA, typically underestimating the orifice. Ischemic MR dynamic variation during systole (Fig. 4, E-F) with typical mid-systolic decrease also influences PISA measurements. Assessment of MR jet temporal variations by means of CW Doppler and color M-MODE can be useful to demonstrate this phenomenon. Some geometric caveats of 2D PISA can potentially be improved with the use of biplane imaging or 3D color-Doppler PISA, which has been shown to have higher diagnostic value compared with 2D PISA and better correlation with MR evaluation by means of CMR.
      • Papolla C.
      • Adda J.
      • Rique A.
      • Habib G.
      • Rieu R.
      In vitro quantification of mitral regurgitation of complex geometry by the modified proximal isovelocity surface area method.
      ,
      • Sköldborg V.
      • Madsen P.L.
      • Dalsgaard M.
      • Abdulla J.
      Quantification of mitral valve regurgitation by 2D and 3D echocardiography compared with cardiac magnetic resonance a systematic review and meta-analysis.
      Despite these promising options, 3D color Doppler remains challenging with TTE, and data linking clinical outcomes to these new metrics are still scarce. In summary, keeping in mind its limitations, 2D PISA derived EROA in ischemic MR remains associated with prognosis and should be routinely assessed. The prognostic implication of lower values of EROA and regurgitant volume in ischemic MR should be highlighted. Finally, in patients with good image quality, the incorporation of biplane/3D measurements can be considered.

      Use of cardiac magnetic resonance to quantify ischemic MR

      CMR can help in quantifying MR. The most common and accepted approach involves comparison between LV stroke volume (obtained from short-axis images covering the entire LV) and aortic forward stroke volume (obtained by phase-contrast flow imaging): The difference between the values is assumed to be the MR volume.
      • Gillam L.D.
      Is it time to update the definition of functional mitral regurgitation?: structural changes in the mitral leaflets with left ventricular dysfunction.
      This indirect assessment does not rely on MR jet characteristics for quantification. CMR regurgitant volume is therefore completely independent from flow orientation or variations during systole. This represents a significant advantage over some static echocardiography-derived parameters, such as EROA or VC. On the other hand, CMR is more limited in assessing the dynamic nature of MR (relation to exercise), cannot be easily repeated in patients with changing volume status, is not widely available, and some patients may have contraindications. Growing data seem to support the use of CMR to quantify MR. Despite possible discordance with echocardiography (more frequently with secondary MR),
      • Lopez-Mattei J.C.
      • Ibrahim H.
      • Shaikh K.A.
      • et al.
      Comparative assessment of mitral regurgitation severity by transthoracic echocardiography and cardiac magnetic resonance using an integrative and quantitative approach.
      CMR regurgitant volume is overall better correlated with prognosis.
      • Myerson S.G.
      • d’Arcy J.
      • Christiansen J.P.
      • et al.
      Determination of clinical outcome in mitral regurgitation with cardiovascular magnetic resonance quantification.
      One recent CMR study shows that MR regurgitant fraction > 35% is associated with adverse outcomes in patients with ischemic MR, and better stratification can also be achieved by integrating MI size.
      • Cavalcante J.L.
      • Kusunose K.
      • Obuchowski N.A.
      • et al.
      Prognostic impact of ischemic mitral regurgitation severity and myocardial infarct quantification by cardiovascular magnetic resonance.
      However, most other severity data from CMR are derived from patients with primary MR, and therefore not directly applicable to the ischemic MR population.

      Assessment of LV function and viability

      LV size and systolic function represent important variables that can be assessed by TTE. In addition to LV ejection fraction, the use of more advanced techniques such as LV strain has been associated with mortality in a recent study involving patients with secondary MR (50% ischemic MR).
      • Namazi F.
      • van der Bijl P.
      • Hirasawa K.
      • et al.
      Prognostic value of left ventricular global longitudinal strain in patients with secondary mitral regurgitation.
      The use of strain to compute indices of LV muscle dyssynchrony can also potentially predict the likelihood of MR improvement after various interventions (Table 1). Myocardial viability represents the potential of each LV segment to recover its function after revascularisation. Myocardial viability can be assessed by dobutamine echocardiography or thallium or technetium radionuclide imaging. When available, CMR and fluorodeoxyglucose–positron-emission tomography can potentially improve the accuracy of viability assessment. A large extent of viable myocardium (> 5 segments) and an absence (≤ 60 ms) of anterior-posterior papillary muscle dyssynchrony have been independently associated with improvement in ischemic MR following revascularisation.
      • Penicka M.
      • Linkova H.
      • Lang O.
      • et al.
      Predictors of improvement of unrepaired moderate ischemic mitral regurgitation in patients undergoing elective isolated coronary artery bypass graft surgery.
      The assessment of myocardial viability could represent a key feature in patients with ischemic MR undergoing revascularisation. More data, however, are needed to support a more generalised clinical applicability.

