CHAPTER 49: ISCHEMIC MITRAL REGURGITATION

Mitral regurgitation (MR) can be classified into two major etiologic categories: primary (degenerative) and secondary (functional). Primary MR is a consequence of disease affecting the leaflets or chordae tendineae, such as in mitral valve (MV) prolapse, myxomatous degeneration, infective endocarditis, or rheumatic disease. These disease processes are discussed in Chap. 48. In secondary MR, leaflet structure is normal and the valve is more of an “innocent bystander.” Regurgitation results from a distortion of the normal spatial and functional relationships of the left ventricle (LV) and valve apparatus, usually as a consequence of adverse LV remodeling. The trigger for LV remodeling can be ischemic (following myocardial infarction [MI]) or nonischemic (as with dilated cardiomyopathy) (Fig. 49–1). This chapter will focus on chronic ischemic MR (IMR) and will not discuss acute severe MR caused by papillary muscle rupture in the acute/subacute phase of MI.

The reported incidence of IMR following MI has ranged from 19% to 50%.^1,2,3,4 Estimates vary in relation to the nature of the screening techniques utilized. Of 1209 patients with coronary artery disease (CAD) amenable to coronary artery bypass grafting (CABG) and LV ejection fraction (LVEF) ≤ 35% enrolled in the Surgical Treatment for Ischemic Heart Failure (STICH) trial, mild, moderate, and severe MR were present in 46%, 15%, and 3% of patients, respectively.⁵ It is estimated that IMR affects 1.6 million to 2.8 million patients in the United States.⁶

Analogous to, but somewhat different than, other types of valvular heart disease, the natural history of IMR can be considered across four overlapping stages:

• Stage A: “At-risk” stage (eg, early following MI).

• Stage B: Symptomatic progressive stage (eg, during the phase of active LV remodeling).

• Stage C: Asymptomatic severe stage (prior to onset of heart failure [HF] symptoms).

• Stage D: Symptomatic severe stage (following onset of HF symptoms).

Descriptions of valve anatomy, valve hemodynamics, associated cardiac findings, and symptoms for each stage are presented in Table 49–1. Boundaries between these stages are not rigid and patients with moderate IMR may also develop HF symptoms (see below and Table 49–1 and Table 49–2 for definitions of moderate and severe ischemic MR). Angina may also be a feature of the disease process.

Normal MV function is dependent on a complex interplay between the LV and the individual components of the MV apparatus, including the papillary muscles and subjacent myocardium, chordae tendineae, MV leaflets, and mitral annulus (Fig. 49–2A). Distortion or dysfunction of any of these components can result in MR. IMR results from a combination of apical and lateral displacement of the papillary muscles, systolic tethering of the mitral leaflets, annular dilation, and an imbalance of valve closing and tethering forces.^6,7 Annular enlargement is typically less pronounced in patients with IMR than in those who have secondary MR as a result of dilated cardiomyopathy. Adverse LV remodeling can occur as a consequence of MI because of myocardial thinning and dilation. Regional LV remodeling (eg, following a postero-basal infarct) with displacement of the posteromedial papillary muscle can result in asymmetric tethering of the posterior leaflet, producing an eccentric and posteriorly directed MR jet (Fig. 49–2B). The anterolateral papillary muscle has a dual blood supply from the left anterior descending and left circumflex arteries, whereas the posteromedial muscle has a singular blood supply from the right or dominant left circumflex coronary artery. Thus, IMR is more common following inferior-posterior rather than an anterior MI.⁸ Alternatively, global LV remodeling after a large anterior MI causing apical and lateral displacement of both papillary muscles with symmetric tethering of both MV leaflets typically results in a central regurgitant jet (Fig. 49–2C). Leaflet coaptation is displaced apically away from the annular plane compromising complete leaflet closure. In addition, mitral annular dilation can further stretch the MV leaflets and contribute to incomplete valve closure. The nonplanar saddle-shape of the MV annulus is important for MV competence, and loss of this saddle shape during remodeling has also been implicated in the genesis of IMR.⁹

