CLINICAL RESEARCH INTERVENTIONS FOR VALVULAR DISEASE AND FAILURE Euro Intervention

2016;11: e 1680- e 1686

published online Impact of percutaneous using the MitraClip system on tricuspid regurgitation

e Antonio H. Frangieh1, MD, MPH; Christiane Gruner2, MD; Fran Mikulicic2, MD; -edition April 2016 April -edition Adrian Attinger-Toller1, MD; Felix C. Tanner2, MD; Maurizio Taramasso3, MD; Roberto Corti1,4, MD; Jürg Grünenfelder3,4, MD; Thomas F. Lüscher1, MD; Frank Ruschitzka5, MD; Dominique Bettex6, MD; Francesco Maisano3, MD; Oliver Gaemperli1*, MD

1. Andreas Grüntzig Laboratories, University Heart Center, Zurich, Switzerland; 2. ,

University Heart Center, Zurich, Switzerland; 3. Cardiac , University Heart Center, Zurich, Switzerland; 4. Heart Clinic Hirslanden, Zurich, Switzerland; 5. Heart Failure Clinic, University Heart Center, Zurich, Switzerland; 6. Cardiac Anesthesiology, University Hospital Zurich, Zurich, Switzerland

KEYWORDS Abstract Aims: Tricuspid regurgitation (TR) severity and right ventricular (RV) dysfunction have been identified as • MitraClip significant predictors of outcome after mitral valve surgery. The aim of the present study was to investigate • mitral regurgitation the impact of percutaneous mitral valve repair (PMVR) with the MitraClip system on functional TR sever- • percutaneous ity and RV function. mitral valve repair Methods and results: • right Among 119 consecutive patients with severe mitral regurgitation who under- • tricuspid went PMVR, 67 had complete baseline and follow-up transthoracic echocardiography after 3-12 months regurgitation (6.8±2.9 months). TR severity was graded as mild, moderate, and severe. RV systolic function was assessed by fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE). Clinical end- points at follow-up included mortality, reoperation of the mitral valve, hospitalisation for congestive heart failure and New York Heart Association (NYHA) functional class. After PMVR, a significant decrease in TR severity (by at least one grade) was observed in 22 (33%) patients, while an increase occurred in only seven (10%) patients (p=0.02). Overall, systolic RV function (FAC and TAPSE), RV dimensions, and tri- cuspid annular diameter did not change significantly. Baseline SPAP was significantly higher (57±15 vs. 43±14 mmHg, p=0.002) and SPAP reduction significantly larger (-14±13 versus 1±15 mmHg, p=0.012) in patients who improved their TR. Multivariate logistic regression analysis identified the change in SPAP as the only significant predictor of changes in TR (odds ratio [OR] [for every change in SPAP by 10 mmHg] DOI: DOI: 1.90, 95% CI: 1.02±3.54; p=0.044). Patients with mild/moderate TR at follow-up after PMVR had lower

10.4244/EIJV11I14A320 event rates compared to those with severe TR (35% vs. 78%, respectively, p=0.025).

Conclusions: PMVR using the MitraClip device improves functional TR severity in approximately one third of patients, particularly in those who experience a significant SPAP reduction after the procedure.

*Corresponding author: Andreas Gruntzig Laboratories and , University Heart Center, Rämistrasse 100, 8091 Zurich, Switzerland. E-mail: [email protected]