      Biomarkers

      The use of cardiac stretch biomarkers, such as B-type natriuretic peptide, can be useful to monitor patients with primary organic MR, with high values predicting mortality.
      • Clavel M.A.
      • Tribouilloy C.
      • Vanoverschelde J.L.
      • et al.
      Association of B-type natriuretic peptide with survival in patients with degenerative mitral regurgitation.
      Higher values are also associated with increased MR severity and mortality in patients with ischemic MR, although elevated levels in this population can also be caused by LV dysfunction and does not always reflect MR severity. Despite encouraging results in predicting secondary MR response after CRT, the clinical applicability of newer biomarkers (sST2, galectin 3) remains to be studied in larger trials.

      Therapeutic Approaches

      Treatment of the underlying LV disease with pharmacologic approaches, biventricular pacing, and revascularisation are usually the first steps in patients with ischemic MR. In those with persistent MR and associated symptoms, surgical or percutaneous interventions can be considered. Many studies highlight the importance of patient selection when considering such interventions. In most advanced disease, conservative medical therapy, consideration for LV assist device, or cardiac transplantation could be more relevant than a mitral intervention, highlighting the importance of multidisciplinary heart team evaluation.

      Medical therapy

      Standard medication for LV remodelling should be given after MI, especially in patients at risk of developing ischemic MR. This includes agents blocking the renin-angiotensin system (angiotensin-converting enzyme inhibitor [ACEI] and angiotensin receptor blocker [ARB]), beta-blockers, and aldosterone antagonists. In addition to their effects on LV remodelling, the use of optimal doses of ACEI/ARB can potentially improve mitral leaflet biology.
      • Bartko P.E.
      • Dal-Bianco J.P.
      • Guerrero J.L.
      • et al.
      Effect of losartan on mitral valve changes after myocardial infarction.
      ,
      • Beaudoin J.
      • Dal-Bianco J.P.
      • Aikawa E.
      • et al.
      Mitral leaflet changes following myocardial infarction: clinical evidence for maladaptive valvular remodeling.
      The use of adjunct neprilysin inhibitor (sacubitril-valsartan combination) has been shown to be more effective to decrease MR severity vs ARB alone and should be used when indicated.
      • Kang D.H.
      • Park S.J.
      • Shin S.H.
      • et al.
      Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation.
      Regarding emerging new molecular targets for heart failure, the ongoing Ertugliflozin for Functional Mitral Regurgitation (EFFORT) trial is specifically exploring the potential effects of a sodium-glucose cotransporter 2 (SGLT2) inhibitor in patients with ischemic and nonischemic secondary MR. Optimisation of medical therapy should be a universal first step in patients with ischemic MR.

      Cardiac resynchronisation therapy

      Several studies have shown that CRT in eligible patients can help reduce the severity of secondary MR in approximately one-half of cases,
      • van Bommel R.J.
      • Marsan N.A.
      • Delgado V.
      • et al.
      Cardiac resynchronization therapy as a therapeutic option in patients with moderate-severe functional mitral regurgitation and high operative risk.
      with better clinical outcomes. MR response to CRT can potentially be predicted by studying mitral and LV morphology (less response with larger LV and increased valve tenting), echocardiography-derived indices of dyssynchrony, and cardiac biomarkers (Table 1).
      • Beaudoin J.
      • Singh J.P.
      • Szymonifka J.
      • et al.
      Novel heart failure biomarkers predict improvement of mitral regurgitation in patients receiving cardiac resynchronization therapy—the BIOCRT study.
      Based on available data, current guidelines suggest CRT when indicated before considering any mitral procedure (surgical or transcatheter replacement or repair). Reassessing clinical status and MR severity after 3-6 months is reasonable to confirm CRT response.

