Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling

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CLINICAL RESEARCH

Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling Évolution de la regurgitation mitrale secondaire chez des patients insuffisants cardiaques après resynchronisation cardiaque : impact sur le pronostic à long-terme au-delà du remodelage inverse Camille Binda a,b, Aymeric Menet a,c, Ludovic Appert a, ¸ois Delelis a, Pierre-Vladimir Ennezat d, Franc Anne-Laure Castel a, Caroline Le Goffic a, Yves Guyomar a, Anne Ringlé a,c, Raphaëlle-Ashley Guerbaai d, Pierre Graux a, Christophe Tribouilloy c,e, Sylvestre Maréchaux a,c,∗ a

Cardiology department, GCS-groupement des hôpitaux, institut catholique de Lille, université catholique de Lille, 59000 Lille, France b Centre hospitalier d’Armentières, 80054 A rmentières, France c Inserm U1088, université de Picardie, 59280 Amiens, France d Cardiology department, centre hospitalier universitaire de Grenoble, 38700 Grenoble, France e Cardiology department, centre hospitalier universitaire d’Amiens, Amiens, France Received 28 February 2017; received in revised form 27 March 2017; accepted 17 May 2017

Abbreviations: CI, Confidence interval; CRT, Cardiac resynchronization therapy; ERO, Effective regurgitant orifice; HR, Hazard ratio; LA, Left atrial; LBBB, Left bundle branch block; LV, Left ventricular; LVEF, Left ventricular ejection fraction; MR, Mitral regurgitation; NYHA, New York Heart Association. ∗ Corresponding author. Cardiology department, hôpital Saint-Philibert, 115, rue du Grand-But, 59462 Lomme cedex, France. E-mail address: [email protected] (S. Maréchaux). http://dx.doi.org/10.1016/j.acvd.2017.05.009 1875-2136/© 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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KEYWORDS Cardiac resynchronization therapy; Heart failure; Outcome; Secondary mitral regurgitation; Echocardiography

MOTS CLÉS Resynchronisation cardiaque ; Insuffisance cardiaque ; Pronostic ; Insuffisance mitrale secondaire ; Échocardiographie

Summary Background. — The prognostic value of secondary mitral regurgitation (MR) at baseline versus immediately after and several months after cardiac resynchronization therapy (CRT), beyond left ventricular (LV) reverse remodelling, has yet to be investigated. Aim. — To evaluate the clinical significance of secondary MR before and at two timepoints after CRT in a large cohort of consecutive patients with heart failure (HF) and reduced LV ejection fraction. Methods. — A total of 198 patients were recruited prospectively into a registry, and underwent echocardiography at baseline and immediately after CRT (on the day of hospital discharge). Echocardiography was also performed 9 months after CRT in 172 patients. The impact of significant secondary MR (≥ moderate) on all-cause death, cardiovascular death and hospitalization for HF was studied at each stage. Results. — The frequency of significant secondary MR decreased from 23% (n = 45) to 8% (n = 16) immediately after CRT. Among the 172 patients who underwent echocardiography 9 months after CRT, 17 (10%) had significant secondary MR. During a median follow-up of 48 months, 49 patients died and 36 were hospitalized for HF. Patients with significant secondary MR immediately after or 9 months after CRT had an increased risk of all-cause death, cardiovascular death and hospitalization for HF during follow-up (P < 0.05 for all endpoints). After adjustment for LV reverse remodelling, significant secondary MR 9 months after CRT remained associated with an increased risk of all-cause death (adjusted hazard ratio [HR] 3.77; P = 0.014), cardiovascular death (adjusted HR 5.36; P = 0.037), and hospitalization for HF (adjusted HR 7.33; P = 0.001). Conclusions. — Significant secondary MR despite CRT provides important prognostic information beyond LV reverse remodelling. Further studies are needed to evaluate the potential role of new percutaneous procedures for mitral valve repair in improving outcome in these very high-risk patients. © 2017 Elsevier Masson SAS. All rights reserved.