IMR is an independent predictor of cardiovascular mortality and HF following MI.^1,2 The magnitude of risk is proportional to the severity of MR.^3,10 Although even mild MR is associated with increased mortality, prognosis is particularly poor for patients with severe IMR, with 1-year mortality estimates ranging from 15% to 40%.¹¹ In a multivariate analysis of 303 patients in the chronic post-MI phase, IMR was associated with an adjusted relative risk of cardiovascular death of 1.83 (95% confidence interval [CI], 1.13-2.96), and this risk increased as a function of MR severity.¹² Similarly, IMR was associated with an adjusted relative risk of HF and cardiac death of 3.65 (95% CI, 1.86-7.75) and 2.96 (95% CI, 1.77-5.16), respectively, in a study of 173 asymptomatic patients following MI who were followed for a mean of 7.6 ± 7.4 years; a graded relationship between MR severity and risk of each outcome was again observed.¹³

As a result of consistent evidence of the prognostic utility of post-MI MR in predicting HF and cardiovascular death, assessment of MR is an accepted component of post-MI risk stratification. Adverse outcomes are associated with a smaller calculated effective regurgitant orifice (ERO) in IMR compared to primary MR, prompting a threshold ERO of ≥ 0.2 cm² for defining severe regurgitation in IMR compared to a corresponding threshold of ≥ 0.4 cm² in secondary MR (Tables 49–1 and 49–2).¹⁴ Unlike in primary mitral regurgitation where an ERO ≥ 0.4 cm² indicates severe MR that eventually causes LV damage, definition of severe secondary MR is fraught with some uncertainty because the LV is already damaged when secondary MR develops. Although some investigators have recommended that an ERO of 0.2 cm² is consistent with severe secondary MR on the basis of natural history studies, recent large clinical trials have defined severe secondary MR as ≥ 0.4 cm².⁶ Thus, the definition of what constitutes severe secondary MR should not rely on a single variable, but should take all indicators of severity into account in an integrative manner (see the next section).

Physical Examination

Findings on physical examination depend on duration and severity of IMR as well as the degree of clinical compensation. The pulse may be unremarkable, irregular because of coexistent atrial fibrillation (AF), or rapid because of sympathetic overdrive in the context of HF. Systolic blood pressure and pulse pressure may be reduced as a result of reduced forward stroke volume, but this finding is nonspecific and variable. The venous pressure may be elevated. The apex beat is displaced downward and to the left in chronic severe IMR as a result of LV dilatation. The typical murmur is holosystolic, loudest at the apex, and radiates to the axilla. The murmur may be more easily heard with the patient lying in the left lateral position in forced expiration and can be made louder with maneuvers that increase LV afterload. Although there is a correlation between murmur intensity and severity of MR, this correlation is weaker for patients with IMR than primary MR.¹⁵ Severe MR may be accompanied by a third heart sound (S₃) produced by rapid emptying of a large left atrial volume under higher than normal pressure into the LV; in this setting, an S₃ may be an indicator of MR severity rather than HF severity.

Transthoracic Echocardiography

Transthoracic echocardiography (TTE) is recommended to confirm the etiology of MR, assess LV size and systolic function, quantitate the severity of MR, screen for the presence of other valve or structural abnormalities, and provide an estimate of pulmonary artery pressures.¹⁴ TTE also allows for an assessment of the MV apparatus, including leaflet morphology, displacement of the papillary muscles, systolic tethering of mitral leaflets, and annular dilation (Videos 49–1 to 49–4).

