JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO. 12, 2015 ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00 PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2015.02.009 THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW Secondary Mitral Regurgitation in Heart Failure Pathophysiology, Prognosis, and Therapeutic Considerations Anita W. Asgar, MD,* Michael J. Mack, MD,y Gregg W. Stone, MDz ABSTRACT The development of secondary mitral regurgitation (MR) due to left ventricular dysfunction, also known as functional MR, is strongly associated with a poor prognosis in patients with heart failure. The mechanisms underlying secondary MR are multifactorial; accurate imaging assessment of secondary MR may be challenging and nuanced; and the appropriate roles of medical, surgical, and interventional therapies for management of secondary MR are controversial and evolving. In this review, the pathophysiology, evaluation, and prognosis of secondary MR in patients with heart failure are discussed, and we evaluate in detail the evidence for the various therapeutic approaches for secondary MR, including guideline-directed medication for left ventricular dysfunction, cardiac resynchronization therapy and revascularization when appropriate, and mitral valve surgery and transcatheter interventions. The role of a multidisciplinary heart team in determining the optimal management strategy for secondary MR is also discussed. (J Am Coll Cardiol 2015;65:1231–48) © 2015 by the American College of Cardiology Foundation. M itral regurgitation (MR) is among the most diagnosis of secondary MR, as well as potential common valvular heart disorders, with an therapeutic approaches. estimated prevalence in the United States of w1.7%, increasing with age to w9.3% in those >75 PATHOPHYSIOLOGY OF SECONDARY MR years of age (1). MR is classified as primary (also known as organic) when principally due to a struc- The MV consists of 2 leaflets (anterior and posterior) tural or degenerative abnormality of the mitral valve sitting within the annulus (Figure 1). The posterior (MV), whether of the leaflets, chordae tendineae, mitral leaflet originates from the left atrial (LA) papillary muscles, or mitral annulus. Secondary endocardium. A subvalvular apparatus, comprising 2 (also known as functional) MR occurs in the absence papillary muscles (anteromedial and posterolateral) of organic MV disease, usually from left ventricular arising from the LV myocardium and the chordae (LV) dysfunction. It is more common than primary tendineae, supports the leaflets. LV dilation due to MR (2), is associated with a worse prognosis (com- ischemic or nonischemic cardiomyopathy secondarily pounded by the underlying cardiomyopathy), and impairs leaflet coaptation of a structurally normal (in contrast to primary MR) the benefits of MV surgery MV, resulting in secondary MR. Specifically, LV are uncertain. The present report reviews the etiol- dysfunction and remodeling lead to apical and lateral ogy, pathophysiology, prognostic implications, and papillary muscle displacement, resulting in leaflet From the *Montreal Heart Institute, Montreal, Quebec, Canada; yHeart Hospital Baylor Plano, Baylor HealthCare System, Dallas, Texas; and the zColumbia University Medical Center and Cardiovascular Research Foundation, New York, New York. Dr. Asgar has served as a consultant for Abbott Vascular. Dr. Mack was a member of the executive committee of the Partner Trial (Edwards Lifesciences, uncompensated); and is co-principal investigator of the Coapt Trial (Abbott Vascular, uncompensated). Dr. Stone has equity in Guided Delivery Systems and Micardia; and is co-principal investigator of the Coapt Trial (Abbott Vascular, uncompensated). Manuscript received December 8, 2014; revised manuscript received January 16, 2015, accepted February 3, 2015. 1232 Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation ABBREVIATIONS tethering (3), dilation and flattening of the posteriorly directed asymmetric regurgitant jet (Car- AND ACRONYMS mitral annulus, and reduced valve closing pentier Type IIIB) (10). Mitral annular dilation typically forces. Because these changes are dependent occurs late in the pathophysiology of secondary MR, on loading conditions and the phase of the and is often asymmetric, with greater involvement cardiac cycle, secondary MR is dynamic in of the posterior annulus (11). Papillary muscle in- nature. farction is rarely the cause of secondary MR (12). ACEI = angiotensin-converting enzyme inhibitor(s) CRT = cardiac resynchronization therapy Papillary muscle displacement occurs as a Nonischemic MR, most commonly due to long- orifice area result of global LV enlargement or focal standing hypertension or idiopathic dilated car- EROA = effective regurgitant GDMT = guideline-directed myocardial scarring, and can affect 1 or diomyopathy, is characterized by global LV dilation medical therapy both papillary muscles, causing posteriorly with increased sphericity and (typically) a centrally HF = heart failure directed or central MR (Figure 2) (4). With located regurgitant jet. Symmetric mitral annular LBBB = left bundle branch chronic MR, the mitral leaflet area may in- dilation is greatest in the septal-lateral direction, and block crease up to 35% over time, an adaptive correlates with the severity of LV dysfunction (13). LVEF = left ventricular response of MR DUE TO ATRIAL FIBRILLATION. An additional, regurgitation; insufficient leaflet remodeling although relatively infrequent, cause of severe sec- may contribute to severe MR (5,6). However, ondary MR is isolated LA enlargement, with or with- even in patients with increased mitral leaflet out atrial fibrillation, resulting in a dilated mitral area, papillary muscle displacement with annulus and reduced leaflet coaptation (without subsequent decreased coaptation length may tenting or prolapse), with normal LV function and still result in significant MR (6). mitral leaflets (Carpentier Type I) (14). In patients ejection fraction MDCT = multidetector computed tomography MR = mitral regurgitation MV = mitral valve NYHA = New York Heart Association that minimizes the degree The normal saddle-shape of the annulus is with atrial fibrillation, improvement in MR severity important for maintaining normal leaflet stress (7). may occur with restoration of sinus rhythm, sug- Loss of this shape and annular flattening with LV gesting a causal relationship (14). remodeling result in increased leaflet stress with secondary MR. In addition, LV systolic dysfunction PROGNOSTIC IMPLICATIONS OF SECONDARY MR reduces the strength of MV closing, which opposes the leaflet tethering forces created by papillary A strong association between secondary MR severity muscle displacement. These pathological changes and both all-cause mortality and heart failure (HF) culminate in failure of leaflet coaptation and de- hospitalizations has been reported. Among 303 pa- creased valvular closing forces due to LV dysfunc- tients with a completed Q-wave MI, any ischemic MR tion, resulting in MR. The Carpentier classification, was detected by echocardiography in 194 patients commonly used by surgeons to describe MV pathol- (64.0%) and was a powerful, independent correlate ogy, categorizes MR using a mechanistic and func- of long-term all-cause mortality (relative risk: 1.88 tional approach to the mitral leaflets (8). Secondary [95% confidence interval (CI): 1.23 to 2.86], p ¼ 0.003) MR is most commonly Carpentier type IIIB, and (15). In a study from the Duke Cardiovascular Data- occasionally type I. bank, qualitatively assessed 3þ to 4þ MR on left ISCHEMIC VERSUS NONISCHEMIC MR. MR can be ventriculography was present in 29.8% of 2,057 HF further classified as either ischemic or nonischemic. patients with an LVEF <40% and was an independent In ischemic MR (the more frequent etiology), LV predictor of 5-year mortality (adjusted hazard ratio remodeling after myocardial infarction (MI) results [HR]: 1.23 [95% CI: 1.13 to 1.34]) (16). Among 1,256 in papillary muscle displacement, causing systolic patients with dilated cardiomyopathy at the Mayo tenting of the MV. Global left ventricular ejection Clinic, quantitatively assessed severe secondary MR fraction (LVEF) does not have to be reduced; regional (defined as an effective regurgitant orifice area wall motion abnormalities with remodeling may [EROA] >0.2 cm 2, a regurgitant volume >30 ml, or a result in sufficient MV tethering to cause severe MR, vena contracta width >0.4 cm) was present in 24% of despite preserved LVEF (9). Symmetric or asymmetric patients, and was an independent predictor of death leaflet tethering may occur. Symmetric tethering or HF hospitalization at median 2.5-year follow-up is associated with substantial systolic dysfunction, (adjusted HR: 1.5 [95% CI: 1.2 to 1.9]), independent global remodeling, and increased LV sphericity of LVEF (17). This relationship was present separately with a central regurgitant jet. Asymmetric tethering for death and HF hospitalizations, and in patients most frequently results from localized remodeling with ischemic and nonischemic MR (Figure 3). Sec- affecting the posterior papillary muscle, with posterior ondary MR is a powerful predictor of death or trans- tenting of both leaflets (most pronounced at the medial plant, even with less severe HF (18). However, or P3 portion of the posterior leaflet) causing a although secondary MR is widely accepted to predict Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation distance and length, and tenting area are useful F I G U R E 1 Mitral Valve Anatomy in evaluating the suitability of secondary MR for various interventional options. Conversely, because LV unloading may lessen regurgitation, quantification of MR severity is most accurately assessed in the awake patient by transthoracic echocardiography, thereby avoiding the vasodilatory effects of sedation, hypovolemia, and/or anesthesia with transesophageal echocardiography. Echocardiography is also indispensable for determining LV volumes, function, and sphericity; for assessing pulmonary artery pressures and right ventricular function and quantifying tricuspid regurgitation; for assessing the anatomic likelihood for successful MV repair or transcatheter approaches; for guiding surgical and transcatheter repair procedures; and for appraising the durability and functional effect of MV therapies through serial assessments over time. The diagram illustrates the valve and supporting structures. The echocardiographic degree of MR, evaluated by integrating qualitative and quantitative assessments, is classified as mild, moderate, or severe (20). Qualia poor prognosis in patients with primary LV dys- tative findings include MV morphology and color flow function and HF, whether this relationship is causal and continuous wave signals of the MR jet. Semi- and whether reducing MR improves patient prognosis quantitative insights into MR severity are provided remain unknown. by pulmonary vein flow and mitral inflow patterns. Quantitative measures include EROA, regurgitant EVALUATION OF SECONDARY MR volume, and regurgitant fraction. Enlarged LA and LV chamber size and increased pulmonary artery pres- Comprehensive evaluation of the patient with HF sures provide supportive data for severe MR. and secondary MR requires a detailed medical history Conventional 2-dimensional (2D) assessment for and physical examination, with laboratory, electro- MR quantification relies on measurement of the MR cardiographic, and echocardiographic assessment. jet core at its vena contracta or proximal convergence Most important is an accurate appraisal of the func- zone using methods that assume circular orifice ge- tional limitations attributable to HF, the MV anatomy ometry. MR severity may, therefore, be significantly and severity of MR, and evaluation of the left and underestimated when the orifice is elliptical (as right heart circulation, including measurement of is typical in secondary MR) (4), a situation that is chamber size and cardiac pressures. By integrating compounded if multiple jets are present. Three- these findings, secondary MR can be categorized into dimensional (3D) echocardiography overcomes this 4 stages that define prognosis and guide therapy: limitation by permitting direct planimetry of the 1) at risk of secondary MR; 2) progressive secondary vena contracta, regardless of orifice shape or number MR; 3) asymptomatic severe secondary MR; and 4) of jets (21). Conversely, both 2D and 3D color flow symptomatic severe secondary MR (Table 1) (19). Doppler tend to overestimate the orifice area because ECHOCARDIOGRAPHY. The diag- of their inability to resolve the high velocity jet core nostic evaluation of MR is echocardiography, with due to aliasing and blooming artifacts. Secondary transesophageal and transthoracic echocardiogra- MR severity also varies during the cardiac cycle, and phy playing complementary roles. Transesophageal can peak in early or late systole, further complicating echocardiography most often accurately identifies evaluation, which is traditionally done in midsystole. cornerstone of the underlying cause and mechanism of MR, whether No single parameter is sufficient to quantify the primary or secondary. A mixed etiology is not un- degree of MR, and multimodality assessment using common (e.g., secondary MR with leaflet thickening both 2D and 3D echocardiography is optimal (22). or mitral annular calcification). Transesophageal Although somewhat controversial, outcomes echocardiographic measurements of leaflet length studies suggest that lesser absolute quantitative and angles (particularly the posterolateral angle, degrees of regurgitation in secondary MR may have signifying posterior leaflet tethering), coaptation the same or greater effect on mortality than in 1233 1234 Asgar et al. JACC VOL. 65, NO. 12, 2015 Secondary Mitral Regurgitation MARCH 31, 2015:1231–48 F I G U R E 2 Secondary MR Due to Left Ventricular Dilation (A) A representative echocardiogram and diagram of ischemic MR, with a posteriorly directed jet. (B) A representative echocardiogram and diagram of MR due to idiopathic dilated cardiomyopathy, with a central jet. Note the lateral displacement of the papillary muscles (arrows). Apical displacement is also typically present, although less well demonstrated in these views. LVOT ¼ left ventricular outflow tract; MR ¼ mitral regurgitation; TEE ¼ transesophageal echocardiography. primary MR (15,20). Whereas severe primary MR is mitral annulus. Such changes can occur in the usually defined as an EROA of $40 mm 2 and a absence of ischemia (26) and may result in acute regurgitant volume of $60 ml, Sarano et al. (15) pro- pulmonary edema (27). Exercise-induced severe MR posed and the most recent U.S. and European valve may identify patients at heightened risk for death or guidelines have accepted EROA $20 mm 2 and regur- HF hospitalization (28). Quantitatively, an exercise- gitant volume $30 ml as consistent with severe sec- induced EROA increase of $13 mm 2 has been as- ondary MR (19,23) (Table 2). However, the amount of sociated with increased morbidity and mortality, MR (assessed by either EROA or regurgitant volume) although measuring EROA during or immediately resulting in loss of >50% of total stroke volume (i.e., after exercise is technically challenging due to the regurgitant volume) depends on the LV end- tachycardia and tachypnea (29). Exercise echocardi- diastolic volume and LVEF (24). This likely explains ography may also demonstrate increasing pulmonary why some studies show an adverse prognostic effect artery pressures and lack of LV contractile reserve, of lesser EROA values, whereas others do not. findings associated with LV dysfunction and poor Exercise