Résumé Contexte. — La valeur pronostique de l’insuffisance mitrale (IM) secondaire en base versus immédiatement après et plusieurs mois après resynchronisation cardiaque, au-delà du remodelage inverse du ventricule gauche, n’a pas encore été évaluée. Objectif. — Le but de cette étude était d’évaluer la signification clinique de l’insuffisance mitrale secondaire avant, précocement et tardivement après resynchronisation cardiaque dans une large cohorte de patients consécutifs insuffisants cardiaques avec dysfonction systolique du ventricule gauche. Méthodes. — Cent quatre-vingt dix-huit patients recrutés prospectivement dans un registre ont bénéficié d’une échocardiographie avant et juste après l’implantation d’un stimulateur cardiaque biventriculaire. Une échocardiographie tardive était réalisée 9 mois après l’implantation chez 172 patients. L’impact de l’IM secondaire significative (≥ grade 2) sur la mortalité totale et cardiovasculaire et sur les hospitalisations pour insuffisance cardiaque était étudié à chaque stade. Résultats. — La fréquence de l’IM secondaire significative diminuait de 23 % (n = 45) en préimplantation à 8 % (n = 16) immédiatement après l’implantation. Parmi les 172 patients qui ont bénéficié d’une échocardiographie tardive, 17 patients (10 %) avaient une IM secondaire significative. Pendant un suivi médian de 48 mois, 49 patients sont décédés et 36 ont été hospitalisés pour insuffisance cardiaque. Les patients avec une IM secondaire significative précocement ou tardivement après resynchronisation biventriculaire présentaient un risque accru de mortalité, de mortalité cardiovasculaire et d’hospitalisation pour insuffisance cardiaque dans le suivi (p < 0,05 pour tous les critères de jugement). Après ajustement sur la survenue d’un remodelage inverse dans le suivi, l’IM secondaire tardivement après resynchronisation biventriculaire restait associée avec un risque accru de mortalité (HR ajusté 3,77 ; p = 0,014), de mortalité cardiovasculaire (HR ajusté 5,36 ; p = 0,037) et d’hospitalisation pour insuffisance cardiaque dans le suivi (HR ajusté 7,33 ; p = 0,001).

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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3 Conclusions. — La présence d’une IM secondaire significative malgré une resynchronisation cardiaque apporte une information pronostique importante au-delà du remodelage inverse post-resynchronisation. D’autres études seront nécessaires pour évaluer le rôle des nouvelles procédures percutanées de réparation valvulaire mitrale pour améliorer le pronostic de ces patients à haut risque. © 2017 Elsevier Masson SAS. Tous droits r´ eserv´ es.

Background Secondary mitral regurgitation (MR) is common in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF), and predicts a poor outcome [1,2]. Secondary MR results from an imbalance between decreased mitral closing forces and increased tethering forces, caused by reduced and/or discoordinated left ventricular (LV) function and global and local remodelling, resulting in mitral valve tenting. Cardiac resynchronization therapy (CRT) induces immediate/short-term and long-term reductions in secondary MR [3—6]. While the immediate/short-term reduction in secondary MR after CRT seems to arise from the improvement in LV mitral closing forces, as a result of better coordination of papillary muscles and improved LV systolic function, the long-term reduction in secondary MR is attributed mainly to the chronic reduction in LV endsystolic size induced by CRT (i.e. LV reverse remodelling) [7,8]. LV reverse remodelling after CRT strongly predicts outcome in patients with HF and reduced LVEF, in terms of mortality and hospitalization for HF, and is commonly used in clinical practice as a surrogate for clinical outcome, to identify CRT responders [9]. While secondary MR at baseline may not be associated with outcome in patients with HF and reduced LVEF who receive CRT, the reduction in secondary MR after CRT has been associated with better clinical outcomes [6,10]. However, to our knowledge, the prognostic value of secondary MR at baseline versus immediately after and several months after CRT, beyond left ventricular reverse remodelling, remains uninvestigated. Hence, the aim of the present prospective study was to evaluate, in a large cohort of patients with HF and reduced LVEF receiving CRT: the time course of secondary MR at baseline, immediately after CRT and 9 months after CRT; the relationship between the presence of significant secondary MR at each stage, LV reverse remodelling during follow-up and adverse long-term clinical outcomes; and whether significant secondary MR long after CRT provides independent prognostic information beyond LV reverse remodelling.

Methods Study population This post-hoc analysis of a prospective cohort study included 198 patients. Clinical, electrocardiography and Doppler echocardiography data were collected prospectively in consecutive patients receiving CRT. As recommended in guidelines, CRT was indicated for patients with an LVEF ≤ 35% who remained in New York Heart Association

(NYHA) functional class II, III or ambulatory IV, despite optimal medical treatment, and with QRS duration ≥ 120 ms in the event of left bundle branch block (LBBB) morphology or QRS duration ≥ 150 ms in the event of non-LBBB morphology. Exclusion criteria were myocardial infarction, acute coronary syndrome or coronary revascularization in the past 3 months; primary mitral or aortic valve disease; and uncontrolled rapid atrial fibrillation. Patients received maximum-tolerated doses of beta-blockers, angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, and spironolactone. The local ethics committee of the Groupement des hôpitaux de l’institut catholique de Lille approved the study.