Color-Flow Doppler Assessment of IMR Severity

Color-flow regurgitant jet area is obtained by calculating the average of the MR jet area traced in the apical two- and four-chamber views. The MR jet area/left atrial area ratio is then calculated, and MR is graded as follows:

• < 20%: Mild MR

• 20% to 39%: Moderate MR

• ≥ 40%: Severe MR

The often eccentric nature of the regurgitant jet in IMR renders this semiquantitative method less helpful in assessment of MR severity in cases of IMR compared to primary MR. In addition, jet area is influenced by physiological loading conditions (eg, blood pressure, volume status).

Vena contracta width is a simple, semiquantitative method of grading MR severity that measures the width of the narrowest portion of the MR jet that occurs at or just downstream from the regurgitant orifice (Fig. 49–3). MR is graded as follows:

• < 0.3 cm: Mild MR

• 0.3-0.69 cm: Moderate MR

• ≥ 0.7 cm: Severe MR

This method is less influenced by loading conditions than regurgitant jet area.

Effective regurgitant orifice area (EROA) and mitral regurgitation regurgitant volume can be measured using the proximal isovelocity surface area (PISA) method. This method is based on the principle that mitral regurgitant flow converges uniformly and radially towards the MV orifice, creating concentric hemispherical shells with gradually decreasing surface area and increasing velocity on the LV side of the MV leaflets. As flow accelerates toward the MV orifice on color-flow Doppler imaging, the aliasing velocity (Nyquist limit) is exceeded and the color reverses, producing a colored hemisphere (Fig. 49–4). The velocity at the surface of the hemisphere equals the Nyquist limit. Applying the conservation of mass principle, flow at the surface of the hemisphere is the same as flow through the regurgitant orifice. Therefore, EROA can be calculated from the radius of the PISA hemisphere at the first aliasing boundary, the aliasing velocity, and the peak MR velocity on continuous-wave Doppler, using the following equation:

Regurgitant volume can then be calculated using the EROA and the velocity time integral (VTI) obtained from tracing the continuous-wave Doppler profile of the regurgitant jet, using the following equation:

The PISA method assumes that the proximal flow convergence is hemispheric, which is rarely the case with eccentric IMR jets. This can result in an underestimate of EROA in IMR cases. This may partly explain why lower thresholds of EROA are associated with worse prognosis in IMR and why valvular heart disease guidelines propose lower threshold values of EROA (≥ 0.2 cm² rather than 0.4 cm²) and regurgitant volume (≥ 30 mL rather than 60 mL) for defining severe IMR compared to those used for primary MR (Table 49–2). IMR is more a disease of the LV than the MV and natural history studies have shown these lower thresholds to be prognostically important. In the context of established LV dysfunction, smaller regurgitant volumes are associated with worse survival, but no study has convincingly demonstrated that correction of secondary MR improves survival. Using Koch’s postulates, this argues against a cause-and-effect relationship between smaller MR volumes and reduced longevity in this setting. Other limitations of the PISA method include lack of validation for multiple jets and poor reproducibility.

Other indicators of severe MR include a peak MV E-wave velocity > 1.2 m/s, a dense triangular continuous-wave Doppler profile, and systolic flow reversal in the pulmonary veins.¹⁶ Grading of IMR should not rely on any single parameter, but rather defining severe MR requires careful integration of multiple echocardiographic parameters, clinical data, and assessment of LV size and function, with discounting of poor-quality data.¹⁷

Transesophageal and Three-Dimensional Echocardiography

Transesophageal echocardiography (TEE) can be complementary to TTE, and often offers superior visualization of the valve apparatus. In particular, the anatomy of individual segments (scallops) of the MV leaflets is better assessed with TEE. In addition, TEE is useful for confirming the necessary anatomic characteristics for sufficient leaflet tissue for mechanical coaptation using the MitraClip system: a leaflet coaptation length of at least 2 mm and a coaptation depth of no more than 11 mm (Fig. 49–5).¹⁸ Given that MR is sensitive to loading conditions, MR grade as assessed at time of TEE in the sedated/anesthetized patient is often lower than in the setting of baseline ambulatory loading conditions. Because intraoperative loading conditions alter assessment of MR severity, surgical planning is based on preoperative assessment of MR severity in the awake patient.