echocardiography may be useful when prognosis after MV surgery (30,31). Exercise may also symptoms appear disproportionate to resting MR induce greater LV dyssynchrony with increased severity (25). Exercise results in greater pre-load MR, which might improve with cardiac resynchroni- and afterload, a more spherical ventricle, increased zation therapy (CRT) (see later discussion). However, coaptation distance, and systolic expansion of the the predictive value of exercise echocardiography is Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation F I G U R E 3 Prognosis of Quantitatively Determined Secondary Mitral Regurgitation in Patients With Ischemic and Nonischemic Cardiomyopathy Survival Free From HF Hospitalization (%) 100 Adj HR for sev FMR = 1.5 (1.2 to 1.9; p=0.001) Adj HR for mild/mod FMR = 1.2 (0.96 to 1.6), p=0.09) 80 60 No FMR (n=335) 40 20 Mild/moderate FMR (n=611) P<0.0001 Severe FMR (n=304) 0 0 1 2 3 4 Years 5 Ischemic cardiomyopathy (n=645) 100 7 Non-Ischemic cardiomyopathy (n=424) 100 80 80 60 No FMR Mild/moderate FMR 40 Severe FMR 20 Survival (%) Survival (%) 6 No FMR 60 Mild/moderate FMR 40 Severe FMR 20 P<0.0001 0 P<0.0001 0 0 1 2 3 4 5 6 0 Years 1 2 3 4 5 6 Years (Top) Freedom from death or heart failure (HF) hospitalization in 1,256 patients according to the degree of functional mitral regurgitation (FMR). (Bottom) Freedom from death according to the degree of FMR in patients with ischemic (lower left) and nonischemic (lower right) cardiomyopathy. Adapted with permission from Rossi et al. (17). HR ¼ hazard ratio. imperfect, given the technical issues of measuring (LV end-diastolic dimension >65 mm, end-systolic key parameters at or just after peak exercise; dimension >51 mm, or systolic sphericity index confounding interpretations due to concomitant >0.7); and 3) local LV remodeling (interpapillary ischemia and/or patient deconditioning (with limited muscle distance >20 mm, posterior papillary-fibrosa exercise capacity); and the potential for LV remodel- distance >40 mm, or lateral wall motion abnormal- ing with changing loading conditions after MV repair ity) (32). In a series of 300 patients with severe MR in some patients. Larger studies are required to undergoing MitraClip (68% of whom had secondary determine the role of exercise echocardiography in MR), failure to achieve #2þ MR occurred in 31 pa- evaluation of the patient with secondary MR. tients (10.3%). By multivariable analysis, predictors Echocardiography is also useful in determining the of failed MitraClip included greater EROA (odds likelihood of successful MV repair by either surgery or ratio [OR]: 1.21 per 10 mm2 increase, p ¼ 0.005) and transcatheter procedures (e.g., the MitraClip, Abbott baseline transmitral pressure gradient $4 mm 2 (OR: Vascular, Menlo Park, California) in patients with 1.26, p ¼ 0.03). Success rates were similar with pri- secondary MR. In patients with secondary MR mary and secondary MR (33). Of note, due to the undergoing surgery, successful repair is less likely double MV orifice and artifacts from the clip(s), in the presence of: 1) MV deformation (coaptation quantifying MR severity after the MitraClip with distance $1 cm, tenting area >2.5 to 3 cm2 , and/or echocardiography can be challenging. complex jets originating centrally and posteromedially, posterolateral angle >45 [high poste- NONECHOCARDIOGRAPHIC IMAGING TECHNIQUES. rior leaflet tethering]); 2) global LV remodeling Cardiac magnetic resonance (CMR) imaging and 1235 1236 Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation T A B L E 1 Stages of Secondary (Functional) MR Valve Anatomy Valve Hemodynamics* Cardiac Structure and Function Symptoms A: At risk of MR Grade Normal valve leaflets, chords, and annulus in a patient with coronary disease or cardiomyopathy No MR jet or small central jet area <20% LA on Doppler Small vena contracta <0.30 cm Normal or mildly dilated LV size with fixed (infarction) or inducible (ischemia) regional wall motion abnormalities Primary myocardial disease with LV dilation and systolic dysfunction Symptoms due to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy B: Progressive MR Regional wall motion abnormalities with mild tethering of mitral leaflet Annular dilation with mild loss of central coaptation of the mitral leaflets EROA <0.20 cm2 Regurgitant volume <30 ml Regurgitant fraction <50% Regional wall motion abnormalities with reduced LV systolic function LV dilation and systolic dysfunction due to primary myocardial disease Symptoms due to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy C: Asymptomatic severe MR Regional wall motion abnormalities and/or LV dilation with severe tethering of mitral leaflet Annular dilation with severe loss of central coaptation of the mitral leaflets EROA $0.20 cm2 Regurgitant volume $30 ml Regurgitant fraction $50% Regional wall motion abnormalities with reduced LV systolic function LV dilation and systolic dysfunction due to primary myocardial disease Symptoms due to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy D: Symptomatic severe MR Regional wall motion abnormalities and/or LV dilation with severe tethering of mitral leaflet Annular dilation with severe loss of central coaptation of the mitral leaflets EROA $0.20 cm2 Regurgitant volume $30 ml Regurgitant fraction $50% Regional wall motion abnormalities with reduced LV systolic function LV dilation and systolic dysfunction due to primary myocardial disease HF symptoms due to MR persist even after revascularization and optimization of medical therapy Decreased exercise tolerance Exertional dyspnea *Several valve hemodynamic criteria are provided for assessment of MR severity; not all criteria for each category will be present in each patient. Categorization of MR severity as mild, moderate, or severe depends on data quality and integration of these parameters in conjunction with other clinical evidence. Adapted with permission from Nishimura et al. (19). EROA ¼ effective regurgitant orifice area; HF ¼ heart failure; LA ¼ left atrium; LV ¼ left ventricular; MR ¼ mitral regurgitation. multidetector row computed tomography (MDCT) (CRT) when appropriate. Coronary revascularization can provide complementary information to echocar- may also be considered in patients with extensive diography in patients with MR. CMR, in particular, ischemia and preserved myocardial viability, al- is highly accurate for quantifying the degree of MR though it rarely markedly reduces or eliminates sec- (34). Given its high spatial resolution, MDCT can ondary MR. The role of surgical and transcatheter accurately depict MV structure and morphology MV repair or replacement to interrupt the progres- (35), and is useful in demonstrating the relationship sive cycle of LV volume overload / LV dilation / of the MV complex to other cardiac structures secondary MR / increasing LV volume overload and (e.g., the relationship of the coronary sinus to the dilation / increasing MR is less well established, mitral annulus and circumflex coronary artery) (36). although some patients may symptomatically benefit. Both techniques provide true volumetric measures of Finally, in patients with severe HF and secondary chamber dimensions and function and also assess MR refractory to standard therapies, consideration myocardial fibrosis (scar). In the future, CMR and should be given to mechanical LV assist devices and MDCT will likely be increasingly used in the evalua- heart transplantation. tion of patients with HF and MR. THERAPEUTIC CONSIDERATIONS FOR SECONDARY MR MEDICAL THERAPY FOR SECONDARY MR GDMT for HF is first-line treatment for patients with secondary MR (19), although the morbidity and mor- The goals of therapy in patients with secondary MR tality of patients with LV dysfunction and secondary are to improve symptoms and quality of life, reduce MR remain high. Among 404 secondary MR patients HF hospitalizations, and