Echocardiography Echocardiography was performed the day before CRT implantation, with a GE Vivid E9 ultrasound system (GE Healthcare, Velizy, France). Echocardiography studies werealso performed on the day of hospital discharge and at 9-month follow-up. Three cardiac cycles were stored for each measurement for subsequent off-line analysis by an investigator blinded to the clinical status of the patient (EchoPAC PC, release BT12; GE Vingmed Ultrasound AS, Horten, Norway). Measurements were made over three cardiac cycles, and the average value was calculated. LVEF was measured by Simpson’s biplane method. LV enddiastolic and end-systolic dimensions were obtained with the use of M-mode recordings acquired at a sweep speed of 100 mm/s. Pulsed-wave Doppler was performed in the apical four-chamber view at end-expiration, with a 3-mm sample volume, to obtain mitral inflow velocities (E and A waves). The left atrial (LA) volume was obtained according to current guidelines. MR was deemed secondary when the leaflets were intrinsically normal, although minor leaflet thickening and annular calcification can be present. Mitral regurgitant orifice area (effective regurgitant orifice [ERO]) was measured by the proximal flow convergence technique. Depth, size and sector settings were optimized for optimal colour Doppler resolution. The Doppler colour flow zero baseline was shifted downward to obtain a satisfactory hemispheric proximal isovelocity surface area. The proximal flow convergence was imaged and expanded in the apical four-chamber view. The aliasing velocity (Vr ) was carefully adjusted (20—40 cm/s). The midsystole radius of the proximal flow convergence region (r) was measured from the point of aliasing to the leaflet tips. Maximum mitral regurgitant velocity and the regurgitant time-velocity integral were obtained from continuous-wave Doppler recordings. The regurgitant flow was measured as 2 ×
× r2 × Vr , and mitral ERO was obtained. MR severity was classified as

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mild (ERO < 10 mm2 ), moderate (10 mm2 ≤ ERO < 20 mm2 ) or severe (ERO ≥ 20 mm2 ). Secondary MR was considered significant in case of mitral ERO ≥ 10 mm2 . The mitral tenting area, which reflects the degree of restrictive leaflet motion and moving of the coaptation zone from the mitral annulus toward the apex, was measured by the area enclosed between the annular plane and the mitral leaflets, in the parasternal long-axis view [11]. LV reverse remodelling was defined as a relative decrease in LV end-systolic volume ≥ 15% between baseline and 9 months after CRT, as previously reported [9].

CRT device implantation Boston Scientific (Natick, MA, USA), Medtronic (Minneapolis, MN, USA), St. Jude Medical (St. Paul, MN, USA), Sorin (Milan, Italy) and Biotronik (Berlin, Germany) CRT devices were implanted by electrophysiologists targeting a basal-lateral, anterolateral or posterolateral coronary sinus vein for LV lead positioning. Interventricular timing was set to zero. A short-sensed atrioventricular delay (80—100 ms) and a paced delay (130 ms) were programmed to promote biventricular pacing. Before hospital discharge, particular attention was paid to verify the absence of fusion or pseudofusion beats on the electrocardiogram and continuous monitoring. For patients with ongoing atrial fibrillation, radiofrequency ablation of the atrioventricular node was performed to obtain a high percentage of biventricular pacing, if sufficient bradycardia was not obtained despite optimal medical treatment. In case of atrioventricular node ablation, devices were subsequently programmed in a VVIR mode with a paced heart rate of 70 beats per minute.

Outcomes During follow-up, patients were monitored by their own private physician. Events were recorded by means of clinical interviews and/or phone calls to physicians, patients, and (if necessary) next of kin. The primary endpoint of the study was all-cause death; the secondary endpoints were cardiovascular death and hospitalization for HF. Cardiovascular death was considered if the death was related to HF, myocardial infarction or arrhythmia, or if it was sudden.

Statistical analysis Quantitative data are presented as means ± standard deviations or medians (25th—75th percentiles). Qualitative data are presented as absolute numbers and percentages. Means were compared using a two-sided Student’s t test or a MannWhitney U test for comparison between two groups if the sample size of one of the two groups was below 30. The median duration of follow-up was computed using the reverse Kaplan-Meier method. Survival curves were obtained using the Kaplan-Meier method, and were compared using the log-rank test. Univariate followed by multivariable Cox regression survival analyses were used to identify the relationship between the presence of significant secondary MR at baseline, immediately after CRT and 9 months after CRT, and the occurrence of events during follow-up. For multivariable Cox analyses, model-building

techniques were not used, and covariates entered in the model were considered for potential prognostic impact, on an epidemiological basis; these covariates included QRS duration, NYHA functional class III—IV, age, coronary artery disease, atrial fibrillation, LBBB, LVEF and LV end-systolic volume at baseline. LV reverse remodelling was also entered into the models, with the aim of studying the impact of significant MR 9 months after CRT on outcome. For continuous variables, assumption of linearity was assessed by plotting martingale residuals against independent variables. The proportional hazards assumption was confirmed using statistics and graphs based on the Schoenfeld residuals. For all tests, a two-tailed P-value ≤ 0.05 was considered statistically significant. Statistical analyses were performed with SPSS software (SPSS, Inc., Chicago, IL, USA) and R software, version 3.0.3 (Youngstown, OH, USA).

Results Baseline characteristics One hundred and ninety-eight patients eligible for CRT prospectively underwent immediate baseline echocardiography before CRT placement and before hospital discharge, and were enrolled in the present report. The flow chart of the study is depicted in Fig. 1. The characteristics of the population are detailed in Table 1.

