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Mitral Valve Area During Exercise AfterRestrictive Mitral Valve Annuloplasty

Importance of Diastolic Anterior Leaflet Tethering

Philippe B. Bertrand, MD, MSC,*y Frederik H. Verbrugge, MD,*y David Verhaert, MD,* Christophe J.P. Smeets, MSC,yLars Grieten, PHD, MSC,*y Wilfried Mullens, MD, PHD,*y Herbert Gutermann, MD,z Robert A. Dion, MD, PHD,zRobert A. Levine, MD,x Pieter M. Vandervoort, MD*y

ABSTRACT

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BACKGROUND Restrictive mitral valve annuloplasty (RMA) for secondary mitral regurgitation might cause functional

mitral stenosis, yet its clinical impact and underlying pathophysiological mechanisms remain debated.

OBJECTIVES The purpose of our study was to assess the hemodynamic and clinical impact of effective orifice area

(EOA) after RMA and its relationship with diastolic anterior leaflet (AL) tethering at rest and during exercise.

METHODS Consecutive RMA patients (n ¼ 39) underwent a symptom-limited supine bicycle exercise test with

Doppler echocardiography and respiratory gas analysis. EOA, transmitral flow rate, mean transmitral gradient, and systolic

pulmonary arterial pressurewere assessed at different stages of exercise. AL opening anglesweremeasured at rest andpeak

exercise. Mortality and heart failure readmission data were collected for at least 20 months after surgery.

RESULTS EOA and AL opening angle were 1.5 � 0.4 cm2 and 68 � 10�, respectively, at rest (r ¼ 0.4; p ¼ 0.014). EOA

increased significantly to 2.0 � 0.5 cm2 at peak exercise (p < 0.001), showing an improved correlation with AL opening

angle (r ¼ 0.6; p < 0.001). Indexed EOA (EOAi) at peak exercise was an independent predictor of exercise capacity

(maximal oxygen uptake, p ¼ 0.004) and was independently associated with freedom from all-cause mortality or

hospital admission for heart failure (p ¼ 0.034). Patients with exercise EOAi <0.9 cm2/m2 (n ¼ 14) compared with

$0.9 cm2/m2 (n ¼ 25) had a significantly worse outcome (p ¼ 0.048). In multivariate analysis, AL opening angle at peak

exercise (p ¼ 0.037) was the strongest predictor of exercise EOAi.

CONCLUSIONS In RMA patients, EOA increases during exercise despite fixed annular size. Diastolic AL tethering plays a

key role in this dynamic process, with increasing AL opening during exercise being associated with higher exercise EOA.

EOAi at peak exercise is a strong and independent predictor of exercise capacity and is associated with clinical outcome.

Our findings stress the importance of maximizing AL opening by targeting the subvalvular apparatus in future repair

algorithms for secondary mitral regurgitation. (J Am Coll Cardiol 2015;65:452–61) © 2015 by the American College of

Cardiology Foundation.

S econdary mitral regurgitation (MR) in ischemicand/or dilated heart disease is associatedwith an unfavorable prognosis (1,2). Restrictive

m the *Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgi

iversity, Diepenbeek, Belgium; zDepartment of Cardiac Surgery, Ziekenh

rasound Laboratory, Massachusetts General Hospital, Harvard Medical S

rted by a grant of the Research Foundation–Flanders (FWO, 11N7214N). D

. Mullens, and Dr. Vandervoort are researchers for the Limburg Clinical Res

ndation Limburg Sterk Merk, Hasselt University, Ziekenhuis Oost-Lim

nsulting fees from Edwards Lifesciences, Johnson & Johnson, Sorin Bio

thors have reported that they have no relationships relevant to the conte

ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Vale

u can also listen to this issue’s audio summary by JACC Editor-in-Chief D

nuscript received September 14, 2014; revised manuscript received Octob

mitral valve annuloplasty (RMA) has evolved as thegold standard treatment for severe secondary MR(3–6); however, recurrence of MR after RMA has an

um; yFaculty of Medicine and Life Sciences, Hasselt

uis Oost-Limburg, Genk, Belgium; and the xCardiacchool, Boston, Massachusetts. Dr. Bertrand is sup-

r. Bertrand, Dr. Verbrugge, Mr. Smeets, Dr. Grieten,

earch Program UHasselt-ZOL-Jessa, supported by the

burg, and Jessa Hospital. Dr. Dion has received

medica, Medtronic, and St. Jude Medical. All other

nts of this paper to disclose.

ntin Fuster.

r. Valentin Fuster.

er 27, 2014, accepted November 4, 2014.