Three-dimensional echocardiography can provide superior imaging of leaflet morphology and allows for direct visualization and measurement of the EROA, offering a more precise alternative to the two-dimensional PISA method of EROA assessment.¹⁹

Cardiac Magnetic Resonance

Cardiac magnetic resonance (CMR) imaging is used increasingly to assess LV volumes and function in patients with MR. In addition, valve leaflet morphology, regional LV function, left atrial size, and myocardial viability on delayed enhancement imaging, can all be assessed with this single test²⁰ (Video 49–5, Fig. 49–6). Indeed, the extent of basal scarring on delayed enhancement imaging in patients undergoing surgical therapy for IMR correlates with LV functional recovery and postoperative adverse outcomes.²¹

Exercise Testing

IMR is a dynamic lesion, and MR severity can vary over time and during exercise.²² Thus, the severity of IMR at rest does not necessarily reflect the severity of MR during exercise. Exercise-induced increase in IMR provides additional prognostic information over resting evaluation and identifies patients at higher risk of adverse clinical outcomes.²³ For example, an increase in EROA of ≥ 13 mm² during exercise is associated with increased mortality and HF hospitalizations.²⁴ Exercise echocardiography has been proposed to evaluate patients with exertional dyspnea out of proportion to the degree of resting IMR and LV dysfunction, patients with IMR and unexplained acute pulmonary edema, and patients with moderate IMR at rest who are due to undergo surgical revascularization with CABG.^23,25 Exercise echocardiography is preferred over dobutamine stress echocardiography because of dobutamine-mediated decreases in afterload and therefore MR severity.²²

Furthermore, given the central importance of symptoms in the management algorithm for IMR, it is paramount that patients’ subjective reports of exertional symptoms are corroborated with objective data. An objective assessment of functional capacity and exercise limitation can be obtained from exercise treadmill testing, 6-minute walk distance, and cardiopulmonary exercise testing (CPET). Such assessments may unmask unrecognized exertional symptoms/limitation.

Coronary Angiography and Noninvasive Stress Imaging/Viability Assessment

In cases of IMR and LV systolic impairment, it is important to evaluate for myocardial ischemia and/or hibernating viable myocardium given the potential for improvement in LV function with revascularization. Noninvasive evaluation for myocardial ischemia can be performed with either exercise or pharmacological stress nuclear myocardial perfusion imaging (single-photon emission computed tomography [SPECT] or positron emission tomography [PET]), CMR, or echocardiography. Viability assessment can also be performed with SPECT, PET, dobutamine stress echocardiography, or CMR. Identification of ischemic or hibernating viable myocardium should prompt consideration of invasive coronary angiography to define coronary anatomy, with subsequent revascularization as appropriate.

Treatment of IMR depends on symptoms, the severity of regurgitation, the degree of LV systolic dysfunction, and its potential improvement with medical and surgical interventions. Therapy consists of an appropriate combination of lifestyle, medical, device, percutaneous, and/or surgical interventions. The pathophysiological differences between primary MR and secondary IMR dictate distinct and separate treatment recommendations for these disease processes. Management decisions for more complex patients with IMR should involve a multidisciplinary “heart” team that includes, but is not restricted to, interventional cardiologists, cardiac surgeons, anesthetists, imaging specialists, and heart failure specialists.²⁶ Established surgical risk scores (eg, Society for Thoracic Surgeons [STS] score, EuroSCORE) should be used as adjuncts to clinical assessment for better risk stratification of patients and to inform management decisions.²⁷

Medical Therapy

Patients with IMR and HF with reduced LVEF should receive standard guideline directed medical therapy for HF, including angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibition (ARNI) as indicated, beta-blockers, aldosterone antagonists, and diuretics.¹⁴ Patients with IMR and HF with preserved ejection fraction may enjoy symptom relief from a trial of loop diuretic therapy. All patients should be educated regarding lifestyle modifications including sodium restriction, fluid restriction, smoking cessation, and regular aerobic exercise as for any patient with HF. Appropriate secondary prevention with moderate or high-intensity statins and antithrombotic therapy should be emphasized. Anticoagulation is indicated for patients who develop AF.