      Coronary revascularisation

      Percutaneous coronary revascularisation of the culprit artery is typically the first action performed at the time of an acute coronary syndrome. Outside the acute setting, indications for revascularisation depend on the underlying coronary anatomy, presence of symptoms, LV dysfunction, and viability. In appropriate cases, revascularisation may lead to reverse remodelling of the LV, which in turn may result in a reduction in MR. Patients with ischemic MR having proven ischemia should therefore undergo coronary angiography and be evaluated for myocardial revascularisation. Decision for percutaneous vs surgical revascularisation is chosen based on anatomic feasibility and risk assessment of both methods. In many cases, a multidisciplinary heart team discussion is required, because each approach can eventually be combined with mitral valve interventions (combined coronary and mitral surgery vs sequential percutaneous revascularisation followed by percutaneous edge-to-edge repair). Relatively preserved annular geometry and the use of viability studies can help in predicting the likelihood of MR improvement with revascularisation alone or conversely identify the patients more likely to benefit from revascularisation combined with a mitral valve intervention.
      • Penicka M.
      • Linkova H.
      • Lang O.
      • et al.
      Predictors of improvement of unrepaired moderate ischemic mitral regurgitation in patients undergoing elective isolated coronary artery bypass graft surgery.
      ,
      • Sun X.
      • Jiang Y.
      • Huang G.
      • et al.
      Three-dimensional mitral valve structure in predicting moderate ischemic mitral regurgitation improvement after coronary artery bypass grafting.

      Mitral valve surgery combined with revascularisation

      Revascularisation alone can leave a significant proportion of patients with residual MR. Thus, the question of combined mitral valve repair or replacement remains critical but is still a matter of debate in many situations. Mitral repair with a restrictive annuloplasty ring with or without subvalvular repair and mitral valve replacement can be performed alone or in combination with coronary artery bypass grafting (CABG).
      In patients with moderate ischemic MR with an indication of CABG, a relevant question is whether a specific additional intervention must be performed on the mitral valve. While some studies have suggested a clear superiority of performing combined CABG and mitral valve repair in this situation,
      • Chan K.M.
      • Punjabi P.P.
      • Flather M.
      • et al.
      Coronary artery bypass surgery with or without mitral valve annuloplasty in moderate functional ischemic mitral regurgitation: final results of the Randomized Ischemic Mitral Evaluation (RIME) trial.
      that finding has been mitigated by a trial in which 301 patients with moderate ischemic MR were randomised to CABG alone or CABG and mitral valve repair.
      • Michler R.E.
      • Smith P.K.
      • Parides M.K.
      • et al.
      Two-year outcomes of surgical treatment of moderate ischemic mitral regurgitation.
      Although the rate of moderate or severe MR was higher in the CABG-alone group (32.3% vs 11.2%; P < 0.001), rehospitalisation and serious clinical events rate were similar (84 vs 92 events per 100 patient-years; P = 0.35), with higher neurologic events and arrhythmias in patients undergoing CABG and mitral repair (14 vs 4 events; P = 0.02). Despite this absence of net overall benefit, the option of mitral valve repair at the time of CABG has still to be prospectively studied in selected patients based on myocardial viability (odds of MR improvement with revascularisation alone) and predictors of mitral repair success. Indeed, several parameters have been associated with outcomes following mitral valve repair, including increased anterior and posterior leaflet angles, increased tenting area, larger LV diameter, annulus size, and interpapillary muscle distance, and increased sphericity
      • Magne J.
      • Pibarot P.
      • Dagenais F.
      • et al.
      Preoperative posterior leaflet angle accurately predicts outcome after restrictive mitral valve annuloplasty for ischemic mitral regurgitation.
      ,
      • Roshanali F.
      • Mandegar M.H.
      • Yousefnia M.A.
      • Rayatzadeh H.
      • Alaeddini F.
      A prospective study of predicting factors in ischemic mitral regurgitation recurrence after ring annuloplasty.
      (Table 1).
      There is more consensus on the fact that severe ischemic MR should generally be addressed during CABG procedure. In that case, mitral repair or mitral valve replacement can both be performed.
      • Baumgartner H.
      • Falk V.
      • Bax J.J.
      • et al.
      2017 ESC/EACTS Guidelines for the management of valvular heart disease.
      However, the benefits of mitral repair over replacement in primary organic MR are not observed in patients with ischemic MR. Observational studies have shown that recurrent MR is more frequent after mitral valve repair, leading to more reoperation and without clear benefits in LV function.
      • Lorusso R.
      • Gelsomino S.
      • Vizzardi E.
      • et al.
      Mitral valve repair or replacement for ischemic mitral regurgitation? The Italian Study on the Treatment of Ischemic Mitral Regurgitation (ISTIMIR).
      This has also been highlighted in a randomised trial comparing mitral repair vs replacement in patients with severe ischemic MR.
      • Goldstein D.
      • Moskowitz A.J.
      • Gelijns A.C.
      • et al.
      Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation.
      Patients with mitral repair had much higher recurrence of MR at 2-year follow-up (58.8% vs 3.8%; P < 0.001), along with increased heart failure (24.0 vs 15.2 per 100 patient-years; P = 0.05) and cardiovascular hospital readmissions (48.3 vs 32.2 per 100 patient-years; P = 0.01), compared with patients with mitral valve replacement. It is worth noting that the use of undersizing annuloplasty does not directly correct the main mechanism of ischemic MR. Mitral repair could potentially be optimised by using adjunct interventions on the subvalvular apparatus and correction of LV and papillary muscle position and shape.
      • Mihos C.G.
      • Capoulade R.
      • Yucel E.
      • Melnitchouk S.
      • Hung J.
      Combined papillary muscle sling and ring annuloplasty for moderate-to-severe secondary mitral regurgitation.
      Current subvalvular corrective strategies including the use of dedicated intra- or extracardiac devices are currently under investigation (Table 2). The long-term clinical impact of these techniques, however, still needs to be defined.
      Table 2Nonexhaustive list of trials for which patients with ischemic mitral regurgitation are included.
      Type of treatmentTrial nameIntervention groupControl groupTarget population/study details
      Pharmacologic treatmentEFFORT
      Randomised trial.
      ErtugliflozinePlaceboFMR ≥ moderate (EROA > 0.10 cm2);