AB BR E V I A T I O N S

AND ACRONYM S

AL = anterior (mitral) leaflet

AR = aortic regurgitation

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453

incidence of approximately 30% (7), and mitral valvereplacement (MVR) has been proposed as a potentialalternative in selected patients (8–11). In addition,several studies have demonstrated the occurrence ofmoderate mitral stenosis (defined as mean transmi-

SEE PAGE 462

EOA = effective orifice area

EOAi = indexed effective

orifice area

LV = left ventricle

MR = mitral regurgitation

MVR = mitral valve

replacement

RMA = restrictive mitral valve

annuloplasty

TMG = transmitral pressure

gradient

TTE = transthoracic

echocardiography

VO2max = maximal oxygen

e

tral pressure gradient [TMG] >5 mm Hg or mitralvalve area <1.5 cm2) after RMA (12–16). Functionalmitral stenosis after RMA is generally attributed toundersizing of the annular ring, yet the subvalvularapparatus might play a role as well. Importantly, theimpact of such functional mitral stenosis on exercisecapacity and clinical outcome remains unclear,mainly because most studies have based stenosisgrading on the mean TMG at rest (13,14,16–19). How-ever, this parameter is certainly flow dependent,potentially masking severe stenosis in low-flow pa-tients (15). There are currently few data on the useof less flow-dependent parameters such as the effec-tive orifice area (EOA) to quantify stenosis in RMApatients.

The aim of this study was to investigate thehemodynamic, functional, and clinical impact ofEOA after RMA and its relationship with diastolicanterior leaflet (AL) tethering at rest and duringexercise.

METHODS

STUDY DESIGN AND STUDY POPULATION. Weincluded consecutive patients who underwent RMAwith a complete semirigid Physio ring (Edwards Life-sciences, Irvine, California), undersized by 1 or 2 sizesto obtain a minimal coaptation length of 8 mm in theA2-P2 segment, for secondary MR (Carpentier classIIIb, i.e., systolic leaflet restriction) between July 2007and September 2012 at a single tertiary care center(Ziekenhuis Oost-Limburg, Genk, Belgium). Exclusioncriteriawere structural leaflet abnormalities at surgicalinspection, inability to undergo a supine bicycle ex-ercise test, more than mild aortic regurgitation (AR)(vena contracta width >3 mm), and more than mildMR recurrence (vena contracta width >3 mm) at restor during exercise. Eligible patients underwent acomprehensive resting transthoracic echocardiogra-phy (TTE) examination, followed by a semisupinesymptom-limited bicycle exercise test with concomi-tantly performed TTE. The study complied with theDeclaration of Helsinki, the protocol was approved bythe local ethics committee, and written informedconsent was obtained from all participating patients.

ECHOCARDIOGRAPHIC MEASUREMENTS. Resting andexercise echocardiography was performed with a

commercially available system (Philips Med-ical Systems, IE33, Andover, Massachusetts).Standard 2-dimensional and Doppler imageswere acquired in the left lateral decubitusposition and stored digitally for offline anal-ysis in the CardioView software (TomTec Im-aging Systems, Unterschleissheim, Germany).All measurements were averaged over 3 con-secutive cardiac cycles for patients in sinusrhythm and 5 consecutive cycles for patientswith atrial fibrillation according to the guide-lines of the American Society of Echocardiog-raphy. The modified Simpson’s biplanemethod was used to calculate ejection fractionat rest and peak exercise (20). Peak and meanTMG were calculated using the modifiedBernoulli equation on the continuous-wavetransmitral Doppler signal, with EOA calcu-lated by the continuity equation (21). Systolic

pulmonary artery pressure (sPAP) was calculated us-ing the modified Bernoulli equation on the trans-tricuspid continuous-wave signal, while adding anestimate of right atrial pressure (22). Because patientswith more than mild MR and AR were excluded, meantransmitral flow rate was defined as the ratio of leftventricular (LV) stroke volume (measured from pulsedwave Doppler in the LV outflow tract) over diastolicfilling time. During each stage of exercise, LV strokevolume, transmitral flow rate, peak and mean TMG,sPAP, and EOA were assessed. The mitral AL openingangle was measured on 2-dimensional TTE in an apicallong-axis view, both at rest and at peak exercise.Measures were taken at peak E-wave, and the angle ofthe maximal excursion of the AL was measured withrespect to the plane of the prosthetic annular ring(Central Illustration).