potentially improve sur- treated with GDMT, 4-year cardiac mortality occurred vival. To date, the most effective therapies for in 43% and 45% with moderate and severe MR, secondary MR are aimed at the underlying LV respectively, compared with only 6% with mild MR dysfunction, including guideline-directed medical (p ¼ 0.003) (37). Moderate or severe MR was also an therapy (GDMT) for HF and biventricular pacing independent predictor of new onset HF in patients Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 with ischemic LV dysfunction (relative risk: 3.2 [95% CI: 1.9 to 5.2], p ¼ 0.0001). Secondary Mitral Regurgitation T A B L E 2 Quantitative Echocardiographic Criteria for Severe MR in Primary and Secondary Disease of the Mitral Valve Beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are recommended for all patients Primary (Organic) MR Secondary (Functional) MR with LV dysfunction and secondary MR. By reversing EROA $0.4 cm2 $0.2 cm2* LV remodeling, maximal GDMT may secondarily Regurgitant volume $60 ml $30 ml reduce severe MR. Surprisingly, however, few studies Regurgitant fraction $50% $50% have examined the effect of medical therapies on Vena contracta $0.7 cm — secondary MR. In several small, nonrandomized Jet area Central jet >40% LA or holosystolic eccentric jet — studies, carvedilol in patients with HF and secondary MR was associated with improved LV systolic function with reduced MR severity lasting 6 to 12 months (38,39). In a randomized trial of 59 patients with *Measurement of the proximal isovelocity surface area by 2-dimensional transthoracic echocardiography in secondary MR underestimates the true EROA due to the crescent shape of the proximal convergence. Adapted with permission from Nishimura et al. (19). Abbreviations as in Table 1. HF and severe dilated cardiomyopathy, treatment with carvedilol versus placebo resulted in reduced LV mass and sphericity, with improved systolic $150 ms. CRT may also be useful in patients with function. The severity of MR, assessed by the ratio of LVEF #35%, with sinus rhythm and non-LBBB pattern MR jet area/LA area, increased during follow-up in with QRS duration $150 ms, and in those with LBBB the placebo group, but decreased in the carvedilol and QRS duration 120 to 149 ms (Class IIa indications) group (p ¼ 0.04) (40). In the largest randomized trial, (43). Randomized trials demonstrated improvements among 138 patients with dilated cardiomyopathy on in both survival and HF rehospitalization rates in stable doses of digoxin, diuretic agents, and ACEI patients treated with CRT with or without a defibril- assigned to metoprolol (titrated to 50 mg, 3 times lator (44), along with reductions in LV end-diastolic a day) or placebo, the metoprolol group had greater and end-systolic dimensions and improved LVEF. 6-month reductions in LV end-diastolic and end- The effect of CRT on secondary MR is inconsistent, systolic volumes, which correlated with improved although most studies show a reduction in overall secondary MR (41). However, MR improved in only MR severity with restoration of synchronous ven- w42% of metoprolol-treated patients (vs. 20% of tricular contraction and LV remodeling. In the control-group patients), and there were no significant sham-controlled MIRACLE (Multicenter InSync Ran- differences in symptoms or rates of cardiac read- domized Clinical Evaluation) trial of 450 NYHA mission or death during follow-up. functional class III/IV HF patients with LVEF #35% Less has been reported on the ability of ACEI and and QRS duration $130 ms, CRT resulted in marked other agents to reduce secondary MR. In a small study reductions in LV end-diastolic and end-systolic vol- of 19 patients with severe dilated cardiomyopathy umes, improved LVEF, and sustained reductions in (mean LVEF w20%) and 3þ/4þ MR on stable doses MR (assessed by the relative size of the mitral jet area of digoxin, diuretic agents, lisinopril, and isosorbide in the LA) (45). Similarly, in a sham-controlled trial of dinitrate, lisinopril was up-titrated from a mean 16 610 NYHA functional class I/II HF patients with to 55 mg/day, and isosorbide from 30 to 286 mg/day. LVEF #40% and QRS duration $120 ms, CRT resulted At 12-month follow-up, MR had decreased to grade in sustained reductions in MR severity at 3 and 0/1þ in 8 patients (42%; the MR responders), and 6 months, with parallel improvements in LV di- remained 3þ/4þ in the remainder. LVEF improved mensions (46). In addition to reducing LV dimen- in both groups, but to a greater degree in the MR sions and restoring papillary muscle geometry, CRT responders, and the LV end-diastolic dimension can acutely reduce secondary MR by increasing the decreased in the responders, but increased in the rise in the transmitral pressure gradient and altering nonresponders (42). the balance between the closing and tethering forces CRT FOR SECONDARY MR moderate/severe MR, 43% experienced immediate on the MV (47). In a study of 63 patients with HF and improvement in MR by $1 grade, as assessed by vena CRT is a well-established treatment for HF in selected contracta width after CRT, and an additional 20% patients with LV dyssynchrony. CRT is a Class I demonstrated late improvement at 6 months (48). recommendation for patients in sinus rhythm with Unfortunately, severe secondary MR improves in New York Heart Association (NYHA) functional class no more than one-half of patients after CRT, although II to IV symptoms on GDMT with LVEF #35%, such improvement identifies a cohort with an left bundle branch block (LBBB), and QRS duration improved prognosis. In a study of 85 HF patients with 1237 1238 Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation 3þ/4þ secondary MR, MR grade at 6 months was long-term follow-up failed to demonstrate a survival reduced after CRT in 42 (49%). Two-year survival was benefit. Isolated MV annuloplasty was performed in 92% in MR responders versus 67% in nonresponders 126 of 419 patients with severe secondary MR and (p < 0.001) (49). In a recent study of 240 HF patients LVEF #30% at the University of Michigan (52). At a (114 with $2þ secondary MR), MR severity at 6 mean 5.5-year follow-up, the propensity-adjusted months decreased in 48 (42%), remained stable in 42 freedom from death, LV assist device, or United (37%), and worsened in 24 (21%). The 4-year adverse Network event rates were strongly predicted by the presence occurred in 41% of patients treated with medical of at least moderate MR after (but not before) CRT therapy alone versus 49% with annuloplasty. Mor- (50). It is not clear whether CRT improves the prog- tality occurred in 38% versus 48% of patients in nosis of secondary MR independent of its effects the medical versus surgical groups, respectively. on LV dysfunction or whether MR responders after Unfortunately, quality of life and functional outcome CRT represent a cohort with a more favorable prog- measures were not assessed. for Organ Sharing-1 transplant listing nosis. In this regard, CRT-treated HF patients with Recurrent MR is frequent after MV annuloplasty for versus without secondary MR have a worse prog- secondary MR. Despite its initial abolition in nearly nosis; EROA $0.20 cm2 predicts poor response to all patients, moderate or greater MR recurs in 15% to CRT, increased mortality, and HF rehospitalizations 25% of patients at 6 to 12 months, increasing to w70% (51). Nonetheless, if otherwise indicated, CRT is a at 5 years (55). Risk factors for MR recurrence include reasonable front-line therapy for secondary MR in HF more severe pre-operative MR, centrally directed or patients (along with GDMT), and should be performed multiple jets, greater degree of LV dilation, symmet- prior to MV surgery or transcatheter intervention. ric anterior leaflet tethering, presence of a basal SURGERY FOR SECONDARY MR aneurysm/dyskinesis, $11 mm coaptation height, and a posterior