      NYHA II-III + LVEF 35%-50%
      Edge-to-edge repairCLASP IID/IIF
      Randomised trial.
      PASCAL SystemMitraClip SystemMR ≥ moderate/severe;

      Primary or secondary MR
      RESHAPE-HF 2
      Randomised trial.
      MitraClip SystemGDMTFMR ≥ moderate/severe;

      NYHA II + LVEF 15%-35% or NYHA III-IV + LVEF 15%-45%
      EVOLVE-MR
      Randomised trial.
      MitraClip SystemGDMTModerate/nonsevere FMR;

      LVEF > 20% + LVEDV 75-110 mL/m2;

      NYHA II-IV
      Percutaneous replacementSUMMIT
      Randomised trial.
      Tendyne Mitral Valve SystemMitraClip SystemMR ≥ moderate/severe;

      Primary or secondary MR;

      NYHA II-IV
      FIMCardiovalve systemNoneSafety/performance study;

      Severe MR, primary or secondary;

      NYHA II-IV
      SATURN TMVR for Functional MRSATURN TA SystemNoneFeasibility study

      FMR ≥ moderate/severe;

      NYHA II-IV
      MISCEND StudyEVOQUE TMVR systemNoneFeasibility study;

      Symptomatic MR, primary or secondary
      Percutaneous annuloplastyCARILLON
      Randomised trial.
      Carillon Mitral Contour SystemGDMTFMR ≥ moderate;

      NYHA II-IV + 6MWT 150-450 m;

      LVEF ≤ 50% + LVESD ≤ 70 mm
      Millipede Feasibility StudyMillipede deviceNoneFeasibility study;

      FMR > moderate, NYHA II-IV
      Transcatheter Mitral Cerclage AnnuloplastyTransmural Systems TMCANoneFeasibility study

      FMR ≥ mild + NYHA ≥ III + LVEF ≤ 50%

      FMR ≥ moderate + NYHA II-IV
      MAVERICARTO SystemNoneFeasibility study;

      MR ≥ moderate + NYHA II-IV;

      LVEF < 40% + LVEDD 50-75 mm
      Left ventricular reshapingCorCinch-EUAccucinch SystemNoneFMR ≥ moderate or No FMR but LVEDD ≥ 55 cm + LVEF 20%-40% and NYHA II-IV
      BACEBACE deviceNoneTo assess safety and efficacy;

      FMR ≥ moderate, NYHA II-IV, LVEF 25%-50%
      OUS Feasibily StudyVenTouch SystemNoneTo assess safety and efficacy;