EXERCISE TEST. All participating patients underwenta symptom-limited graded bicycle test in the semi-supine position on a tilting exercise table. Workloadwas initiated at 20 W, with increments of 20 W every 3min. In patients with poor general condition, anadjusted protocol was applied with 10 W of initialworkload and increments of 10 W every 3 min.Blood pressure, a 12-lead electrocardiogram, ergo-spirometry (Jaeger, Würzburg, Germany), and echo-cardiography measurements were recorded at eachstage.

CLINICAL ENDPOINTS. All-cause mortality and heartfailure admissions (defined as hospitalization becauseof signs or symptoms of congestion that warrantedtreatment with parenteral drugs) were registered inall study patients from the day of surgery untilJuly 31, 2014, which yielded a follow-up of at least

uptak

CENTRAL ILLUSTRATION Mitral Valve Area During Exercise After Restrictive Annuloplasty: Mechanistic Insights and Clinical Impact

At rest, diastolic anterior (mitral) leaflet tethering plays a role in the postoperative mitral stenosis caused by restriction of leaflet opening and deviation of blood flow.

During exercise, increases in left atrial (LA) pressure and flow and a positive left ventricular (LV) response (i.e., a decrease in LV end-systolic volume) can augment the

opening of the leaflet, thereby increasing effective orifice area (EOA). Increasing EOA during exercise is associatedwith improved clinical outcome, as shown by the Kaplan-

Meier cumulative survival curve for freedom from all-cause mortality or heart failure admission in patients with exercise indexed EOA (EOAi) $0.9 cm2/m2 (blue line)

versus patients with exercise EOAi <0.9 cm2/m2 (red line). Crosses indicate that patients’ data were censored at that point. Ao ¼ aorta; ALA ¼ anterior leaflet angle.

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TABLE 1 Baseline Characteristics

RMA Patients(n ¼ 39)

Age at surgery, yrs 63 � 11

Male 30 (77)

Body surface area, m2 1.88 � 0.17

Pre-operative NYHA functional class, I/II/III/IV, n 1/12/21/5

Pre-operative LV ejection fraction, % 40 � 12

Pre-operative LV end-diastolic volume, ml 153 � 57

Pre-operative LV end-systolic volume, ml 93 � 48

Pre-operative sPAP, mm Hg 50 � 12

Diabetes mellitus 12 (31)

Pathogenesis of functional MR

Ischemic 34 (87)

Nonischemic dilated 5 (13)

Operative data

Aortic clamp time, min 160 � 46

Physio ring size, measured, 28/30/32/34/36/38 4/15/9/6/4/1

Physio ring size, implanted, 24/26/28/30/32/34 3/10/12/7/5/2

Postoperative A2-P2 coaptation length, mm 8.6 (7.7–9.0)

Concomitant TVA 19 (49)

Concomitant CABG 29 (74)

Study visit

Time since surgery, months 33 � 17

Atrial fibrillation 4 (10)

NYHA functional class, I/II/III/IV 18/17/4/0

Values are mean � SD, n (%) or n.

CABG ¼ coronary artery bypass graft; LV ¼ left ventricular; MR ¼ mitralregurgitation; NYHA ¼ New York Heart Association; RMA ¼ restrictive mitralannuloplasty; sPAP ¼ systolic pulmonary artery pressure; TVA ¼ tricuspid valveannuloplasty.

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20 months after surgery for every patient. Thisfollow-up included retrospective clinical data col-lected during the postoperative period before thestudy visit, as well as prospective data from the studyvisit until July 31, 2014.