© Europa Digital & Publishing 2016. All rights reserved. SUBMITTED ON 02/03/2015 - REVISION RECEIVED ON 1st 24/04/2015 / 2 nd 16/05/2015 - ACCEPTED ON 29/05/2015 e1680 EuroIntervention 2016;11:e1680-e1686 1681 e . - - 17 with echocardio 16 . . 18 15,17 . Systolic 15 MitraClip and tricuspid regurgitation tricuspid and MitraClip . MR severity was graded from 1+ to 4+ . MR severity 17 . 17 In brief, TR severity was graded as mild, moderate or severe moderate as mild, was graded severity TR In brief, STATISTICAL ANALYSIS STATISTICAL 20 (IBM Version Statistical analysis was performed with SPSS, USA). Quantitative data are expressed Armonk, NY, Corp., as mean±SD or median with interquartile range (IQR) where t-test or the appropriate and were compared using the Student’s according to ASE recommendations to according based on integration of various Doppler parameters (central of various Doppler parameters based on integration hepatic and width contracta vena contour, and density area, jet chambers. End- vein flow) and the dimensions of the right-sided by were measured dimensions RV and end-diastolic systolic 4-chamber (4CH) view apical from the RV-focused planimetry graphic (three-dimensional transoesophageal echocardiography) echocardiography) transoesophageal (three-dimensional graphic Acute anaesthesia. general under and guidance, fluoroscopic and as successful MitraClip success (APS) was defined procedural grade 2+ or less by to reduction MR with immediate implantation echocardiography. ECHOCARDIOGRAPHY (shortly baseline at was performed echocardiography Transthoracic months 12 to three follow-up at and procedure) PMVR the to prior in our clini- films were stored All echocardiographic after PMVR. experienced an by reviewed independently and database image cal second A history of the patient. to the clinical blinded reader, assess to follow-up) and (baseline severity TR re-evaluated reader as evaluation as well quantification, TR variability. inter-observer according to the dimensions and function, were performed of RV American Society of Echocardiography of the recommendations and the Association of Echocardiography (ASE), the European of Echocardiography Society Canadian RV function was assessed through fractional area change (FAC) (FAC) change area fractional was assessed through function RV area]/4CH end-systolic area–4CH as ([4CH end-diastolic defined sys plane annular tricuspid as the as well area×100) end-diastolic through tracings on M-mode acquired excursion (TAPSE) tolic the tricuspid annulus CLINICAL FOLLOW-UP direct by or records hospital from was obtained outcome Clinical Clinical practitioner. general his/her or patient the of interrogation for congestive hospitalisation recurrent death, included endpoints Heart York and New surgery, valve (CHF), mitral failure heart by the class. CHF was defined (NYHA) functional Association with two major or one major and two classic Framingham criteria, required to diagnose CHF minor criteria pressure (SPAP) was calculated from peak tricuspid regurgitant jet regurgitant from peak tricuspid was calculated pressure (SPAP) an and adding equation Bernoulli’s simplified using the velocity from the inferior vena pressure estimated of right atrial estimate diameter cava PERCUTANEOUS MITRAL VALVE REPAIR (PMVR) REPAIR VALVE MITRAL PERCUTANEOUS PROCEDURE according was performed device MitraClip the PMVR with elsewhere described technique to standard