Device Therapy

Left ventricular dyssynchrony resulting from left bundle branch block (LBBB) or right ventricular (RV) pacing can contribute to the development of secondary MR.^28,29 Cardiac resynchronization therapy (CRT) significantly reduced severity of secondary MR in a small study of 24 patients with HF and LBBB.³⁰ In another study of 98 patients with moderate-to-severe secondary MR who underwent CRT, 49% demonstrated an improvement of ≥ 1 grade in MR at 6 months post-device implantation compared to baseline, and this improvement was associated with improved survival.³¹ Similarly, Di Biase et al. demonstrated an improvement of ≥ 1 grade in MR after 12 months of CRT in 46% of 275 patients with moderate-to-severe or severe secondary MR at baseline.³² This study also demonstrated that MR improvement after 3 months of CRT predicts subsequent MR improvement at 12 months, and so 3 months has been proposed as a waiting period beyond which MR reduction in response to CRT is unlikely and other treatment options should be considered.³³ CRT-mediated improvement in IMR is associated with LV reverse remodeling³⁴ while associated changes in LV contraction and MV apparatus geometry can reduce mitral leaflet tethering.⁷ Thus, CRT is recommended for symptomatic patients with chronic severe IMR with guideline indications for device therapy, including HF with QRS duration > 150 ms.¹⁴ In addition, many patients with IMR will often have a coexisting or independent indication for implantable cardioverter defibrillator (ICD) therapy given the associated LV systolic impairment and history of MI.

Surgery

Significant improvements in surgical techniques and outcomes over recent decades, as reported by high volume-major referral centers of excellence, have lowered the threshold for operative intervention in patients with valvular heart disease. Surgical outcomes depend on the experience of the center and surgeon, and these factors should be considered in decision making. There is general agreement that IMR that is less than moderate in severity does not require surgical intervention. Surgical decisions require consideration of operative morbidity and mortality, type of operation (repair vs replacement), durability of MR reduction, and downstream clinical end points, including functional capacity, HF hospitalizations, and survival. To date, studies have failed to show a survival benefit with surgery for IMR, and thus conservative recommendations have been adopted. Surgical intervention for moderate or severe IMR is discussed below.

Surgery for Moderate IMR

Although moderate IMR is common among patients referred for surgical coronary revascularization, the role of MV repair during CABG in these patients remains uncertain. Revascularization alone may result in sufficient LV reverse remodeling to reduce IMR and improve functional capacity. However, improvement in IMR following CABG alone is variable, difficult to predict and likely a complex function of regional myocardial viability, papillary muscle synchrony, and LV size. Because untreated and persistent, moderate IMR may limit the extent of reverse remodeling that can occur with CABG alone, surgeons have traditionally chosen to perform down-sized annuloplasty repair at the time of CABG, though evidence favoring this approach has been largely observational.