STATISTICAL ANALYSIS. Results of continuous var-iables were expressed as mean � SD if normallydistributed or otherwise by median and interquartilerange. Normality was assessed by the Shapiro-Wilkstatistic. The paired or unpaired Student t test andWilcoxon signed rank test were used wheneverappropriate. Categorical variables were expressed aspercents and compared with Fisher exact test.Linear regression models were used to assess thecorrelation between TMG, EOA, and the square oftransmitral flow rate. Predictors of maximal oxygenuptake (VO2max) and EOA with a p value <0.1 atunivariate analysis were entered in multiple linearregression models. Cox proportional hazards regres-sion was used to assess variables associated withfreedom from all-cause mortality or heart failurereadmission since surgery, and variables with p < 0.1were entered in a multivariate Cox regression model.An assumption was made that hemodynamic data atthe time of study were representative for the entirefollow-up period. Cumulative survival rates werecalculated according to the Kaplan–Meier method,and groups were compared with the log-rank test.Receiver operating characteristic curves were used todetermine area under the curve, sensitivity andspecificity of different parameters, and cutoffs for theprediction of impaired exercise capacity (VO2max <15ml/kg/min). Statistical significance was always setat a 2-tailed probability of p < 0.05. All statisticalanalyses were performed with the Statistical Packagefor Social Sciences version 20.0 (SPSS Inc., Chicago,Illinois).

RESULTS

PATIENT POPULATION. Of 103 screened patients,27 patients had died. Nine were excluded because ofstructural leaflet abnormalities at surgical inspection,and 24 patients did not perform an exercise testfor various reasons (orthopedic or neurologicallimitations, n ¼ 9; distance to hospital, n ¼ 3; andrefusal to participate, n ¼ 12). Four patients wereexcluded from the analyses because they had recur-rent MR or AR at rest or during exercise at the time ofthe study visit. Accordingly, the final study popula-tion consisted of 39 patients. Table 1 summarizes theirbaseline characteristics. None of the study patientshad angina pectoris at rest or during the exercise test,

there were no new ischemic alterations on the 12-leadelectrocardiogram monitoring during exercise, andno obvious new wall motion abnormalities wereobserved at peak exercise in standard apical views.

TRANSMITRAL PRESSURE-FLOW RELATIONSHIP AT

REST AND DURING EXERCISE. Echocardiographicmeasures at rest and at maximal exercise for all39 patients after mean follow-up of 33 � 17 monthsare presented in Table 2. Mean and peak TMG, cardiacoutput, and sPAP increased significantly during ex-ercise. The evolution of the mean TMG with respect tocardiac output at each stage of exercise is displayed inFigure 1A. There was a strong and significant corre-lation between the mean TMG and the square ofthe cardiac output (r ¼ 0.81; p < 0.001), as well asthe square of the transmitral flow rate (r ¼ 0.81;p < 0.001) (Figure 1B). This quadratic relationship is inagreement with fundamental hydraulic notionsderived from the Bernoulli equation and the principleof continuity, in which the pressure gradient DPacross a stenotic orifice EOA is known to be a functionof the flow rate F squared (23,24), as displayed inEquations 1 and 2:

TABLE 2 Resting and Exercise Doppler Echocardiography

Resting Peak Exercise p Value

Heart rate, beats/min 64 � 11 101 � 21 <0.001

Stroke volume, ml/beat 64 � 12 72 � 18 <0.001

Cardiac output, l/min 4.0 � 0.8 6.9 � 2.2 <0.001

LV ejection fraction, % 50 � 13 56 � 14 <0.001

LV end-diastolic volume, ml 121 � 40 127 � 38 0.04

LV end-systolic volume, ml 64 � 37 59 � 36 0.01

Mean transmitral flow rate, ml/s 132 � 41 263 � 99 <0.001

Mean transmitral gradient, mm Hg 4.1 � 1.9 9.4 � 4.6 <0.001

Peak transmitral gradient, mm Hg 10.8 � 3.8 18.4 � 6.4 <0.001

EOA, cm2 1.5 � 0.4 2.0 � 0.5 <0.001

Indexed EOA, cm2/m2 0.8 � 0.2 1.0 � 0.3 <0.001

sPAP, mm Hg* 40 � 15 54 � 16 <0.001

Values are mean � SD. *Echocardiographic assessment of sPAP during exercise only successful inn ¼ 33 because of absence of measurable tricuspid regurgitant signal in 6 cases.

EAO ¼ effective orifice area; LV ¼ left ventricular; sPAP ¼ systolic pulmonary artery pressure.

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EOA ¼ F50:4

ffiffiffiffiffiffiffiDP

p (Equation 1)

DP ¼�

F50:4 EOA

�2

(Equation 2)

A display of this theoretical hydraulic relationshipfor various EOA orifices ranging from 0.5 to 3.5 cm2 issuperposed in Figure 1B.