. ------8 3-6 . Some . Some 11 and/or geo- 6 . PMVR with . PMVR with system (Abbott 9,12 ® . Recently, percutaneous . Recently, 2 , the technique has gained 7 , with a high risk for surgery. , with a high risk for surgery. 15 . In Europe, MR is the second most. In Europe, 1 . , but its effect on RV dimensions and function, tri on RV , but its effect 14 13 . Paradoxically, TR tends to worsen after mitral valve worsen after mitral valve tends to TR . Paradoxically, 9 (particularly in patients with ischaemic or dilative car (particularly in patients with ischaemic or 10 . The severity of TR may increase even further in the years TR may increase even further in the years of The severity . 9 The purpose of this study was therefore to explore changes to explore The purpose of this study was therefore Functional tricuspid regurgitation (TR), which occurs on struc Functional tricuspid regurgitation wide acceptance with more than 16,000 patients treated so far. On more than 16,000 patients treated so far. wide acceptance with approval for use in MitraClip received FDA 24 October 2013 the risk MR and at prohibitive surgical patients with degenerative following surgery, and is associated with worse outcomes following surgery, Vascular, Santa Clara, CA, USA) has emerged as a safe, less inva USA) has emerged Santa Clara, CA, Vascular, withpatients in surgery, to option therapeutic alternative sive, risk. Based on the favour and high surgical moderate to severe MR registries investigator-driven multicentric several of able results the MitraClip has only a slight impact on mitral annular geom the MitraClip has only a slight impact on etry and has been shown to induce reverse left ventricular (LV) left ventricular (LV) etry and has been shown to induce reverse remodelling line and follow-up transthoracic echocardiography (TTE) availa (TTE) echocardiography and follow-up transthoracic line or infarction included a recent myocardial ble. Exclusion criteria repeat PMVR, or , any cardiac revascularisation, <6 weeks implantation device (CRT) therapy resynchronisation TR prior to the index PMVR or during follow-up, or degenerative moderate symptomatic for PMVR included Indications aetiology. to severe (3+) or severe (4+) MR Methods AND STUDY DESIGN POPULATION PATIENT who underwent PMVR using the patients included consecutive We and had base Zurich Hospital University the system at MitraClip Introduction with progressive left (MR) is associated regurgitation Severe mitral to high heart failure, leading dysfunction and congestive ventricular and mortality rates of morbidity surgery frequent valve disease requiring surgery disease requiring frequent valve the MitraClip repair (PMVR) with mitral valve metrical distortion of the tricuspid annulus after MV surgery as as surgery after MV metrical distortion of the tricuspid annulus TR the underlying mechanism for postoperative cuspid annular geometry and TR has not been extensively inves cuspid annular geometry and tigated as yet diomyopathy), with close to 50% of patients having postoperative having postoperative diomyopathy), with close to 50% of patients with lowering of pulmonary pres TR despite successful surgery sure An interdisciplinary Heart Team, which included an interventional included which Team, Heart An interdisciplinary and a car an echocardiographer, surgeon, a cardiac cardiologist, for PMVR. eligibility subject’s each discussed anaesthetist, diac a pro in consent to be included informed written gave All patients The proto- 2010-0466). registry (KEK-ZH-Nr. MitraClip spective committee ethical col of the registry was approved by the cantonal of Zurich. in TR severity and RV function after PMVR, and to relate these relate to PMVR, and after function and RV TR severity in patient and success procedural long-term and acute to findings outcome. turally normal tricuspid valves, is frequently observed in patients in patients observed frequently is valves, normal tricuspid turally with MR and the results of one randomised trial and the results of one have proposed impaired right ventricular function have proposed impaired right ventricular - -value 0.540 0.058 0.728 0.697 0.853 0.260 0.442 0.390 0.260 0.296 0.174 0.015 0.082 0.062 0.001 1.0 0.381 0.551 0.277 0.033 p ­ 7 (10) 7 (10) 20 (30) 20 (30) 27 (40) 63 (94) 22 (33) 38 (57) 38 (57) 40 (60) 45±18 12 (18) 20 (30) 36 (54) 12 (18) 26 (39) 20 (30) 34 (51) 37 (55) 13 (19) 50 (75) 41 (61) 73±11 graphy (n=67) 25.5±5 Follow-up echocardio 9 (8) Total Total 40 (34) 26 (22) 53 (44) 15 (13) 37 (31) 67 (56) 69 (58) 88 (66) 46±18 18 (15) 31 (26) 70 (59) 16 (13) 35 (29) 28 (24) 51 (43) 50 (42) 23 (19) 85 (71) 70 (59) 75±11 patients (n=119) 111 (93) MitraClip 25.1±5.1 ) 2 Moderate Severe Mild Atrial fibrillation CRT Pacemaker/ICD Previous heart failure Previous valve surgery Previous CABG Previous PCI Previous myocardial infarction Hyperlipidaemia Diabetes mellitus Hypertension Baseline LVEF (%) Baseline LVEF Tricuspid regurgitation Tricuspid Acute procedural success Mixed Degenerative Mitral regurgitation mechanism Functional Renal failure Previous cardiac history BMI (kg/m Cardiovascular risk factors Age (years) Gender (male) Values are n (%) or mean±SD. p-values refer to comparison between Values subgroups of patients with or without available follow-up BMI: body mass index; CABG: coronary artery bypass echocardiography. implantable cardiac resynchronisation therapy; ICD: graft; CRT: left ventricular ejection fraction; cardioverter defibrillator; LVEF: PCI: percutaneous coronary intervention Table 1. Baseline characteristics. Comparison between patients between Comparison characteristics. 1. Baseline Table echocardiography follow-up transthoracic with and without available. clinical and echocardiographic characteristics associated with clinical and echocardiographic characteristics associated with was significantly higher (57±15 TR evolution. Baseline SPAP reduction significantly vs. 43±14 mmHg, p=0.002) and SPAP (-14±13 versus 1±15 mmHg, p=0.012) in patients who larger TR and TR. In fact, the magnitude of SPAP improved their There was no change was directly correlated (r=0.41, p=0.006). in any of the remaining parameters. Most significant difference parameters of dimension and nor RV neither LV importantly, TR. Multivariate logis function appeared to predict changes in as the only tic regression analysis identified the change in SPAP ------. All 19 (Table 2). (Table (Table 2). (Table (Table 1). Acute (Table shows shows 3 Table . Inter-observer agreement for agreement (Figure 2). Inter-observer Baseline and follow-up echocardiography was available in 67 was available and follow-up echocardiography Baseline TR severity (by at least one grade) significant decrease in A and dimensions, RV TAPSE), and (FAC function RV Systolic p-values reported are two-sided and a value of p<0.05 was consid p-values reported are for all tests. ered statistically significant FACTORS ASSOCIATED WITH TR IMPROVEMENT ASSOCIATED FACTORS TR improved in 22 (33%) patients, and was After PMVR, patients. (77%) 45 in worse or unchanged There was a trend towards a decrease in systolic pulmonary artery pulmonary in systolic was a trend towards a decrease There mmHg, versus 41.9±14.0 mmHg 46.2±16.2 pressure (SPAP; p=0.072). IMPACT OF PMVR ON ECHOCARDIOGRAPHIC PARAMETERS IMPACT at 6.8±2.9 months afterFollow-up echocardiography was obtained in 17 (22%) and 46PMVR. MR was grade 3 and 4 at baseline At follow-up, five (8%) and seven (78%) patients, respectively. (10%) patients remained in grade 3 or 4 MR, respectively tion (EF) was <35% in 48 (40%) patients, 35 to 50% in 18 (15%) 18 in 50% to 35 patients, (40%) 48 in was <35% (EF) tion and >50% in 53 (45%) patients. patients, dif significant There were no statistically patients. of these 119 characteristics baseline two groups regarding the between ferences and previous percu of hyperlipidaemia for age, prevalence except 1). (PCI) (Table taneous coronary intervention occurred while an increase was observed in 22 (33%) patients, TR was mild, 1). (p=0.02) (Figure only in seven (10%) patients or severe in 27 (40%), 20 (30%), and 20 (30%) patients moderate at baseline, and in 32 (48%), 26 (39%), and 9 (13%) patients at follow-up, respectively kappa=0.56, p=0.002). was good (Cohen’s TR severity did not change significantly tricuspid annular diameter PATIENT POPULATION PATIENT who underwent PMVR using patients consecutive 119 included We 59% males). MR was functional system (age 75±11, the MitraClip in 31% and mixed in 13% in 56%, degenerative Results procedural success of PMVR was achieved in 111 (93%) patients. procedural success of PMVR was achieved in 111 40 (34%), and in 53 (44%), moderate in was mild TR Baseline frac ejection (LV) ventricular Left in 26 (22%) patients. severe sion analysis was used to correlate clinical and echocardiographic was used to correlate sion analysis using a dichotomised population: bet TR in variables with changes results of logistic regression are givenThe ter versus same/worse. inter confidence 95% respective their with (OR) ratios odds as were generated using the Kaplan-Meiervals (CI). Survival curves between were used to evaluate differences method. Log-rank tests calculated as 1.96 times was The reproducibility coefficient groups. Altman by Bland and as proposed the SD of the differences, Mann-Whitney U test, respectively. Categorical data are given in data are Categorical test, respectively. U Mann-Whitney test compared by the chi-square and percentages and proportions wasTR severity variability of Inter-observer test. or McNemar’s data were Numerical kappa coefficient. Cohen’s measured using logistic regres method. Multivariate using Spearman’s correlated