Frequency of significant secondary MR MR before and immediately after CRT At baseline, 45 patients (23%) had significant secondary MR (34 patients with mitral 10 ≤ ERO < 20 mm2 ; 11 patients with mitral ERO ≥ 20 mm2 ). One hundred and fifty-three patients had no MR (n = 107) or mild MR (n = 46). The frequency of significant secondary MR decreased from 23% (45/198) at baseline to 8% (16/198) immediately after CRT implantation (13 patients with mitral 10 ≤ ERO < 20 mm2 ; three patients with mitral ERO ≥ 20 mm2 ), whereas 182 patients had no MR (n = 141) or mild MR (n = 41). The comparison of clinical data between patients with and without significant secondary MR at baseline and immediately after CRT is depicted in Table 1. Patients with significant secondary MR at baseline and immediately after CRT were more often in NYHA functional class III—IV.

MR 9 months after CRT Echocardiographic follow-up 9 months after CRT was available in 172 patients (87%); 14 patients (7%) died before their echocardiographic examination and 12 (6%) did not attend their echocardiographic examination. Seventeen patients (17/172, 10%) had significant secondary MR 9 months after CRT (12 patients with mitral 10 ≤ ERO < 20 mm2 ; five patients with mitral ERO ≥ 20 mm2 ). One hundred and fifty-five patients had no MR (n = 129) or mild MR (n = 26). Patients with significant secondary MR 9 months after CRT were more often in baseline NYHA functional class III—IV, and had a shorter baseline QRS duration (Table 1).

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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Figure 1.

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Study flow chart. CRT: cardiac resynchronization therapy; echo: echocardiography.

Table 1 Clinical baseline characteristics according to the presence of significant secondary mitral regurgitation (≥ moderate) at baseline and immediately and 9 months after cardiac resynchronization therapy. Baseline Overall

Age (years) Men BMI (kg/m2 ) Diabetes Dyslipidaemia Hypertension Coronary artery disease Atrial fibrillation NYHA functional class III—IV QRS width (ms) LBBB Beta-blockers Renin-angiotensin system blockers

MR ≥ No or mild P moderate MR

Immediately after CRTa

9 months after CRT

MR ≥ moderate

No or mild P MR

MR ≥ moderate

No or mild P MR

(n = 16)

(n = 182)

(n = 17)

(n = 155)

70 ± 14 10 (63) 28 ± 7 5 (31) 7 (44) 4 (25) 5 (31)

71 ± 11 118 (65) 27 ± 5 54 (30) 68 (37) 80 (44) 66 (36)

0.91 0.85 0.72 1.0 0.63 0.14 0.69

69 ± 11 10 (59) 28 ± 7 5 (29) 4 (24) 6 (35) 5 (29)

71 ± 11 101 (65) 27 ± 5 46 (30) 63 (41) 63 (41) 56 (36)

0.57 0.60 0.85 0.98 0.16 0.67 0.61

36 (20) 82 (45)

0.11 4 (24) 0.005 14 (82)

31 (20) 67 (43)

0.75 0.002

167 ± 27 140 (77) 165 (91) 161 (88)

0.11 0.77 0.66 1.0

168 ± 27 119 (77) 140 (90) 137 (88)

0.002 1.0 1.0 0.70

(n = 198) (n = 45)

(n = 153)

71 ± 11 128 (64) 27 ± 5 59 (30) 75 (38) 84 (42) 71 (36)

71 ± 12 29 (64) 27 ± 6 19 (42) 15 (33) 16 (36) 14 (31)

71 ± 11 99 (65) 27 ± 5 40 (26) 60 (39) 68 (44) 57 (37)

0.40 0.97 0.81 0.038 0.46 0.29 0.45

14 (7) 95 (48)

38 (84) 30 (67)

28 (18) 65 (42)

0.065 6 (38) 0.004 13 (81)

166 ± 26 152 (77) 179 (90) 175 (88)

160 ± 26 34 (76) 42 (93) 40 (89)

167 ± 27 118 (77) 137 (90) 135 (88)

0.13 0.83 0.57 0.90

156 ± 28 12 (75) 14 (88) 14 (88)

146 ± 25 13 (76) 16 (94) 16 (94)

Data are expressed as mean ± standard deviation or number (%). BMI: body mass index; CRT: cardiac resynchronization therapy; LBBB: left bundle branch block; MR: mitral regurgitation; NYHA: New York Heart Association. a On the day of hospital discharge.

Relationship between significant MR and echocardiographic variables The comparison of echocardiographic data between patients with and without significant secondary MR at baseline, immediately after CRT and 9 months after CRT is presented in Table 2. Patients with significant secondary MR at baseline had a larger LV size, a lower LV ejection fraction and larger LA volumes (Table 2). Mitral valve tenting and systolic pulmonary artery pressure were significantly higher, and right ventricular systolic function variables were depressed in patients with significant secondary MR compared with in those

without. Similar results were found for patients with significant secondary MR immediately after CRT and 9 months after CRT, except for global longitudinal strain, which differed significantly between patients with and without significant secondary MR only at the 9-month echocardiography examination.