RELATIONSHIP BETWEEN TRANSMITRAL FLOW

RATE AND EOA. The mean EOA at rest was 1.5 �0.4 cm2 (EOA indexed for body surface area, or EOAi,0.8 � 0.2 cm2/m2) in RMA patients. On the basis ofthis resting value and assuming a constant EOA, theexpected mean TMG at maximal flow rate would bemuch higher than the observed mean gradient atmaximal flow rate. During exercise, however, anincrease in EOA was observed with increasing flowrate (quadratic correlation: r ¼ 0.78; p < 0.001)(Figure 2). EOA at maximal exercise was 2.0 �0.5 cm2 (EOAi 1.0 � 0.3 cm2/m2, p < 0.001 for thechange from rest).

DIASTOLIC AL OPENING ANGLE. The AL openingangle at rest (68� � 10�) showed a moderate correla-tion with EOA at rest (r ¼ 0.4; p ¼ 0.014). However,exercise EOA was much better correlated to ALopening angle at peak exercise (r ¼ 0.6; p < 0.001).Larger increases in AL opening angle during exercisewere associated with higher relative increases in EOA(r ¼ 0.42; p ¼ 0.001). Univariate linear regressionidentified annuloplasty ring size (r ¼ 0.4; p ¼ 0.007),AL opening angle at peak exercise (r ¼ 0.6; p < 0.001),and peak cardiac output (r ¼ 0.5; p ¼ 0.002) asdeterminants of EOAi at peak exercise. In the

multivariate model, AL opening angle at peak exer-cise (p ¼ 0.037) remained the strongest determinantof EOAi, independent of ring size (p ¼ 0.087) andpeak cardiac output (p ¼ 0.137).

IMPACT OF EOAI ON EXERCISE CAPACITY AND

CLINICAL OUTCOME. VO2max was 15.2 � 4.3 ml$ kg�1

$min�1 in the population overall. In multivariateanalysis, patient age (p ¼ 0.004) and exercise EOAi(p ¼ 0.004) emerged as independent predictors ofVO2max. At a cutoff value of 0.9 cm2/m2, exerciseEOAi (area under the curve 0.750) had 86% sensitivityand 62% specificity to predict an exercise capacitylower than 15 ml/kg/min. During the entire follow-upperiod (55 � 16 months), 11 patients were admitted tothe hospital for decompensated heart failure, and 2patients died. In a multivariate Cox regression modelto assess freedom from all-cause mortality or heartfailure admission (Table 3) exercise EOAi (p ¼ 0.034)and age (p ¼ 0.008) were independently associatedwith outcome. Patients with exercise EOAi below theabove-mentioned cutoff of 0.9 cm2/m2 (n ¼ 14) hadsignificantly worse outcome than patients with higherexercise EOAi (n ¼ 25), as shown in the CentralIllustration.

DISCUSSION

This study quantified the transmitral pressure-flowrelationship in patients with secondary MR treatedwith RMA and demonstrated an increase in EOAduring exercise. Exercise EOAi was independentlyassociated with outcome and was a stronger predictorof exercise capacity than was EOAi at rest, whichstresses the importance of exercise echocardiographyin this patient population. In addition, our findingschallenge the concept that functional mitral stenosisfrom RMA for secondary MR solely results from asmall annular size. If that were the case, the stenoticvalve area would be fixed and less responsive to ex-ercise. Instead, our findings suggest that the observedstenosis after RMA has an important subvalvularcomponent as well (in addition to ring size), dictatedby the diastolic restriction of anterior leaflet opening,likely caused by diastolic leaflet tethering.

DIASTOLIC LEAFLET TETHERING: PATHOPHYSIOLOGICAL

INSIGHTS. Secondary MR results from LV motion ab-normalities or dilation, causing an imbalance betweenclosing forces and papillary muscle tethering, therebyinterfering with normal systolic coaptation (25). These“culprit” LV abnormalities have diastolic implicationsas well, not only impairing LV relaxation but alsoinhibiting diastolic leaflet opening caused by severeleaflet tethering. This phenomenon can be aggravated

FIGURE 1 Transmitral Pressure-Flow Relationship During Exercise

25.0

20.0

15.0

10.0

5.0

0.0

Mea

n TM

G (m

mHg

)

2.5 5.0 7.5 10.0 12.5Cardiac Output (L/min)

r2 = 0.65

25.0

20.0

15.0

10.0

5.0

0.0

Mea

n TM

G (m

mHg

)

0 100 200 300 400 500Transmitral Flow (mL/s)

r2 = 0,66

0.5cm2 1.0cm2 1.5cm22.0cm2

2.5cm2

3.0cm2

3.5cm2

A B

Mean transmitral pressure gradient (TMG) as a function of cardiac output (A) and transmitral flow (B) in patients who have undergone

restrictive mitral valve annuloplasty. Theoretical pressure-flow curves for fixed effective orifices ranging from 0.5 to 3.5 cm2 are superposed

in B.