EuroIntervention 2016;11: 1680-e1686 1682

e e EuroIntervention 2016;11:e1680-e1686 1683 e -value -value 0.188 0.362 0.020 0.093 0.867 0.356 0.714 0.072 0.956 1.0 1.0 0.002 0.310 0.963 0.952 1.0 0.471 0.891 0.418 0.744 0.270 1.0 0.012 p p <0.001 TR n=45 8 (18) 9 (13) 5 (8) 7 (10) 73±10 45±18 17±5.5 1±14.7 28 (62) 26 (58) 27 (60) 3.2±0.5 or worse 32 (48) 26 (39) 29 (43) 26 (39) 18.2±5.7 34.1±8.5 25.1±7.6 32.9±9.6 19.1±5.1 25.5±6.6 20.4±6.9 21.3±5.9 Follow-up 41.9±13.9 43.1±14.1 3.18±0.69 unchanged 184.4±120.4 4,578±5,568

0 0 n=22 4 (18) 73±12 45±19 13 (59) 12 (55) 13 (59) 3.2±0.6 Baseline 27 (40) 20 (30) 20 (30) 17 (22) 46 (78) TR better 19.3±5.6 32.3±9.7 24.9±6.6 30.8±9.6 18.6±6.5 25.4±7.2 17.5±6.6 22.1±5.3 21.1±6.3 46.2±16.2 57.2±15.2 3.32±0.44 MitraClip and tricuspid regurgitation tricuspid and MitraClip –14.2±13.2 185.9±91.2 3,546±3,172 ) 2 ) ) 2 2 ) 2 ) 2 Mild Moderate Severe Grade 1 Grade 2 Grade 3 Grade 4 Tricuspid valve annulus Tricuspid diameter (cm) RA end-systolic area (cm TAPSE (mm) TAPSE Tricuspid regurgitation Tricuspid RV systolic area (cm RV RV-FAC (%) RV-FAC SPAP (mmHg) SPAP diastolic area (cm RV Age (years) Gender (male) MR mechanism (functional) Baseline echocardiographic parameters (mmHg) SPAP RA end-systolic area (cm Mitral regurgitation LVEDV (ml) LVEDV (%) LVEF Atrial fibrillation (ng/mL) Baseline NT-proBNP change* SPAP RV-FAC (%) RV-FAC (mm) TAPSE valve annulus Tricuspid diameter (cm) RV end-diastolic area (cm RV Follow-up MR (grade >2+) Values are n (%) or mean±SD. * Follow-up SPAP minus baseline SPAP. minus baseline SPAP. are n (%) or mean±SD. * Follow-up SPAP Values left ventricle end-diastolic volume; area change; LVEDV: fractional FAC: N-terminal prohormone of brain MR: mitral regurgitation; NT-proBNP: systolic right ventricle; SPAP: natriuretic peptide; RA: right ; RV: tricuspid annular plane systolic pulmonary artery pressure; TAPSE: excursion; TR: tricuspid regurgitation Values are n (%) or mean±SD. FAC: fractional area change; RA: right are n (%) or mean±SD. FAC: Values systolic pulmonary artery pressure; right ventricle; SPAP: atrium; RV: tricuspid annular plane systolic excursion TAPSE: Table 3. Clinical and echocardiographic characteristics Table Comparisonassociated with tricuspid regurgitation evolution. or worse tricuspidbetween patients with better versus unchanged regurgitation after MitraClip implantation. Table 2. Echocardiographic parameters at baseline and follow-up and at baseline parameters 2. Echocardiographic Table (n=67). Baseline Follow-up Severe : NYHA NYHA (Figure 3): Table 4). On univariate Table Moderate TR severity Mild Tricuspid regurgitation severity at baseline and follow-up severity at baseline and regurgitation Tricuspid