      FMR ≥ moderate, NYHA II-IV
      6MWT, 6-minute walk test; BACE, Evaluation of Safety and Efficacy of the Basal Annuloplasty of the Cardiac Externally (BACE) Device in the Treatment of Functional Mitral Regurgitation; CARILLON, Assessment of the Carillon Mitral Contour System in Treating Functional Mitral Regurgitation Associated With Heart Failure; CLASP, Edwards PASCAL Transcatheter Valve Repair System Pivotal Clinical Trial; CorCinch-EU, Evaluate of the Safety and Performance of the AccuCinh Ventricular Repair System; EFFORT, Ertugliflozin for Functional Mitral Regurgitation; EROA, effective regurgitant orifice area; EVOLVE-MR, Evaluation of Outcomes of Transcathether Mitral Valve Repair for the Treatment of Low Ejection Fraction and Moderate Functional Mitral Valve Regurgitation in Heart Failure; FIM, Cardiovalve Transfemoral Mitral Valve System in Patients at High Surgical Risk With Severe Mitral Regurgitation; FMR, functional mitral regurgitation; FU, follow-up; GDMT, guideline-directed medical therapy; LVEDD, left ventricular end-diastolic diameter; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; MAVERIC, Treatment of Heart Failure and Associated Functional Mitral Valve Regurgitation; Millipede, A Feasability Study of the Millipede Transcatheter Annuloplasty Ring System in Patients With Functional Mitral Regurgitation; MISCEND, Edwards EVOQUE Eos Mitral Valve Replacement: Investigation of Safety and Performance After Mitral Valve Replacement With Transcatheter Device; MR, mitral regurgitation; NYHA, New York Heart Association functional classification; OUS, Evaluation of the Minimally Invasive VenTouch System in the Treatment of Functional Mitral Regurgitation; RESHAPE-HF 2, RandomizeStudy of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation; SATURN TMVR, SATURN Transcatheter Mitral Valve Replacement for Functional Mitral Regurgitation; SUMMIT, Clinical Trial to Evaluate the Safety and Effectiveness of Using the Tendyne Mitral Valve System for the Treatment of Symptomatic Mitral Regurgitation; TMCA, transcatheter mitral cerclage annuloplasty; TMVR, transcatheter mitral valve replacement.
      Randomised trial.