Changes in degree of secondary MR severity over time Changes in the degree of secondary MR were assessed in 198 patients immediately after CRT, and in 172 patients from immediately after CRT to 9 months after CRT, and are

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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C. Binda et al. Table 2 Echocardiographic characteristics at each stage according to the presence of significant secondary mitral regurgitation (≥ moderate) at baseline and immediately and 9 months after cardiac resynchronization therapy. Immediately after CRTa

9 months after CRT

No or mild P MR

MR ≥ moderate

No or mild P MR

MR ≥ moderate

No or mild P MR

(n = 198) (n = 45)

(n = 153)

(n = 16)

(n = 182)

(n = 17)

(n = 155)

26 ± 5 245 ± 70 67 ± 8 182 ± 58 8.0 ± 2.7 73 ± 27

24 ± 5 262 ± 75 70 ± 8 201 ± 63 7.4 ± 2.5 88 ± 27

27 ± 5 24 ± 68 65 ± 8 177 ± 55 8.1 ± 2.8 69 ± 26

26 ± 8 265 ± 75 70 ± 8 196 ± 60 7.8 ± 3.1 66 ± 17

31 ± 8 229 ± 71 64 ± 8 161 ± 60 8.0 ± 2.7 49 ± 21

28 ± 9 233 ± 75 67 ± 10 170 ± 62 7.2 ± 3.8 57 ± 16

41 ± 11 187 ± 67 60 ± 10 116 ± 61 10.3 ± 4.0 46 ± 20

3.16 ± 0.94 0 (0—9)

4.10 ± 0.9 2.9 ± 0.8

< 0.0001 4.34 ± 1.28 2.68 ± 0.77 < 0.0001 4.18 ± 1.49 2.64 ± 0.83 < 0.0001

13 (11—20) 0 (0—3)

< 0.0001 14 (12—17) 0 (0—0)

38 ± 13

44 ± 11

36 ± 13

0.001

44 ± 11

36 ± 12

20 ± 5 9.7 ± 3.2

0.009 0.035

17 ± 5 8.6 ± 2.2

20 ± 5 0.023 10.2 ± 3.1 0.031

Baseline Overall

LVEF (%) LVEDV (mL) LVEDD (mm) LVESV (mL) GLS (%) LA volume (mL) LA tenting (cm2 ) Mitral ERO (mm2 ) sPAP (mmHg) TAPSE (mm) RV S wave (cm/s)

MR ≥ moderate

20 ± 5 18 ± 6 9.4 ± 3.3 8.5 ± 3.4

0.003 0.07 0.001 0.015 0.14 < 0.0001

0.033 0.066 0.007 0.028 0.78 0.002

< 0.0001 12 (11—21) 0 (0—0) 0.001

< 0.0001 0.013 0.001 0.001 0.003 0.012

< 0.0001

49 ± 13

34 ± 10

16 ± 4 8.7 ± 2.1

20 ± 5 0.001 10.4 ± 2.8 0.026

< 0.0001

Data are expressed as mean ± standard deviation or median (25th—75th percentile). CRT: cardiac resynchronization therapy; ERO: effective regurgitant orifice; GLS: global longitudinal strain; LA: left atrial; LVEDD: left ventricular end-diastolic diameter; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESV: left ventricular end-systolic volume; MR: mitral regurgitation; RV: right ventricular; sPAP: systolic pulmonary artery pressure; TAPSE: tricuspid annular plane systolic excursion. a On the day of hospital discharge.

shown in Fig. 2 (panels A and B). All patients with no MR or mild MR at baseline had no MR or mild MR immediately after CRT. Seventeen patients had significant secondary MR 9 months after CRT. Among these 17 patients, nine (53%) had no MR or mild MR at baseline, and eight (47%) had significant secondary MR immediately after CRT. Acute changes in LV size or ejection fraction were similar between patients with and without significant secondary MR immediately after CRT (Fig. 3, panels A, B and C). In contrast, patients with significant secondary MR 9 months after CRT had a poorer improvement in LVEF and a lower decrease in both LV enddiastolic and end-systolic volumes from baseline to the 9-month echocardiography examination (Fig. 3, panels D, E and F; all P < 0.01). Early/late changes in mitral tenting area or LA volume did not differ immediately after and 9 months after CRT between patients with and without significant secondary MR at each stage (all P not significant).