0

10 20 30 40 50 60 Patients (%) Patients Clinical events were recorded up to a median of 16 months (IQR months 16 of median a to up recorded were events Clinical CLINICAL FOLLOW-UP class functional PMVR improved NYHA significant predictor for changes in TR (OR [for every change in [for every change in (OR TR predictor for changes in significant by 10 mmHg] 1.90, 95% CI: 1.02±3.54; p=0. 044). SPAP Class III or IV was present in 76% of patients at baseline, which was present in 76% of patients at baseline, Class III or IV As a consequence, decreased to 23% at follow-up (p<0.001). from 24% I or II increased in NYHA the proportion of patients (NT-proBNP) peptide natriuretic pro-brain 77%. N-terminal to difference but the from 4,246±671 to 3,642±526 ng/L, decreased significance. short of statistical fell follow-up after TR at with mild/moderate 8-27 months). Patients for heart rehospitalisation PMVR had lower event rates (death, TR (35% with severe to patients compared reoperation) failure, p=0.025) (Figure 4, vs. 78%, respectively, significant as a emerged TR follow-up analysis, Cox regression after adjusting predictor of outcome, but fell short of significance class. and NYHA MR, NT-proBNP, residual SPAP, for age, EF, Figure 2. Evolution of tricuspid regurgitation severity at baseline regurgitation Figure 1. Evolution of tricuspid and follow-up after MitraClip. after MitraClip. ------. Particularly . Furthermore, . Furthermore, . 24 10 9,10,20 . Thus, surgeons are now surgeons Thus, . and to induce reverse LV and to induce reverse LV 8 23 . 22 . Several mechanisms have been consid been have mechanisms . Several 21 . We can only speculate on the possible explanations for explanations possible on the speculate only can We . 8 , while a rigid MV prosthesis (particularly when associated prosthesis (particularly , while a rigid MV 22 Surgical reports investigating the natural history of functional the natural reports investigating Surgical In contrast, in our patients none of the aforementioned risk fac risk aforementioned the of none patients our in contrast, In remodelling (which may favourably affect the RV) (which may favourably affect remodelling in patients with functional MR aetiology (and underlying ischae MR aetiology in patients with functional TR worsens early after surgery cardiomyopathy), mic or dilative valvular lesions, and despite successful correction of left-sided follow-up longer-term at deteriorate further may more in favour of correcting significant functional TR by recon TR functional significant of correcting favour in more if annular or RV particularly struction to prevent late deterioration, is present at baseline dilatation LV function, PMVR did not increase TR severity in the majority majority the in TR severity increase did not PMVR function, LV reduc TR a significant In fact, follow-up. six-month at of patients tion (by at least one grade) was observed in approximately one approximately was observed in one grade) least (by at tion only in seven (10%) occurred increase while an third of patients, RV TAPSE), and function (FAC RV systolic However, patients. not change signifi did diameter and tricuspid annular dimensions, patients 14 TR, baseline severe with patients 20 of Notably, cantly. remained after PMVR, and only six or mild to moderate improved had moder who patients 20 of the TR. Moreover, in severe PMVR. TR after TR, only one progressed to severe baseline ate (87%) had only mild or moderate of patients Overall, the majority PMVR. TR at follow-up after For results. conflicting yielded have surgery valve mitral after TR success after TR decreases functional that many years, the concept Recent by surgeons. accepted was largely surgery valve ful mitral about this concept, raising awareness reports have challenged TR of functional the potential undertreatment this finding. On the one hand, PMVR avoids cardiopulmonary On the this finding. ischae to myocardial which may lead bypass and cardiotomy, changes of annular mia, ventricular dysfunction and geometrical has system MitraClip the PMVR with hand, other the On planes. contractility been shown to spare LV the MitraClip has only a slight impact on mitral annular geom annular mitral on impact slight a has only MitraClip the etry with chordal ablation) or annuloplasty device causes more annu- forces on the disruptive lar distortion which could possibly exert atrial left further Interestingly, annulus. tricuspid neighbouring TR progression is associated with a poorer prognosis in terms of with a poorer prognosis in terms TR progression is associated mortality and morbidity tors was predictive of TR progression, except for SPAP. In fact, In SPAP. for except progression, TR of was predictive tors reduction after PMVR was the with a large a high baseline SPAP, nor LV RV Neither improvement. TR of predictor significant only TR. of any changes in were predictive dimensions nor function Thus, it appears that after PMVR profile (i.e., the haemodynamic TR evo that determines pulmonary pressures) is the only variable lution ered responsible for persistence or progression of TR after MV TR after MV of ered responsible for persistence or progression as well as RV annular dilatation, These include tricuspid surgery. The tethering. with increased leaflet and dilatation remodelling surgery MV after TR progression for risk factors most important higher dilatation, RV size, atrial left larger gender, female age, are dis heart or ischaemic pressure, a history of rheumatic pulmonary ease, and prosthetic valve dysfunction NYHA IV NYHA III NYHA II NYHA I -value 0.025 0.236 1.0 0.083 p 2,000 0 7 (78) 4 (44) 4 (44) (n=9) Mild/moderate TR Severe TR p=0.003 1,500 Severe TR Follow-up Mild/ 3 (5) 1,000 20 (35) 14 (24) 10 (17) moderate TR (n=58) Time of follow-up (days) Time 00 Baseline 05