leaflet angle of >45 (56). Recurrent MR is also more frequent with use of partial bands or Surgical options for secondary MR include surgical flexible complete rings (57–59), although recurrence MV repair and replacement, mechanical LV assist rates remain high even with complete rigid rings (60). devices, and orthotopic heart transplantation. Al- The current standard repair uses a complete rigid though secondary MR can be acutely corrected by ring, most commonly 28 mm in men and 26 mm in MV surgery, the surgery has never clearly been women. Various ring designs have been developed, demonstrated to alter the natural history of the pri- including 1 specifically for ischemic MR, which mary disease (dilated cardiomyopathy) or improve overcorrects for the increased tethering of the P3 survival (52–55). Moreover, whether the response to segment (61). In patients with severe tethering, surgery is different in secondary MR due to ischemic chordal-sparing replacement may be preferable to versus nonischemic cardiomyopathy has not been annuloplasty due to less frequent MR recurrence, established. as discussed in the following text. MV ANNULOPLASTY. MV reconstruction with pres- STUDIES IN NONISCHEMIC MR. In 54 patients with ervation of annular-chordal-papillary muscle conti- dilated cardiomyopathy at a single center, secondary nuity results in maintenance of LV systolic function MR was treated primarily with undersized annulo- with reduced LV volumes and end-systolic wall plasty rings with or without concomitant edge- stress. The most commonly performed surgical tech- to-edge repair (57). At 5-year follow-up, 30% of nique is MV annuloplasty, which addresses only 1 patients had died, and moderate/severe MR had component of secondary MR: mitral annular dilation. recurred in 19%. In the ACORN trial, 193 patients with “Undersizing” the annuloplasty ring by matching predominately nonischemic MR underwent MV sur- the ring size to the anterior leaflet overcorrects the gery (84% with an annuloplasty ring) with or without annular dilation, minimizing the effects of leaflet placement of the CorCap LV restraint device (Acorn tethering (56). Annular dilation is most pronounced Cardiovascular, St. Paul, Minnesota). ACORN patients in the septal lateral dimension, and various ring were younger and more often female than in most designs have been used to overcorrect in this surgical series of secondary MR, and 30-day mortality dimension, thus restoring leaflet coaptation. was only 1.6% (62). However, during 5-year follow- The risk-benefit ratio for MV annuloplasty in pa- up, 30% of patients died, 15% had recurrent MR, tients with secondary MR not requiring coronary and 5% underwent repeat MV surgery (63). Additional artery bypass grafting (CABG) compared with med- studies are required before surgery can routinely ical therapy alone is uncertain. Although initial re- be recommended for secondary MR in nonischemic sults of undersized annuloplasty were encouraging, cardiomyopathy. Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation MV ANNULOPLASTY VERSUS REPLACEMENT. MV replacement (with either mechanical or bioprosthetic replacement was used initially for secondary MR, but valves) at 13 Italian centers between 1996 and 2011, was quickly abandoned due to frequent ventricular although the 8-year mortality rate was similar be- decompensation. LV dysfunction in this setting was tween the 2 groups, recurrent MR and MV reoperation due to early techniques including excision of the was 2.8-fold more common with repair (70). mitral leaflets and subvalvular apparatus, resulting The issue of repair versus replacement was in annular-ventricular discontinuity. Current valve- addressed in a recently reported National Institutes sparing MV replacement techniques, which leave of Health–sponsored trial from the Cardiothoracic the leaflets and subvalvular apparatus intact, pre- Surgical Trials Network (CTSN), in which 251 patients serve LV function. In general, valve-sparing MV with severe ischemic MR were randomized to un- replacement is preferred in patients with the most dergo either MV repair with an undersized rigid or severe degrees of tethering, as determined by a semirigid complete annuloplasty ring or chordal- tenting height >11 mm, a posterior leaflet angle >45 , sparing MV replacement (60). As seen in Table 3, or a basal aneurysm or dyskinesis (64–69). Other sit- there were no significant differences in the 1-year uations in which replacement is preferred include: primary endpoint of LV end-systolic volume index ruptured papillary muscle (acute ischemic MR); pa- or mortality. However, recurrence of at least moder- tients in cardiogenic shock; complex MR leaks with ate MR at 1 year was substantially greater with MV multiple jets; failure of an initial repair; and for repair compared with replacement (32.6% vs. 2.3%, surgeons who do not do many repairs. p < 0.001). The strongest predictor of MR recurrence Clinical studies suggested that repair is associated after repair was a basal aneurysm/dyskinesis at with lower perioperative mortality, whereas replace- baseline (present in 62.1% of patients with vs. 20.5% ment provides better long-term correction with a without recurrence, p < 0.001) (71). Hence, MV lower risk of recurrence (an important consideration, replacement should be strongly considered when an because MR recurrence predisposes to HF, atrial inferobasal aneurysm is present. fibrillation, and readmission). This perceived tradeoff between reduced operative morbidity and mortality OTHER SURGICAL PROCEDURES FOR SECONDARY MR. with repair versus better long-term correction of Although MV annuloplasty and replacement are the ischemic MR with replacement has generated sub- most common surgical procedures, a number of stantial variation in surgical practice for this high- other techniques have been employed with varying prevalence condition. degrees of success. In at least 2 series, cutting of the A meta-analysis of 9 retrospective, nonrandomized 2 critical secondary chords to the anterior leaflet studies from 2004 to 2009, comprising 1,730 total corrected secondary MR without significant ven- patients, compared MV repair with replacement for tricular decompensation (72,73). This technique is ischemic MR, with the majority of patients also un- most commonly employed in patients with severe dergoing CABG (69). The OR for short-term mortality with MV replacement versus repair was 2.67 (95% CI: 1.86 to 3.82), with a long-term mortality HR of 1.35 (95% CI: 1.13 to 1.62). A more recent single-center T A B L E 3 Selected 1-Year Outcomes of MV Repair Versus Replacement for Severe Ischemic MR (From the Cardiothoracic Surgical Trials Network) nonrandomized series confirmed this observation: 2.3% in-hospital mortality with MV repair versus 12.5% with replacement (p ¼ 0.03), a difference LVESVI (ml/m2; primary endpoint) maintained at a median 2.3-year follow-up (70). In Recurrent moderate/severe MR addition, those treated with MV repair (but not Moderate replacement) experienced improved LV function with Severe reverse LV remodeling. Some studies have suggested that MV replacement with preservation of the subvalvular apparatus may be associated with similar or even lower mortality than repair in HF, especially in patients with severe bileaflet tethering (posterior lateral angle >45 ), complex jets, and/or severe LV dysfunction or multiple comorbidities (67). Among 244 propensitymatched patient pairs with ischemic MR undergoing CABG with either MV ring annuloplasty or Death MV Repair (n ¼ 126) MV Replacement (n ¼ 125) 54.6 25.0 60.7 31.5 0.18* 32.6% 2.3% <0.001 28.4% 2.3% — 4.2% 0% — 14.3% 17.6% 0.45 0.25 p Value MV reoperation 2.4% 0% Major adverse cardiac events† 32.5% 33.6% 0.86 New York Heart Association functional class III/IV 9.0% 14.0% 0.28 24.5 23.1 19.6 19.4 0.12 Minnesota Living With Heart Failure score Values are mean SD or %. *Adjusted for death. †Death, stroke, New York Heart Association functional class increase by $1 grade, heart failure rehospitalization, or mitral valve reoperation. Adapted with permission from Acker et al. (60). LVESVI ¼ left ventricular end-systolic volume index; MV ¼ mitral valve. 