Relationship between MR at baseline and after CRT and LV reverse remodelling The proportion of CRT responders (defined by a relative reduction in LV end-systolic volume relative to baseline ≥ 15%) was similar in patients with and without significant secondary MR at baseline: 30/41 (73%) vs 102/135 (75%) (P = 0.76). Likewise, LV end-systolic volume decreased and LVEF increased similarly from baseline to 9-month follow-up in patients with and without significant secondary

MR at baseline: —64 ± 57 vs —60 ± 50 mL (P = 0.78) and 12 ± 12 vs 13 ± 11% (P = 0.41), respectively. The proportion of CRT responders was also similar in patients with and without significant secondary MR immediately after CRT: 9/14 (64%) vs 123/162 (76%) (P = 0.36). In contrast, the proportion of CRT responders was significantly lower in patients with significant secondary MR at 9-month follow-up compared with other patients: 7/17 (41%) vs 123/155 (79%) (P = 0.001).

Impact of secondary MR at baseline and after CRT on outcome During a median follow-up of 48 ± 2 months, 49 patients died (including 27 from cardiovascular causes), and 36 patients were hospitalized for decompensated HF. The survival free of death from any cause, cardiovascular death and hospitalization for HF in patients with and without significant secondary MR at baseline is depicted in Fig. 4 (panels A, B and C). Compared with patients without significant MR at baseline, patients with significant secondary MR at baseline had an increased risk of hospitalization for HF (hazard ratio [HR] 2.71, 95% confidence interval [CI] 1.33—5.48; P = 0.006) and cardiovascular death (HR 2.61, 95% CI 1.21—5.63; P = 0.015), and there was a trend towards an increased risk of death from any cause (HR 1.78, 95% CI 0.97—3.28; P = 0.063). After adjustment, only a trend towards an increased risk of hospitalization for

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7 (Fig. 6, panels A, B and C). After adjustment for predefined covariates, including LV reverse remodelling, patients with significant secondary MR 9 months after CRT had an independent increased risk of death from any cause (adjusted HR 3.77, 95% CI 1.30—10.92; P = 0.014), cardiovascular death (adjusted HR 5.36, 95% CI 1.11—25.96; P = 0.037) and hospitalization for HF (adjusted HR 7.33, 95% CI 2.21—24.29; P = 0.001) (Table 3). Both LV reverse remodelling and significant secondary MR 9 months after CRT were independent predictors of long-term outcome (Table 3).

Discussion

B

Figure 2. Course of degree of secondary mitral regurgitation (MR) after cardiac resynchronization therapy (CRT). A. Changes in degree of secondary MR immediately after CRT were studied in 198 patients. B. Changes in degree of secondary MR 9 months after CRT were studied in 172 patients.

HF was observed in patients with significant secondary MR at baseline (Table 3). The survival free of death from any cause, cardiovascular death and hospitalization for HF in patients with and without significant secondary MR immediately after CRT is depicted in Fig. 5 (panels A, B and C). Patients with significant secondary MR immediately after CRT had a significantly increased risk of death from any cause (HR 3.27, 95% CI 1.58—6.77; P < 0.001), cardiovascular death (HR 4.69, 95% CI 1.98—11.13; P < 0.0001) and hospitalization for HF (HR 5.98, 95% CI 2.75—12.98; P < 0.0001). Similar results were found after adjustment (Table 3). Patients with significant secondary MR 9 months after CRT had a significantly increased risk of death from any cause (HR 3.34, 95% CI 1.42—7.82; P = 0.006), cardiovascular death (HR 5.25, 95% CI 1.79—15.38; P = 0.003) and hospitalization for HF (HR 7.78, 95% CI 3.39—17.86; P < 0.0001)

While significant secondary MR before CRT did not add independent prognostic information, significant secondary MR immediately after and 9 months after CRT did provide important prognostic information in terms of mortality and hospitalization for HF. In addition, significant secondary MR 9 months after CRT provided independent prognostic information beyond LV reverse remodelling, during long-term follow-up. Secondary MR is a common condition in patients with HF, and is a predictor of poor prognosis. Progressive distortion of global or local LV architecture leads to apical and lateral displacement of papillary muscles, causing tethering and restrictive motion of the mitral leaflets [12,13]. Moreover, the decrease in LV ejection phase efficiency produced by LV dyssynchrony in patients with enlarged QRS reduces mitral closing forces. Conversely, CRT, by increasing LV closure forces resulting from improved myocardial contractility, and by restoring papillary muscle coordination, acutely reduces secondary MR. In agreement with previous studies, this occurred in twothirds of our patients with HF and baseline secondary MR [14,15].

Clinical significance of MR before CRT Patients with significant secondary MR at baseline had indices of more advanced HF, including larger LV and LA size, higher pulmonary pressures and depressed right ventricular function. However, after CRT, baseline MR did not predict outcome after adjustment for classical HF prognostic factors. Consistently, LV reverse remodelling during follow-up did not differ in patients with or without significant secondary MR at baseline. These findings suggest that CRT may largely improve the poor prognosis of patients with HF, including those with secondary MR. These findings differ slightly from those of Verhaert et al. [6], who reported that patients with severe MR before CRT experienced a larger decrease in LV end-systolic volume index. However, similar to our findings, baseline MR severity was not associated with adverse events. Hence, these results suggest that baseline MR should not be considered as a predictor of poor outcomes in patients with a CRT indication. Baseline secondary MR is not likely to be an appropriate therapeutic target in itself in this clinical setting, as suggested by current European society of cardiology guidelines on valvular heart diseases. Improving LV function is the primary therapeutic strategy for reducing MR [16].