1.0 0.8 0.6 0.4 0.2 0.0 Event-free survival Event-free

0

80 60 40 20 100 (%) Patients Combined endpoint* Hospitalisation for HF Reoperation of the MV All-cause mortality Values are n (%). *Combined endpoint of all-cause mortality, are n (%). *Combined endpoint of all-cause mortality, Values hospitalisation for heart failure, MV reoperation. HF: heart failure; TR: tricuspid regurgitation mitral valve; MV: Table 4. Patient outcomes. Comparison between patients with Table mild or moderate versus severe TR at follow-up. Discussion the of PMVR with impact the study explored present The In our population of TR severity. MitraClip system on functional systolic MR and reduced functional predominantly with patients Kaplan-Meier survival free of the composite endpoint Figure 4. Kaplan-Meier survival free for patients reoperation) for heart failure, (death, rehospitalisation TR at follow-up. with mild/moderate TR versus severe New York Heart Association (NYHA) functional class atAssociation Heart Figure 3. New York after MitraClip. baseline and follow-up

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- AP AP , tricuspid annular ­ tion. In the future, a ­ der 1996;335:1417-23. M, Seward JB, Tajik AJ, Tajik M, Seward JB, 2013;62:1052-61. Eur Heart J. 2012;33:2451-96. MitraClip and tricuspid regurgitation tricuspid and MitraClip ge reduction of SPAP after PMVR. ge reduction of SPAP G, Gaemperli O, Biaggi P, Felix C, G, Gaemperli O, Biaggi P, N Engl J Med. J Am Coll Cardiol. J ­ nificantly lar , Franzen O, Baldus S, Schafer U, Hausleiter J, ment can be predicted by higher baseline SP ment can be predicted ­ T, Kar S, Rinaldi M, Fail P, Hermiller J, Smalling R, J, Smalling Hermiller P, M, Fail Rinaldi S, Kar T, Surder D, Pedrazzini Ling LH, Enriquez-Sarano Joint Feldman Maisano F