1239 1240 Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation tethering of the anterior leaflet by the secondary be addressed at the time of CABG, because coronary chords (seagull deformity). The restriction of the revascularization alone will only occasionally ame- anterior leaflet can be relieved and coaptation liorate MR (77,78). In the RIME (Randomised Ischae- restored with the free margin of the leaflet left intact. mic Kron et al. (74) described subvalvular repositioning moderate secondary MR were randomized to CABG of the displaced posterior papillary muscle toward plus MV annuloplasty versus CABG alone (79). the right, fibrous trigone as an adjunct to annulo- MV repair prolonged the duration of aortic cross- plasty when severe degrees of tethering are present. clamping, cardiopulmonary bypass, intubation, and Another technique employed restoration of both hospitalization, and led to more blood transfusions, papillary muscles from their apical and lateral although operative mortality was 3% in both groups. distracted position into a more physiological parallel At 1 year, MV annuloplasty resulted in improved alignment, resulting in less leaflet tethering. peak oxygen consumption during exercise (the pri- In patients with severe mitral annular calcification in which the annulus has been rendered immobile, Mitral Evaluation) trial, 73 patients with mary endpoint), LV remodeling, and reduced MR severity (80). annuloplasty will not be effective, and replacement Several retrospective nonrandomized studies have is often not feasible. In these patients, a free edge- failed to demonstrate a survival benefit of MV repair to-edge approximation with suture (Alfieri tech- in patients undergoing CABG for ischemic heart nique) can improve the degree of MR (75). Likewise, disease with coexisting secondary MR (81,82). Con- in patients undergoing surgical aortic valve replace- versely, in the prospective STICH (Surgical Treatment ment with concomitant moderate secondary MR, an of Ischemic Heart Failure) trial, 220 patients had site- Alfieri suture can be placed through the LV outflow reported moderate/severe MR. Of 104 such patients track after the aortic valve has been excised. assigned to CABG, MV repair was performed at oper- VENTRICULAR APPROACHES TO SECONDARY MR. Two investigational extracardiac devices, the CorCap (Acorn Cardiovascular) and Coapsys (Myocor, Maple Grove, Minnesota), have been used to reshape the LV, which may secondarily reduce the degree of secondary MR (Figure 4). The CorCap is a passive external LV mesh restraint intended to reduce wall stress (62). In the 300-patient randomized ACORN trial, the CorCap reduced LV dimensions, but not MR severity or mortality compared with control patients (63). The Coapsys cardiac support device also reshapes the ventricle by placing a tether between anteriorly and posteriorly placed extracardiac pads, with some correction of the mitral annulus in the septal lateral dimension, thereby reducing secondary MR (76). The randomized RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) trial in patients undergoing CABG with at least moderate secondary MR was terminated prematurely. Analysis of available data in 165 patients at mean 28-month follow-up showed a survival advantage for those treated with CABG plus Coapsys without MV repair compared with CABG plus selective MV repair (HR: 0.42 [95% CI: 0.20 to 0.87], p ¼ 0.04). Although LV dimensions were reduced to a greater degree with Coapsys, MR reduction was greater with conventional MV repair (p < 0.0001). ator discretion in 49, whereas 116 were assigned to medical therapy only (83). The 5-year adjusted HR for mortality in patients with MR treated with CABG plus MV repair versus medical therapy alone (without CABG) was 0.41 (95% CI: 0.22 to 0.77, p ¼ 0.006), whereas no survival advantage was evident with CABG alone versus medical therapy. Thus, although surgical correction of severe MR in patients undergoing CABG is generally recommended to improve quality of life, in the absence of a large-scale randomized trial, it is uncertain whether survival is improved by mitral repair or replacement in this setting. The recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of valvular heart disease give MV surgery for secondary MR in the setting of CABG a Class IIa indication (Level of Evidence [LOE]: C), noting that addressing the MV at the time of surgery is reasonable to avoid leaving the patient with severe MR, despite the absence of conclusive evidence that this approach prolongs life or ameliorates symptoms (19). The management of moderate MR in patients undergoing cardiac surgery has been controversial. In a recently reported National Institutes of Health– sponsored randomized trial from the CTSN, 301 patients with moderate ischemic MR undergoing CABG were randomized to coronary revascularization MANAGEMENT OF SECONDARY MR DURING CABG. alone versus coronary revascularization plus MV Optimal management of concomitant secondary MR annuloplasty with an undersized rigid annuloplasty in patients undergoing CABG is still uncertain. ring (84). The addition of annuloplasty resulted There is general agreement that severe MR should in a longer duration of aortic cross clamping and Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 1241 Secondary Mitral Regurgitation cardiopulmonary bypass, and a longer hospital stay. Annuloplasty did result in a reduction in the prev- F I G U R E 4 Extracardiac Devices Used to Remodel the Left Ventricle, Which May Reduce Secondary Mitral Regurgitation alence of moderate or severe MR at 1 year (11.2% vs. 31.0%, p < 0.001), but no significant improvement in CorCap device Coapsys implant LV systolic volume index, the primary endpoint of the trial (p ¼ 0.61). There were also no signi- Right ventricle ficant between-group differences in deaths, read- Mitral valve Posterior pad missions, functional status, or quality of life at 1 year, although the annuloplasty group had a higher 1-year rate of neurological events (9.6% vs. 3.1%, p ¼ 0.03). Thus, although longer-term follow-up is required to determine whether there is late benefit Sub–valvular chord Anterior pad from the observed difference in MR at 1 year, ring annuloplasty of moderate ischemic MR cannot be routinely recommended in patients Left ventricle undergoing CABG at this time. CURRENT GUIDELINES FOR MV SURGERY IN SECONDARY MR. The 2014 ACC/AHA valvular heart (Left) The CorCap cardiac support device is a passive external mesh restraint that directly disease guidelines contain 3 recommendations for reduces the left ventricular end-diastolic dimension and wall stress. (Right) The Coapsys surgery in secondary MR (19). The first states that MV device consists of a single-headed anterior pad and a dual-headed posterior pad connected surgery is reasonable for patients with chronic, severe secondary MR (stages C and D) undergoing CABG by a flexible cord that reduces the left ventricular end-diastolic and end-systolic dimension. or aortic valve replacement (Class IIa, LOE: C). The second states that MV repair may be considered for patients with chronic moderate secondary MR (stage B) undergoing other cardiac surgery (Class IIb, LOE: C). This latter recommendation was reached prior to the negative results of the randomized moderate ischemic MR trial being known (84). The third recommendation states that isolated MV surgery may be considered for severely symptomatic patients perform direct or indirect annuloplasty, edge-to-edge repair, chordal plication or replacement, complete MV replacement, or other