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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C. Binda et al.

Figure 3. Respective changes in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), according to the presence (+) or absence (—) of significant secondary mitral regurgitation (MR) immediately (A, B, C) and 9 months (D, E, F) after cardiac resynchronization therapy (CRT).

Clinical significance of MR after CRT Few studies have reported temporal changes in secondary MR after CRT. Half of the patients with significant secondary MR 9 months after CRT had no or only mild MR immediately after CRT, thus demonstrating that the amount of MR varies widely from the early period to the late period after CRT. Significant secondary MR immediately after CRT was an independent predictor of clinical outcome, even after adjustment for classical HF prognostic factors. However, MR immediately after CRT was not related to acute changes in LV function and size, as previously reported [6]. In contrast, CRT failure to reverse LV remodelling and improve LV function did correlate with significant secondary MR 9 months after CRT. These data confirm the hypothesis that secondary MR mirrors LV remodelling status in part. Indeed, LV reverse remodelling induced by CRT reduces LV dilation and sphericity, thus minimizing the tethering forces on the mitral valve apparatus, and thereby reducing the amount of MR [8]. However, both LV remodelling and MR 9 months after CRT were independent predictors of long-term outcomes in the present study.

Identification of ‘‘responders’’ and ‘‘non-responders’’ to CRT has attracted considerable attention, as 20—40% of patients fail to respond to CRT [17]. Left ventricular reverse remodelling (defined as LV end-systolic volume reduction ≥ 15%) is a strong and reproducible predictor of outcome after CRT [9]. Yu et al. also found higher long-term mortality and HF events in patients who had CRT with a lack of reduction in LV end-systolic volume of 9.5% or more [18], and mortality was more than 4-fold higher in the 25% of the REVERSE patient cohort with further LV remodelling despite CRT. Given the results of the present study, response to CRT should not only rely on changes in LV end-systolic volume at 6—9 months’ follow-up, but also on the assessment of secondary MR at the same timepoint. Indeed, patients without LV reverse remodelling and significant secondary MR at 9month follow-up were at very high risk in this study, and may derive benefit from specific therapeutic management, targeting the secondary MR. Ongoing trials are evaluating the efficacy of new percutaneous procedures for mitral valve repair, such as MitraClip. Pilot studies have concluded that the treatment is safe, and results in an improvement in NYHA functional class, with evidence of reverse LV remodelling [19,20].

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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Table 3 Relationship between presence of significant secondary mitral regurgitation (≥ moderate) at baseline and immediately and 9 months after cardiac resynchronization therapy and all-cause death, cardiovascular death and hospitalization for heart failure during follow-up, by Cox multivariable analysis. All-cause death

MR at baseline Age (years) Atrial fibrillation CAD NYHA III—IV Baseline LVESV (mL) Baseline LVEF (%) QRS width (ms) LBBB MR immediately after CRTa Age (years) Atrial fibrillation CAD NYHA III—IV Baseline LVESV (mL) Baseline LVEF (%) QRS width (ms) LBBB MR 9 months after CRT LV reverse remodelling Age (years) Atrial fibrillation CAD NYHA III—IV Baseline LVESV (mL) Baseline LVEF (%) QRS width (ms) LBBB