2. 4. 5. 1. 3. Impact on daily practice Impact on daily third of patients after PMVR.TR improves in one Functional This improve values and a sig at baseline, worseningTR is moderate On the other hand, if of age, gen remains unlikely regardless dilatation or dysfunc or RV enlargement, of the treatment TR solution will possibly allow transcatheter pro thereby may (or staged after PMVR) and MR TR alongside outcomes. vide better long-term BA, Kaufmann Maur CA, Jeger R, Buser P, K, der Rufibach M, Hurlimann D, Buhler I, Bettex D, Scherman J, Moccetti P, Erne TF, Luscher T, Zuber M, Moccetti FF, Pasotti E, Faletra Conflict of interest statement to declare. of interest The authors have no conflicts References regur mitral of outcome RL. Clinical KR, Frye Bailey HV, Schaff gitation due to flail leaflet. Association European of the European Society of Cardiology (ESC), Alfieri O, A, Vahanian (EACTS), for Cardio-Thoracic Surgery Antunes MJ, Baron-Esquivias G, Baumgartner H, HeartDisease Andreotti F, Valvular ForceontheManagementof Task Iung B, V, A, Falk De Bonis M, Evangelista TP, Carrel MA, Borger Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Lancellotti P, S, Windecker Oppell UO, Von J, Takkenberg K, Swedberg Zamorano JL, Zembala M. Guidelines on the management of valvu lar heart disease (version 2012). S, Foster E, HC, Lim Low R, Herrmann W, PL, Gray Whitlow repair Investigators. Percutaneous mitral Glower D; EVEREST ini- the in durability midterm and safety system: MitraClip the with Study) REpair Edge-to-Edge Valve (Endovascular EVEREST tial 2009;54:686-94. Am Coll Cardiol. cohort. J T, JD, Moccetti Widder Sievert H, Richardt G, Butter C, Ussia GP, Percutaneous mitral valve interventions in the real W. Schillinger ACCESS-EU, a prospective, world: early and 1-year results from the nonrandomized post-approval study of the MitraClip multicenter, therapy in Europe. Conclusions TR sever functional improves device the MitraClip PMVR using Funding and educational Lüscher has received T.F. Outside of this study, Abbott to the institution. research grants from ity in approximately one third of patients, particularly in those particularly of patients, one third in approximately ity procedure. after the reduction SPAP a significant who experience ------. We . We 9 may con- 25 . Hence, it seems justi 5 and first preliminary data from data and first preliminary 21 . 14 . The limited sample size also prevented explo prevented also size sample limited The . 9,10 , may increase the accuracy in this regard. Nonetheless, 15 Our findings have potentially relevant clinical implications clinical relevant Our findings have potentially PMVR patients ration of the differences between degenerative and functional degenerative between differences of the ration Cox regression analysis. MR patients or to perform multivariate and semi-quantitative, TTE is only using TR of grading Moreover, ASE recommen- approach, as suggested by using an integrative dations Study limitations to the This is related sample size. a limited acknowledge We echocar and intervention, novel relatively a PMVR is that fact diographic follow-up was not available in all of our patients. in all follow-up was not available diographic sur to previous Nonetheless, the size of the cohort is comparable reports gical unloading into the right atrium through the iatrogenic atrial septal atrial iatrogenic the through atrium the right into unloading catheter guide by the 22 Fr steerable defect induced for the treatment of double valve regurgitation. Functional TR Functional of double valve regurgitation. for the treatment This improve- after PMVR. of patients improves in one third values and a sig SPAP by higher baseline can be predicted ment nificantly large reduction of SPAP after PMVR. Thus, a patient a Thus, PMVR. after SPAP of reduction large nificantly improve to MR is likely accompanying TR baseline severe with and is elevated SPAP if baseline PMVR, particularly TR after his from success can be expected in SPAP reduction a significant TR is moderate On the other hand, if implantation. ful MitraClip gen of age, regardless unlikely worsening remains baseline, at dysfunc- or dilatation RV or enlargement, annular tricuspid der, TR of treatment TR solution would allow the transcatheter A tion. provide thereby and may candidates MR in MitraClip alongside outcomes. long-term better cannot exclude late TR impairment in our study population based in our study population TR impairment late exclude cannot mechanisms different on the present findings. It may well be that haemo Potentially, TR impairment. play a role in early versus late dynamic changes (i.e., pulmonary pressures) play a more impor RV postoperative period, while delayed tant role in the immediate evolution. TR long-term processes affect and annular remodelling However, our patients. in relevant become also may latter The older and have shorter life tend to be significantly PMVR patients by surgery treated than patients expectancy - variabil inter-observer is subject to significant TR quantification echocardiography, not resonance, magnetic cardiac Moreover, ity. ventricular of right for evaluation standard gold the is considered Previous was short. period follow-up the Furthermore, function. reports have followed patients for several years after the surgical TR of procedure, and have also reported late deterioration tribute to TR worsening in the long term after PMVR. However, PMVR. However, after long term the in worsening TR to tribute in our study popu- tended to improve regurgitation since tricuspid is rather defect septal atrial from effect the that we believe lation, reduction. Moreover, of SPAP to the effect compared marginal at follow-up after PMVR had TR with mild/moderate patients reop failure, for heart rehospitalisation (death, rates event lower which is consist TR, severe with to patients compared eration) reports ent with previous surgical fied to evaluate short-term follow-up periods. short-term fied to evaluate - - - Heart. Lancet. Eur Heart J Am J Cardiol. T. Secondary tri T. Cardiol. Coll Am J Soc Echocardiogr. Am J WB, Levy D. The epidemiology WB, Levy D. AS, De Carlo M, Guarracino F, Conte L, AS, De Carlo M, Guarracino F, 2013;127:1018-27. O, Biaggi P, Gugelmann R, Osranek M, Gugelmann P, O, Biaggi Altman DG. Statistical methods for assessing Altman DG. Statistical O, Moccetti M, Surder D, Biaggi P, Hurlimann D, Hurlimann P, D, Biaggi Surder M, O, Moccetti 2005;79:127-32. Ann Thorac Surg. 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25. 19. 20. 21. 22. 23. 24. 16. 17. 18. septal defect after percutaneous of new atrial Functional effect valve repair using the MitraClip device. mitral M. Almalla K, S,Brehmer E, Reith Altiok R, fmann measurement. between two methods of clinical agreement 1986;1:307-10. replace valve left-sided after regurgitation of secondary tricuspid ment. Predictors Y. ChenJ,SuG,Ke Y, J, Deng ang G,SunZ,Xia J, MJ, Fail PS, Hermiller A, Rogers JH, Kar S, Rinaldi Schwartz DD; EVEREST DS, Glower HC, Lim Herrmann PL, Whitlow initial the in repair valve mitral Percutaneous Investigators. remodeling. left ventricular of reverse evidence cohort: EVEREST Imaging. 2013;6:522-30. Cardiovasc Circ D, Felix C, Bettex TF, Schreuder JJ, Buhler I, Surder D, Luscher pressure-volume ventricular left R. Real-time J, Corti Grunenfelder valve repair with the MitraClip mitral loops during percutaneous system. Circulation. reverse left and right Integrated V. A, Di Bello Pieroni Fiorelli F, in functional remodelling after MitraClip implantation ventricular study. echocardiographic an regurgitation: mitral Imaging. 2014;15:95-103. Cardiovasc 2014;113:1228-33. V, Falk TF, I, Bettex D, Felix C, Luscher Kretschmar O, Buehler percu- after changes haemodynamic Acute R. J, Corti Grunenfelder outcomes. to mid-term relation repair: valve taneous mitral Solomon SD, Louie EK, Schiller NB. Chandrasekaran K, of the right heart assessment Guidelines for the echocardiographic of Echocardiography Society American the in adults: a report from a reg Echocardiography, Association of endorsed by the European Study. Framingham the failure: heart of 2012;98:126-32. the and Cardiology, of Society European of the branch istered Echocardiogr. Am Soc J Canadian Society of Echocardiography. 2010;23:685-713. 1993;22:6A-13A. cuspid regurgitation or dilatation: which should be the criteria for which should be the criteria or dilatation: cuspid regurgitation repair? surgical Rakowski H, Stewart WJ, Waggoner A, Weissman NJ; American NJ; Weissman A, Rakowski H, WJ, Waggoner Stewart of for evaluation Recommendations of Echocardiography. Society with two-dimensional of native valvular regurgitation the severity echocardiography. and Doppler 2003;16:777-802.