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by insertion of a prosthetic ring, anteriorly displacingthe posterior annulus and increasing the importanceof the AL during diastole (which then acts like thelid of a pedal-operated waste bin). AL tethering

FIGURE 2 EOA as a Function of Transmitral Flow Rate

3.5

3.0

2.5

2.0

1.5

1.0

0.5

EOA

(cm

2 )

Transmitral Flow (ml/s)0 100 200 300 400 500

R2 quadratic = 0.602

Effective orifice area (EOA) as measured at each step of exercise

with respect to the transmitral flow rate. A quadratic correlation

curve is superposed as a dashed line.

caused by papillary muscle displacement decreasesthe opening angle of this lid and obstructs inflow(Figure 3). During exercise, increasing flow and leftatrial pressure might (in part) overcome the tetheringforce and increase the opening angle to some extent.Importantly, however, the AL “opening reserve”might also be determined by the LV response to ex-ercise (17). In patients with a positive LV response(i.e., a significant decrease in LV end-systolic vol-ume), papillary muscle tethering decreases and ALopening and EOA increase (Central Illustration).

Importantly, increasing the AL opening angle willnot only increase the geometric orifice area at the tipof the restricted leaflets but also has an impact on thecoefficient of flow contraction. An alteration of theinflow angulation during exercise, caused by aconformational change in the subvalvular apparatus,is known to increase the coefficient of contraction(26). Thus, any exercise-induced increase in leafletangulation will result in both an increase in geometricorifice area and an increase in the coefficient ofcontraction, which compounds the effect on EOA.COMPARISON WITH PREVIOUS WORK. In a similarRMA population, Magne et al. (12) also observed asignificant increase in EOA during exercise with aconcomitant rise in LV ejection fraction (Table 4).Kubota et al. (17), on the other hand, observed asignificant decrease in EOA during exercise after

FIGURE 3 Diastoli

Transthoracic echoca

inflow restriction in

(RMA), with and wit

restricted because of

of blood inflow towa

TABLE 3 Predictors of Clinical Endpoint on Univariate and

Multivariate Cox Regression Analysis

Parameter

Univariate Analysis Multivariate Analysis

HR 95% CI p Value HR 95% CI p Value

Age 1.09 1.02–1.17 0.013 1.09 1.02–1.17 0.008

Male 0.74 0.20–2.70 0.653 — — —

Ring size 0.84 0.65–1.08 0.167 — — —

Aortic clamp time 0.99 0.98–1.01 0.215 — — —

Diabetes mellitus 2.05 0.65–6.50 0.222 — — —

Atrial fibrillation 0.89 0.11–6.90 0.908 — — —

LV end-diastolic volume 1.0 0.98–1.01 0.793 — — —

LV end-systolic volume 1.0 0.99–1.02 0.944 — — —

LV ejection fraction 0.99 0.95–1.04 0.770 — — —

Cardiac output 0.52 0.23–1.14 0.103 — — —

EOAi at rest 0.11 0.01–3.35 0.203 — — —

EOAi at peak exercise 0.11 0.01–1.36 0.086 0.08 0.01–0.84 0.034

Mean TMG at rest 0.80 0.56–1.14 0.211 — — —

Peak TMG at rest 0.95 0.82–1.10 0.492 — — —

CI ¼ confidence interval; EOAi ¼ indexed effective orifice area; HR ¼ hazard ratio; LV ¼ left ventricular;TMG ¼ transmitral gradient.

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RMA. However, LV contractile reserve was severelyimpaired in this population, with the ejection fractiondecreasing during exercise. Moreover, the study byKubota et al. (17) suggested diastolic subvalvulartethering as an important contributor to functionalmitral stenosis after RMA. Finally, Fino et al. (27)

c Leaflet Tethering After RMA on Echocardiography

rdiographic images in apical long-axis view show the typical diastolic

a patient who has undergone restrictive mitral valve annuloplasty

hout color Doppler flow. Opening of the anterior (mitral) leaflet is

diastolic papillary muscle tethering, which typically causes deviation

rd the inferolateral wall.

found no exercise-induced increase in EOA in RMApatients despite an increase in ejection fraction.Increasing ejection fraction during exercise, however,might be characterized by increased LV end-diastolicvolume rather than a decrease in end-systolic vol-ume. This might have caused a difference in exercisetethering in the patient group in the study by Finoet al. (27) compared with the RMA population in thestudy by Magne et al. (12) and the present study.Moreover, in the patient group in the study by Finoet al. (27), exercise EOAi was an independent pre-dictor of exercise sPAP (as a surrogate of exercisecapacity).