Cardiovascular death

Hospitalization for CHF

Adjusted HR 95% CI

P

Adjusted HR 95% CI

P

1.33 1.08 1.02

0.69—2.58 1.04—1.12 0.50—2.05

0.39 < 0.001 0.97

1.99 1.12 1.51

0.83—4.77 1.06—1.19 0.65—3.50

0.12 2.19 < 0.001 1.02 0.34 0.91

0.99—4.83 0.99—1.06 0.39—2.17

0.052 0.225 0.84

1.27 1.98 1.01

0.71—2.26 0.99—3.93 1.00—1.01

0.43 0.05 0.009

1.31 1.56 1.01

0.58—2.95 0.61—3.98 1.00—1.02

0.52 0.36 0.005

0.89 1.18 1.002

0.41—1.92 0.53—2.59 0.99—1.01

0.77 0.69 0.49

0.99

0.93—1.06

0.92

0.99

0.91—1.08

0.83

0.92

0.85—0.99

0.047

0.99

0.98—1.01

0.33

0.98

0.96—0.99

0.015

0.99

0.97—1.00

0.059

0.99 2.48

0.48—2.06 1.10—5.57

0.99 0.028

0.59 2.90

0.23—1.54 1.06—7.92

0.28 0.038

0.45 5.52

0.19—1.03 0.059 2.27—13.45 < 0.001

1.08 0.97

1.04—1.12 0.48—1.96

< 0.001 0.94

1.12 1.52

1.06—1.18 0.65—3.55

< 0.001 1.02 0.33 0.81

0.98—1.06 0.34—1.95

0.32 0.64

1.39 1.78 1.00

0.77—2.51 0.89—3.54 1.00—1.01

0.27 0.10 0.012

1.39 1.48 1.01

0.61—3.18 0.58—3.79 1.00—1.02

0.44 0.42 0.005

0.94 1.03 1.00

0.43—2.04 0.46—2.32 0.99—1.01

0.88 0.95 0.57

1.00

0.94—1.07

0.95

1

0.92—1.09

0.99

0.92

0.84—0.99

0.039

0.99

0.98—1.00

0.39

0.98

0.96—0.99

0.03

0.99

0.97—1.00

0.059

0.96 3.77

0.47—1.98 0.91 1.30—10.92 0.014

0.58 5.36

0.22—1.54 0.28 1.11—25.96 0.037

0.41 7.33

0.18—0.94 0.036 2.21—24.29 0.001

0.26

0.11—0.62

0.002

0.16

0.04—0.64

0.009

0.23

0.09—0.61

0.003

1.10 0.52

1.04—1.17 0.19—1.48

< 0.0001 1.16 0.22 0.76

1.05—1.28 0.21—2.70

0.003 0.67

1.01 0.43

0.97—1.06 0.13—1.37

0.56 0.15

1.27 2.48 1.01

0.59—2.75 0.94—6.56 1.00—1.02

0.54 0.068 0.003

1.04 1.58 1.01

0.30—3.54 0.43—5.84 1.00—1.02

0.96 0.50 0.009

1.05 0.87 1.00

0.40—2.78 0.31—2.41 0.99—1.01

0.92 0.79 0.84

1.03

0.94—1.13

0.50

0.99

0.87—1.12

0.83

0.91

0.83—1.01

0.066

1.00

0.99—1.02

0.54

0.99

0.97—1.02

0.78

1.00

0.99—1.02

0.60

0.83

0.33—2.09

0.70

0.31

0.07—1.27

0.10

0.32

0.12—0.87

0.025

Adjusted HR 95% CI

P

CAD: coronary artery disease; CHF: congestive heart failure; CI: confidence interval; HR: hazard ratio; LBBB: left bundle branch block; LV: left ventricular; LVEF: left ventricular ejection fraction; LVESV: left ventricular end-systolic volume; MR: mitral regurgitation; NYHA: New York Heart Association. a On the day of hospital discharge.

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Figure 4. Kaplan Meier event-free survival according to the presence (+) or absence (—) of significant secondary mitral regurgitation MR at baseline. A. All-cause death. B. Cardiovascular death. C. Hospitalization for heart failure.

C. Binda et al.

Figure 5. Kaplan Meier event-free survival according to the presence (+) or absence (—) of significant secondary MR immediately after cardiac resynchronization therapy (CRT). A. All-cause death. B. Cardiovascular death. C. Hospitalization for heart failure.

Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009

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Study limitations Limitations are inherent to observational studies. This single-centre study included a relatively small number of patients. Clinical and echocardiographic data were analysed post hoc, but were collected prospectively with off-line analysis; patient follow-up was planned prospectively. Secondary MR is a dynamic and progressive complex disease; it depends not only on LV disease variables, but also on external conditions, such as therapeutic compliance and daily salt intake. Changes in secondary MR observed in the present study do indeed reflect those occurring in routine practice. We only reported mitral valve tenting as a measure of mitral valve tethering, as the aim of this study was to correlate the severity of secondary MR with outcome, and not to assess the mechanisms responsible for secondary MR. In addition, we reported previously that mitral valve tenting is an independent determinant of secondary MR, while mitral annulus dilation is not [11]. Lastly, multivariable models might be overfitted. Further larger multicentre studies are needed to confirm these exploratory results.

Conclusions Significant secondary MR immediately after and 9 months after CRT provides important long-term prognostic information. Significant secondary MR 9 months after CRT provides independent detrimental prognostic information beyond LV reverse remodelling. Patients with significant secondary MR 9 months after CRT have a considerably increased risk of mortality during long-term follow-up. Hence, the present data reinforce the potential role of alternative therapies, as well as new percutaneous procedures for mitral valve repair, in improving outcome in these very high-risk patients.

Sources of funding None.

Acknowledgments The authors wish to acknowledge the technical assistance of Dr Amélie Lansiaux, MD, PhD, Magali Demilly, PhD and Domitille Tristram, RN.

Disclosure of interest The authors declare that they have no competing interest.

References Figure 6. Kaplan Meier event-free survival according to the presence (+) or absence (—) of significant secondary MR 9 months after cardiac resynchronization therapy (CRT). A. All-cause death. B. Cardiovascular death. C. Hospitalization for heart failure.

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Please cite this article in press as: Binda C, et al. Time course of secondary mitral regurgitation in patients with heart failure receiving cardiac resynchronization therapy: Impact on long-term outcome beyond left ventricular reverse remodelling. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2017.05.009