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8. 7. 6. 9. 1 13. 15. 14. 12. 10. Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, RA, Nihoyannopoulos P, Kraft CD, Levine comes after percutaneous mitral valve repair with the MitraClip comes after percutaneous mitral Registry. System: 30-day and 12-month follow-up from the GRASP Imaging. 2014;15:1246-55. Eur Heart J Cardiovasc AM, A, Pistritto M, Caggegi S, Barbanti M, Ministeri Imme S, G, Giaquinta S, Farruggio S, Mangiafico M, Ronsivalle Chiaranda Association of Grasso C. P, C, Capranzano Tamburino Scandura S, F, S, Dipasqua CapodannoD,Cannata GF, Attizzani Y, out and echocardiographic with clinical tricuspid regurgitation Acute changes A, Nickenig G, Hammerstingl C. Mueller C, Ghanem of mitral valve geometry during interventional edge-to-edge repair with the MitraClip system are associated with midterm outcomes in patients with functional valve disease: preliminary results from a pro tricuspid regurgitation Predictors of residual T. Matsuo Y, Tokuda 2003;75:1826-8. Ann Thorac Surg. after mitral valve surgery. Y, 1. Topilsky C, Vannesson AS, M, Polge G, Richardson Fayad ven Right C. M, Bauters JN, Enriquez-Sarano Trochu F, Juthier C, N, Foucher-Hossein G, Lamblin Deswarte T, Tourneau cutaneous repair versus surgery for mitral regurgitation. regurgitation. for mitral versus surgery repair cutaneous mitral for functional repair valve mitral after regurgitation pid Surg. Eur J Cardiothorac cardiomyopathy. in dilated regurgitation 2008;33:600-6. of impact regurgitation: mitral systolic function in organic tricular biventricular impairment. spective single-center study. tricus of O. Evolution Alfieri L, Torracca F, A, Maisano Grimaldi regurgitation. regurgitation.

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