approaches (86). The present review is restricted to the MitraClip, the only device in widespread use (>15,000 implants to date) and with sufficient outcomes data to provide comment. (NYHA functional class III to IV) with chronic severe THE secondary MR (stage D) who have persistent symp- polyester-covered cobalt-chromium clip inserted via MITRACLIP toms despite optimal GDMT for HF (Class IIb, LOE: B). the Similarly, the most recent European guidelines (2012) esophageal echocardiographic guidance into the LA give a Class IIb (LOE: C) recommendation for MV following trans-septal puncture (Figure 5). The clip is repair for isolated severe secondary MR, but only for opened, positioned above the regurgitant jet, and patients at low surgical risk with LVEF $30% (23). advanced into the LV. It is then retracted to grasp the femoral vein DEVICE. The and MitraClip advanced under is a trans- free edges of the mitral leaflets, the grippers are TRANSCATHETER DEVICES FOR SECONDARY MR dropped, and the clip is closed and released, emulating a surgical edge-to-edge repair (Figure 6) Despite the poor prognosis with GDMT, most HF pa- (87). Multiple clips may be safely placed, if necessary. tients with secondary MR do not undergo MV surgery. The MitraClip has CE mark approval for general use, Between 2000 and 2008 at the Cleveland Clinic, only and Food and Drug Administration approval in the 36% of 814 patients with 3þ/4þ secondary MR un- United States for treatment of symptomatic patients derwent MV surgery, and secondary MR comprised with severe primary MR at prohibitive risk for MV 90% of all nonoperated patients with severe MR (85). surgery, although not for secondary MR. Given the uncertain risk–benefit ratio, MV surgery In the EVEREST II (Endovascular Valve Edge- is uncommon in patients not requiring CABG. As a to-Edge REpair Study), 278 relatively low-risk pa- result, technologies tients with 3þ/4þ MR were randomized to the have been developed to treat secondary MR. These lesser-invasive transcatheter MitraClip or surgical MV repair. Compared with MV devices are designed to imitate surgical approaches surgery, the MitraClip was substantially safer, but that have proven to be successful in acutely reducing not as effective in reducing MR and LV remodeling MR, and may be classified according to whether they (88). Moreover, reflecting the early learning curve 1242 Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation F I G U R E 5 The MitraClip Device contraindicated for MV surgery, most commonly for secondary MR. Numerous registries have demonstrated high rates of procedural success and favorable short-term outcomes (Table 4) (90–103). The TRAMI (Transcatheter Mitral Valve Interventions) study is the largest published registry to date (90). Among 1,064 patients treated with the MitraClip at 20 German centers, the median age was 75 years; 87% had NYHA functional class III/IV HF symptoms; 69% had LVEF <50%; secondary MR was present in 71% of patients; and the median Society of Thoracic Surgeons mortality score was 10. Procedural success was achieved in 95% of patients, with no procedural deaths. At w3-month follow-up, 12% of patients had Close-up views of the MitraClip device’s fabric-covered clip (left) and guiding catheter died and 12% had been hospitalized for HF, although with clip delivery system (right). Images courtesy of Abbott Vascular, Menlo Park, 66% remained in NYHA functional class I/II. In the California. ACCESS-EU (MitraClip Therapy Economic and Clinical Outcomes Study Europe) registry, the MitraClip was with this device, acute procedural success (MR #2þ at discharge) was achieved in only 77% of patients, and 21% required MV surgery. Nonetheless, with followup to 4 years, NYHA functional class and overall survival were similar in the 2 groups (89). Of note, 73% of the patients had primary MR, and only 27% had secondary MR. A significant interaction was present between the randomized therapy and the primary composite endpoint of death, MV surgery, or 3þ/4þ MR at both 1 and 4 years according to MR etiology; patients with primary MR had significantly improved results with surgical MV repair, whereas outcomes were at least as good with the MitraClip in patients with secondary MR (Central Illustration) (88,89). Since device approval in Europe, the MitraClip has been used extensively in patients at high risk or implanted in 567 patients at 14 sites between April 2009 and April 2011 (91). The mean logistic EuroSCORE was 23, and 77% of patients had secondary MR. The clip implant rate was 99.6%, with multiple clips used in 40% of patients. MR was reduced to #2þ in 91% of patients, and there were 0 procedural deaths. NYHA functional class and 6-min walk distance substantially improved at 1-year follow-up. Similarly, in the 25-center, 8-country, 2011 to 2012 European Sentinel Pilot Registry, 72% of 628 MitraClip-treated patients had secondary MR, 86% had NYHA functional class III/IV symptoms, and the mean EuroSCORE was 20.4 (92). Acute procedural success was high (95.4%), with multiple clips used in 39% of patients. In-hospital (2.9%) and 1-year (15.3%) mortality were similar in patients with secondary and primary MR, although rehospitalization for HF was more common in the secondary MR group (25.8% vs. 12.0%, p ¼ 0.009). At 1 year, severe MR F I G U R E 6 Pathological Changes After Edge-to-Edge Repairs was present in only 6% of patients. Pooled data from the EVEREST II High-Risk Registry and U.S. REALISM (Real World Expanded Multi-center Study of the MitraClip System) registry were recently published in which the MitraClip was used in 351 patients with a Society of Thoracic Surgeons score or surgeonpredicted operative mortality of $12% (70% of whom had secondary MR) (93). By paired echocardiographic core laboratory analysis, MR was #2þ in 89.7% of patients at discharge and in 83.4% of patients at 1 year. Mortality was 4.8% at 30 days and 22.8% at (Left) Double orifice appearance 4 years after a surgical Alfieri repair for a patient with 1 year. LV end-diastolic and end-systolic dimensions severe secondary MR due to ischemic cardiomyopathy. A indicates the anterior leaflet. The decreased through 1-year follow-up, the physical and arrow denotes tissue growth over the suture site. Reproduced with permission from Privitera et al. (87). (Right) Pathological appearance 6 months after creation of a double mental components of the Short Form-36 quality- orifice mitral valve with the MitraClip. MR ¼ mitral regurgitation. Image courtesy of of-life score improved, and the proportion of patients Frederick St. Goar. with NYHA functional class III/IV symptoms was reduced from 82.1% at baseline to 17.1% at 1 year. Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation CENTRAL I LLU ST RAT ION Secondary MR in Heart Failure: Interaction Between the Etiology of MR and the Relative Success Rates of MV Surgery and MitraClip in the Randomized EVEREST II Trial Success was defined as freedom from the combined outcome of death, MV surgery, or reoperation, or MR >2þ (echocardiographic core laboratory determination). Adapted with permission from Feldman et al. (88) and Mauri et al. (89). EVEREST II ¼ Endovascular Valve Edge-to-Edge REpair Study; MR ¼ mitral regurgitation; MV ¼ mitral valve. The rate of hospitalizations for HF was significantly The MitraClip cohort was significantly older, and reduced insertion, had more diabetes and chronic kidney disease, compared with the year before (median per patient higher logistic EuroSCOREs, lower LVEFs, and more 0.41 vs. 0.79, p < 0.0001). All outcomes were direc- comorbidities. Conversely, 35% of the surgical MV tionally consistent in patients with secondary and repair patients also underwent CABG (and other primary MR. The MitraClip has also been used suc- cardiac procedures). MitraClip-treated patients had cessfully in HF patients who are nonresponders to