The first single-center randomized trial of patients with moderate IMR assigned 102 patients to CABG plus MV repair (n = 48) or CABG alone (n = 54) and demonstrated significant decreases in LV end-systolic and end-diastolic dimensions, pulmonary artery systolic pressure, mean MR grade (by qualitative assessment), and New York Heart association (NYHA) functional class with CABG plus MV repair versus CABG alone.⁸ There was no between-group difference in survival at 5 years. HF outcomes were not reported. Nearly 40% of patients randomized to CABG alone had only trivial or mild MR at 5 year follow-up. Aortic cross-clamp and cardiopulmonary bypass times were significantly longer in the CABG plus MV repair group. The multicenter, single blinded Randomized Ischemic Mitral Evaluation (RIME) trial randomized 73 patients referred for CABG with moderate IMR to CABG alone (n = 39) or CABG with MV repair using a downsized annuloplasty ring (n = 34). Functional capacity as assessed by peak oxygen consumption at year (primary end point) was reported for only 59 patients, but significantly improved in the CABG plus MV repair cohort compared to the CABG alone cohort by a difference of 2.2 mL/kg/min (95% CI 0.7-3.6, P = .004). Similarly, greater LV reverse remodeling and reduction in MR volume and plasma B-type natriuretic peptides (BNP) were observed at 1 year in the CABG plus MV repair cohort. However, the addition of MV repair to CABG was associated with increased operation duration, blood transfusions, intubation duration, and length of hospital stay.³⁵ In contrast, a larger randomized trial that assigned 301 patients with moderate IMR to CABG alone (n = 151) versus CABG plus MV repair (n = 150) failed to demonstrate a clinically meaningful advantage of adding MV repair at 1 year. The degree of LV reverse remodeling (the primary end point of this trial) at 1 year was similar in both groups, despite a reduced prevalence of moderate or severe MR in the CABG plus MV repair group compared to the CABG alone group (11.2% vs 31%, respectively; P < .001). It is interesting to note that the severity of IMR in 69% of patients in the CABG alone group had improved to none or mild MR at 1 year. This trial redemonstrated longer bypass times and longer lengths of hospital stay with combined CABG and MV repair, as well as an increased rate of serious neurologic events (stroke, transient ischemic attack, and metabolic encephalopathy) and supraventricular arrhythmias, but no mortality difference between treatment groups.³⁶ Two-year results from this study did not identify any significant differences in LV reverse remodeling, overall hospital readmissions, mortality or a composite end point of death, stroke, subsequent mitral-valve surgery, hospitalization for HF, or worsening functional class between treatment groups. The frequency of moderate-to-severe MR remained lower in the combined CABG-MV repair group (11.2% vs 32.3% for CABG alone, P < .001). Neurologic events and supraventricular arrhythmias remained more frequent in the combined CABG-MV repair group.³⁷

In summary, the addition of MV repair to CABG in patients with moderate IMR does not appear to increase perioperative mortality risk but may increase perioperative morbidity as performed in some centers.³⁸ Studies to date have not been powered to detect differences in survival or functional outcomes between CABG alone and CABG combined with MV repair. Although surgical revascularization alone can decrease MR severity in patients with preoperative moderate IMR, the addition of MV repair is associated with reduced prevalence of moderate or severe MR in follow-up, but whether this translates into clinically meaningful improvements in hard end points remains uncertain. The American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines for Management of Patients With Valvular Heart Disease provide a class IIb recommendation (level of evidence: C) that MV repair may be considered for patients with chronic moderate, secondary MR who are undergoing other cardiac surgery (Table 49–3).¹⁴

Surgery for Severe IMR

Observational data from the STICH trial suggest that adding MV repair to CABG in patients with LVEF ≤ 35% and moderate-to-severe MR may improve survival compared to CABG alone (adjusted hazard ratio (HR) for mortality 0.41 (95% CI, 0.22-0.77); P = .006), though the number of events in this trial was small.⁵ Current AHA/ACC recommendations state that MV surgery is reasonable for patients with chronic severe IMR (stages C and D) who are undergoing CABG or aortic valve replacement (class of recommendation: IIa; level of evidence: C). Surgery may also be considered for patients with chronic severe IMR (stage D) who remain severely symptomatic (NYHA class III to IV) despite optimal guideline-directed medical therapy for HF (class of recommendation: IIb; level of evidence: B).¹⁴ A summary of AHA/ACC and ESC recommendations for surgical management of chronic severe MR is presented in Table 49–3.