      Surgical and percutaneous options for isolated mitral interventions

      Isolated mitral surgery in patients with ischemic MR but without the need for revascularisation should be reserved for patients with persistent symptoms despite optimal medical therapy and CRT (if indicated). Those cases should be carefully evaluated because LV systolic function is not expected to improve in the absence of revascularisation. Surgical risk should be assessed, and patients deemed at high or prohibitive surgical risk may be considered for transcatheter mitral valve repair or advanced heart failure therapies.
      • Baumgartner H.
      • Falk V.
      • Bax J.J.
      • et al.
      2017 ESC/EACTS Guidelines for the management of valvular heart disease.
      Edge-to-edge leaflet repair is the most widely accepted percutaneous mitral valve intervention and is a less invasive treatment option for patients with moderate-severe secondary MR who are denied surgery because of high risk. The MitraClip device (Abbott Vascular, Santa Clara, CA) is the only system currently approved in Canada, the US, and Europe. The Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trials have demonstrated its feasibility and safety for primary and secondary MR, but resulting in a lower efficacy compared with surgery regarding the presence of residual MR.
      • Feldman T.
      • Foster E.
      • Glower D.D.
      • et al.
      Percutaneous repair or surgery for mitral regurgitation.
      ,
      • Ailawadi G.
      • Lim D.S.
      • Mack M.J.
      • et al.
      One-year outcomes after mitraclip for functional mitral regurgitation.
      Patient selection for edge-to-edge repair mostly depends on mitral valve anatomy: Leaflet length and mobility, mitral valve orifice area, presence of calcifications, origin of regurgitant jet(s), measurement of coaptation gap, and interatrial septum morphology represent important variables to collect. Benefits of the MitraClip device over optimal medical treatment in patients with secondary MR have been studied in 2 randomised controlled trials: COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) and MITRA-FR (Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation).
      • Obadia J.F.
      • Messika-Zeitoun D.
      • Leurent G.
      • et al.
      Percutaneous repair or medical treatment for secondary mitral regurgitation.
      ,
      • Stone G.W.
      • Lindenfeld J.
      • Abraham W.T.
      • et al.
      Transcatheter mitral-valve repair in patients with heart failure.
      Both studies included ~60% of patients with ischemic MR. The COAPT study demonstrated that percutaneous repair reduced the risk of all-cause mortality (29.1% vs 46,1%; P < 0.001) and rehospitalisation (35.8% vs 67.9% per patient-year; P < 0.001) at 24 months and was associated with positive LV remodelling compared with medical treatment alone. These results were validated in subgroups of patients: ischemic vs nonischemic and surgical high vs low risk.
      • Stone G.W.
      • Lindenfeld J.
      • Abraham W.T.
      • et al.
      Transcatheter mitral-valve repair in patients with heart failure.
      Conversely, MITRA-FR demonstrated no benefit of percutaneous repair over medical treatment for the same primary outcomes at 12 and 24 months (all-cause mortality and rehospitalisation for HF occurred in 63.8% vs 67.1%: hazard ratio 1.01, 95% confidence interval 0.77-1.34).
      • Obadia J.F.
      • Messika-Zeitoun D.
      • Leurent G.
      • et al.
      Percutaneous repair or medical treatment for secondary mitral regurgitation.
      ,
      • Iung B.
      • Armoiry X.
      • Vahanian A.
      • et al.
      Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years.
      These opposite results can be partly explained by different inclusion criteria. In the COAPT study, patients had higher severity of MR (baseline EROA of 0.41 cm2 vs 0.31 cm2) but smaller LV end-diastolic volume (baseline 101 ± 34 mL/m2 vs 135 ± 35 mL/m2). Also, MR reduction was more sustained in the COAPT trial. Therefore, it was supposed that in COAPT, outcomes were driven by the reduction of MR, whereas in MITRA-FR, LV dysfunction and heart failure might have been the main determinants of the outcomes. These 2 trials emphasise the importance of patient selection when planning an intervention for ischemic MR—further information in this regard are likely to be revealed by ongoing trials such as Randomized Study of the Mitra Clip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF 2).

      Future Perspectives

      Several devices and treatment approaches for ischemic MR are under investigation. Newer generations of edge-to-edge repair devices with independent arm control might improve procedural results. Other devices target the mitral annulus or subvalvular apparatus, and others involve percutaneous mitral replacement (Fig. 5). While the role of optimal medical therapy is well acknowledged, it is not clear how new medications for heart failure (particularly, neprilysin inhibitors and SGLT2 inhibitors) will affect the prevalence of ischemic MR. With the availability of multiple treatment options, and given the disease heterogeneity, the importance of patient selection for each approach will deserve attention in future studies. Some of the numerous devices under investigation are listed in Table 2. A suggested algorithm for diagnostic evaluation and therapeutic strategies for patients with ischemic MR is presented in Figure 6.
      Figure thumbnail gr5
      Figure 5Illustration of current and investigational therapeutic options for secondary mitral regurgitation.
      Figure thumbnail gr6
      Figure 6Proposed evaluation and therapeutic orientation algorithm for patients with ischemic mitral regurgitation. While the algorithm can provide general guidance for ischemic MR management, it does not replace clinical evaluation and local expertise, given the complexity and variable presentation of the disease. In some cases, advanced heart failure therapies could be more appropriate than an intervention for mitral regurgitation. CABG, coronary artery bypass graft; CRT, cardiac resynchronisation therapy; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; NYHA, New York Heart Association functional classification.

      Conclusion

      Ischemic MR is a complex disease with difficult management. Its pathophysiology involving both functional and intrinsic leaflet changes will require more fundamental and clinical studies, which could provide new pharmacologic therapeutic opportunities. Despite the understanding of different severity thresholds associated with adverse prognosis, and the success of some (but not all) therapeutic trials, it is now clear that no universal therapy can be applied to this heterogeneous population. The interlinked relations between LV (function, dilation, viability) and mitral valve (regurgitation severity, geometric alterations, intrinsic leaflet anomalies) will require more attention to select the most appropriate and individualised therapy.

      Acknowledgements

      The authors thank Ahmed Benhamadi for graphic design.

      Funding Sources

      J.B. is funded by the Fonds de Recherche Québec—Santé. His research program is funded by the Canadian Institutes for Health Research (grant no 399323) and the Fondation de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec.

      Disclosures

      The authors have no conflicts of interest to disclose.

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