significantly lower rates of hospital mortality and CRT (an especially high-risk group), with resultant major infections, and a shorter length of stay improvements in MR grade, functional capacity, and compared with surgical patients, although MR was LV remodeling (104). reduced to a lesser degree. Survival in the 2 groups in the year after MitraClip In a retrospective study, investigators in Italy was similar at 1 year (105). In contrast, comparable compared the outcomes of 91 patients with 3þ/4þ in-hospital and 6-month results were reported from secondary MR undergoing surgical MV repair be- a retrospective comparison of 171 patients with tween 2001 and 2011 with those of 52 patients secondary MR treated with either the MitraClip treated with MitraClip between 2008 and 2011. (n ¼ 95) or isolated MV repair (n ¼ 76) from the 1243 1244 Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation T A B L E 4 Large-Scale Published Registries of the MitraClip: Baseline Characteristics and Acute Procedural Success Registry (Ref. #) N Mean Age (yrs) Male Mean or Median Risk NYHA Functional Class III/IV Mean LVEF FMR Etiology #2þ MR Post Multiple Clips Procedural Success* 1,064 75 62% 10%† 87% ‡ 71% 96% 1.5 mean 95% ACCESS-EU (91) 567 78 64% 23%§ 85% k 77% 91% 40% 99.6% European Sentinel (92) 95% TRAMI (90) 628 74 63% 20%§ 86% 43% 72% 98% 37% EVEREST II and REALISM (93) 351 76 61% 11%† 85% 48% 70% 86% 39% — GRASP (94) 171 71 62% 7%† 81% 37% 78% 93% 41% 99% MARS (95) 142 71 64% 17%§ 68% 47% 54% 77% 47% 94% Taramasso et al. (96) 109 69 84% 22%§ 82% 28% 100% 87% 65% 99% MitraSwiss (97) 100 77 67% 17%§ 82% 48% 62% 85% 40% 85% 62 73 72% 19%§ 81% 40% 74% 88% 17% 95% 202 75 63% 44%§ 98% 44% 65% 92% 35% 92% 121 77 69% 11%† 96% 42% 59% 99% 28% 97% 104 74 62% 36%§ 100% 43% 66% 92% 38% 92% French multicenter (98) Treede et al. (99) Bozdag-Turan et al. (100) Rudolph et al. (101) Braun et al. (102) 119 71 67% 28%§¶ 86% 35%‡ 35%¶ - - 86% Neuss et al. (103) 157 74 67% 22%§ 100% 41% 73% 100% 16% 98% *According to the registry protocol definition, which varied per study. †By Society for Thoracic Surgery score. ‡LVEF #50% in 69% of patients. §By the logistic EuroSCORE. kLVEF #40% in 53% of patients. ¶In patients with FMR. ACCESS-EU ¼ MitraClip Therapy Economic and Clinical Outcomes Study Europe; EVEREST II ¼ Endovascular Valve Edge-to-Edge REpair STudy; FMR ¼ functional mitral regurgitation; GRASP ¼ Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation; LVEF ¼ left ventricular ejection fraction; MARS ¼ MitraClip Asia-Pacific Registry; MR ¼ mitral regurgitation; NYHA ¼ New York Heart Association; REALISM ¼ Real World Expanded Multi-center Study of the MitraClip System; TRAMI ¼ Transcatheter Mitral Valve Interventions. University of Hamburg (106). Differences in baseline CURRENT GUIDELINES FOR TRANSCATHETER DEVICE characteristics treated USE IN SECONDARY MR. The 2012 European Society of groups in these studies emphasize the challenges Cardiology/European Association for Cardio-Thoracic in Surgery valve and HF guidelines provide a Class IIb and interpreting procedures the results of between nonrandomized (LOE: C) recommendation to consider MitraClip use comparisons. T A B L E 5 Comparison of Ongoing Randomized Trials of the MitraClip in Patients With Heart Failure and Secondary Mitral Regurgitation COAPT RESHAPE-HF MITRA-FR Number of patients and sites 430 patients at 75 U.S. and Canadian sites 800 patients at 50 E.U. sites 288 patients at 18 French sites Secondary MR grade (core laboratory verified) $3þ (EROA $30 mm2 and/or Rvol >45 ml) $3þ (EROA $30 mm2 and/or Rvol >45 ml) Severe (EROA >20 mm2 þ Rvol >30 ml) NYHA functional class II, III, or ambulatory IV III or ambulatory IV II–IV LVEF $20% to #50% $15% to #40% $15% to #40% Surgical criteria Not appropriate for mitral valve surgery (heart team) None None Left ventricular volume entry criterion LV end-systolic dimension #70 mm LV end-diastolic dimension $55 mm None Control arm Guideline-directed medical therapy (þCRT, if indicated) Guideline-directed medical therapy (þCRT, if indicated) Guideline-directed medical therapy (þCRT, if indicated) Primary efficacy endpoint (superiority) Heart failure rehospitalizations at 1 yr Death or heart failure hospitalization at 1 yr Death or recurrent heart failure hospitalization at 1 yr Primary safety endpoint (noninferiority) The composite of: SLDA; device embolization; endocarditis requiring surgery; echocardiography core laboratory-confirmed mitral stenosis requiring surgery; LVAD implant; heart transplant; or any device-related complications requiring nonelective cardiovascular surgery at 12 months None None Health economics Assessed Assessed Follow-up, yrs 5 None 2 2 COAPT ¼ Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation; EROA ¼ effective regurgitant orifice area; LV ¼ left ventricular; LVAD ¼ left ventricular assist device; MITRA-FR ¼ Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation; Rvol ¼ regurgitant volume; RESHAPE-HF ¼ Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation; SLDA ¼ single leaflet device attachment; other abbreviations as in Table 4. Asgar et al. JACC VOL. 65, NO. 12, 2015 MARCH 31, 2015:1231–48 Secondary Mitral Regurgitation in symptomatic patients with severe secondary of MR severity in such patients can be challenging, MR, despite GDMT and CRT, who are inoperable or at but is essential to help define patient risk and guide high risk (23). The 2013 ACCF/AHA HF guidelines treatment decisions. GDMT for HF is foundation provide a Class IIb (LOE: B) recommendation to therapy for moderate and severe secondary MR, consider MitraClip in symptomatic patients with along with CRT and coronary revascularization if severe secondary MR despite GDMT after “careful indicated. When effectively applied, these measures candidate selection” (43). Transcatheter MV repair will often reduce secondary MR and improve pa- for secondary MR did not receive an official recom- tient prognosis. The appropriate role of surgical and mendation in the 2014 ACCF/AHA valvular heart transcatheter interventions for persistent severe disease guidelines, although it is recommended with secondary MR is less clear and is evolving; both Class IIb (LOE: B) guidance for severe primary MR options may be considered in carefully selected in symptomatic patients at prohibitive risk for patients after balancing the likely risks and bene- MV surgery (19). fits. Adequately designed randomized trials are are essential to further guide optimal use of these randomizing symptomatic HF patients with 3þ/4þ invasive strategies, and several such trials with secondary MR to the MitraClip plus GDMT versus the MitraClip are ongoing. Collaboration among GDMT alone (Table 5). The results of these trials will HF clarify the role of the MitraClip in secondary MR, as diac surgeons, and imaging experts as a multi- well as whether a therapy purely aimed at reducing disciplinary heart team is imperative to reach secondary MR improves prognosis in patients with consensus on appropriate care for patients with LV dysfunction as the primary pathophysiologic secondary MR. ONGOING TRIALS. Three large-scale trials specialists, interventional cardiologists, car- disturbance. CONCLUSIONS REPRINT REQUESTS AND CORRESPONDENCE: Dr. Gregg W. Stone, Columbia University Medical Center, The development of secondary MR is strongly asso- The Cardiovascular Research Foundation, 111 East ciated with a worsened prognosis in patients with 59th Street, 11th Floor, New York, New York 10022. HF, regardless of its etiology. Accurate assessment E-mail: [email protected]. REFERENCES 1. Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. 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KEY WORDS cardiac resynchronization therapy, echocardiography, heart failure, mitral valve annuloplasty, prognosis, therapy
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