In the setting of severe IMR, debate has focused on the role of MV repair versus MV replacement (MVR). Repair has been felt safer with lower perioperative mortality and morbidity, though generally associated with a higher rate of recurrent MR compared with replacement. A randomized multicenter trial assigned 251 patients with severe IMR to undergo either MV repair (n = 126) or chordal-sparing MVR (n = 125) and did not demonstrate any significant difference in LV end-systolic volume indexed to body surface area at 1 and 2 years (primary end point). No differences in survival or the incidence of major adverse cardiac and cerebrovascular events were found. The rate of recurrence of moderate or severe MR was significantly higher in the repair compared to the replacement group (32.6% vs 2.3% at 1 year, P < .001; and 58.8% versus 3.8% at 2 years, P < .001), resulting in more adverse events related to HF and cardiovascular readmissions. ^6,11 Numerous observational studies have identified echocardiographic predictors of recurrent MR following MV annuloplasty, including an LV end-diastolic diameter > 65 mm, coaptation depth > 1 cm, and systolic sphericity index > 0.7.²⁶ In the randomized trial of repair versus replacement, only basal aneurysms and dyskinesis were significantly associated with recurrent moderate or severe MR in patients following repair for severe IMR.³⁹ It is important to note that none of the prediction models for recurrent MR have been externally validated. Durability of repair is also influenced by the natural history of underlying ventricular dilation over time; progressive dilation will undermine the integrity of MV repair.

Percutaneous Interventions

Although a variety of percutaneous therapies for MR have been developed, the MitraClip system (Abbott Vascular, CA, USA) has emerged clinically as the most tolerated and effective approach to date. The MitraClip is a transcatheter mitral device for use in high-risk or inoperable patients with severe MR and suitable anatomic criteria. Favorable and unfavorable anatomic criteria are presented in Table 49–4. By means of venous access, the device is advanced into the left atrium using a transseptal approach and grasps the MV leaflets, achieving edge-to-edge approximation, and thereby creating a double MV orifice (Fig. 49–7). It is currently approved by the US Food and Drug Administration for use in symptomatic patients with primary (degenerative) MR who are at prohibitive risk for surgery; it is not approved for treatment of IMR in the United States, but is under investigation for this indication through the Clinical Outcomes Assessment of MitraClip Percutaneous Therapy for Extremely High-Surgical-Risk Patients (COAPT) trial.¹⁶ In contrast, the MitraClip system has already received a class IIb recommendation by the European Society of Cardiology for secondary MR (Table 49–3). Worldwide, it is estimated that approximately two-thirds of the MitraClip procedures have been performed in patients with secondary MR.

Only 27% of patients in the original Endovascular Valve Edge-to-Edge Repair (EVEREST) II study, which was designed to assess the safety and effectiveness of the MitraClip device, had secondary MR.⁴⁰ In contrast, 77% of 567 patients enrolled in the European prospective, muticenter, nonrandomized postapproval ACCESS-EU study of MitraClip therapy had secondary MR. Of patients with secondary MR in this real-world postapproval experience, 41% were over 75 years of age (mean age = 73 y) and 48% had a logistic EuroSCORE ≥ 20%. Mortality at 1 year for these patients was 17%. Most patients (91.7%) achieved reduction in MR to ≤ 2+ at discharge, but 21.5% manifested > 2+ MR at 12 months. Improvements were observed in NYHA functional class, six-minute walk distance, and Minnesota Living with HF Questionnaire score.⁴¹ Fifty-nine percent of the 78 patients with severe symptomatic MR and an estimated surgical mortalityr of ≥ 12% who underwent the MitraClip procedure as part of the EVEREST II high-risk study had secondary MR. In this study, the MitraClip device reduced MR in the majority of patients, resulting in LV reverse remodeling, improvement in NYHA functional class, and improvements in quality of life over 12 months. Furthermore, the 12-month survival rate for this high-risk cohort treated with MitraClip was 76% compared to 55% in a group of patients screened concurrently but not enrolled in the study who received standard of care.⁴² Direct, nonrandomized comparisons between MitraClip therapy and surgery are difficult because of significant differences in patients referred for either strategy.

It will be necessary to continuously reappraise safety and efficacy of MitraClip therapy as experience grows in high-volume centers treating higher surgical risk patients with secondary MR with advanced LV dysfunction/remodeling and greater burden of comorbidities. In summary, percutaneous edge-to-edge repair using the MitraClip system is an alternative that can reduce symptoms and induce LV reverse remodeling, but is often associated with residual and recurrent MR. As such, it can be considered as an adjunct to guideline directed medical therapy (with or without CRT) in stage D IMR who fulfill anatomical criteria and are judged high-risk or inoperable by a multidisciplinary heart team in Europe,²⁶ but it is not currently approved for IMR in the United States outside of clinical trials. Intense investigational efforts are underway in the application of other transcatheter therapies in the management of MR.⁴³

Management of CAD

Given the causal association of CAD and IMR, guideline-directed management of CAD is important in patients with IMR.⁴⁴ Prompt reperfusion in the setting of acute ST-segment elevation MI to minimize adverse LV remodeling and injury to papillary muscles is paramount to prevent/reduce subsequent IMR. Evidence of myocardial ischemia and/or myocardial viability on cardiac imaging in patients with IMR should prompt consideration of percutaneous or surgical revascularization, in the hope of promoting LV reverse remodeling.

Management of Atrial Fibrillation

AF is commonly associated with MR, and is present in up to 50% of patients undergoing MV surgery.⁴⁵ Left atrial chamber enlargement as a consequence of increased pressure and volume load to the left atrial from MR is implicated in genesis of AF.⁴⁶ AF may be a marker of disease progression and worse prognosis in IMR. Management of AF in terms of rate control, rhythm control, and anticoagulation should be according to international practice guidelines.⁴⁷ Surgical approaches for AF with/without left atrial appendage ligation can be considered in patients undergoing MV surgery. Risk factors for return of AF after the Cox maze procedure include duration of preoperative AF, left atrial size, and reduced LV function.⁴⁸

Advanced Heart Failure Therapies

Select patients with advanced stage D HF and IMR, who are refractory to guideline-directed medical therapy, should be referred to an advanced HF service for consideration of cardiac transplantation and/or durable mechanical circulatory support (eg, left ventricular assist device) either as destination therapy or bridge to transplantation. Advanced age and significant burden of comorbidities render many patients with IMR ineligible for these therapies.

Palliative Care

The morbidity and mortality associated with IMR increase with severity of disease, and the trajectory of the disease is unpredictable. Therefore, it is important to consider referral to palliative care services at a timely point in this chronic life-limiting illness. Involving palliative care specialists can facilitate conversations around advanced care planning.⁴⁹

IMR frequently complicates ischemic heart disease and is associated with functional and prognostic limitations. The mechanism of IMR is related to distortion of the normal spatial and functional relationships of the LV and MV apparatus, usually as a consequence of LV adverse remodeling following myocardial ischemia/MI. Noninvasive imaging, which usually employs echocardiography at rest and stress, is useful to establish etiology and severity of IMR, and to assess for myocardial ischemia and/or viability. Accurate grading of IMR severity is challenging and requires careful integration of multiple imaging parameters at rest and/or during exercise, and clinical data, in addition to a careful assessment of LV size and function. Given that IMR is primarily a disease of the myocardium, guideline-directed medical therapies of associated CAD and HF, including appropriate use of CRT, that may promote LV reverse remodeling are paramount in IMR. The role of MV surgery in IMR remains controversial, especially in patients who do not require concomitant CABG or other valve surgery. Percutaneous MV repair offers an invasive alternative to surgery in select patients and its role in management of IMR is the subject of a large randomized clinical trial (COAPT). IMR appropriately remains the focus of much clinical research because of the need for better therapies to improve outcomes for this common, progressive, and morbid disease.