In MVR patients, severe valve prosthesis–patientmismatch (defined as EOAi <0.9 cm2/m2) is known tobe associated with postoperative pulmonary hyper-tension and worse outcomes (28,29). Our findingsindicate that similar mismatch hemodynamics andphysiology can also be observed in patients afterRMA, with 2 important differences, however. First,EOAi was an independent predictor of outcome inRMA patients not at rest but at peak exercise. Wehypothesize that in MVR patients, the EOA is fixedduring exercise and therefore is an identical predictorof outcome both at rest and peak exercise. Second,because the mechanism of inflow obstruction isrelated to diastolic leaflet restriction, patients withadverse remodeling and LV dilation will have thelowest EOAi at peak exercise, further aggravatingexercise capacity and outcome in a vicious circle. Thismight explain the independently strong associa-tion between exercise EOAi, exercise capacity, andoutcome in this small sample population.CLINICAL IMPLICATIONS. The demonstration of adynamic mitral valve area in RMA patients becauseof diastolic leaflet restriction may add importantinsights with respect to functional capacity, exercisehemodynamics, and treatment options in this pa-tient population. First, the increase in TMG duringexercise is more attenuated in RMA patients than inpatients with similar resting hemodynamics butwith a more fixed orifice, as seen in organic mitralstenosis (30,31) and mechanical MVR (32). Whendescribing and grading the degree of functionalstenosis after RMA on the basis of resting data alone,it is important to realize the possible dynamicbehavior of the EOA, especially in patients withbeneficial LV remodeling. In case of doubt, exerciseechocardiography with assessment of EOA at peakexercise should be applied. Second, our findingsstrongly support further research of concomitantsubvalvular procedures for patients with secondaryMR to relieve leaflet tethering. Prior studies havedemonstrated that ongoing leaflet tethering is

TABLE 4 Comparison With Previous Exercise Studies After RMA Using Physio Ring I

First Author, Year (Ref. #) nMedianRing Size

Mean TMG(mm Hg)

Peak TMG(mm Hg)

CO(l/min)

EOA(cm2)

sPAP(mm Hg)

LVEF(%)

Present study 28

Resting 39 4.1 � 1.9 10.8 � 3.8 4.0 � 0.8 1.5 � 0.4 40 � 15 50 � 13

ESE 39 9.4 � 4.6 18.4 � 6.4 6.9 � 2.2 2.0 � 0.5 54 � 16 56 � 14

Magne et al., 2008 (12) 26

Resting 24 6 � 2 13 � 4 4.6 � 1.2 1.5 � 0.3 42 � 13 43 � 11

DSE 24 8 � 3 19 � 6 7.8 � 1.6 1.8 � 0.3 58 � 12 56 � 13

ESE 9 14.4 � 5.0 24 � 7 8.5 � 1.2 1.7 � 0.3 69 � 14 58 � 10

Kubota et al., 2010 (17) 28

Resting 31 3.5 � 2.7 10.6 � 6.2 — 1.6 � 0.2 — 42 � 13

ESE 12 6.0 � 2.2 18.5 � 6.2 — 1.4 � 0.2 — 42 � 12

Fino et al., 2014 (27) 28

Resting 57 4.5 � 1.3 8.6 � 2.6 4.6 � 1.0 1.8 � 0.5 38 � 7 40 � 4

ESE 57 11.0 � 3.7 19.7 � 6.6 7.6 � 1.3 1.8 � 0.4 55 � 11 49 � 6

CO ¼ cardiac output; DSE ¼ dobutamine stress echocardiography; ESE ¼ exercise stress echocardiography; LVEF ¼ left ventricular ejection fraction; other abbreviations as inTables 2 and 3.

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involved in the mechanism of MR recurrence (33,34).Our study shows leaflet tethering probably plays arole in diastolic inflow restriction as well. Relievingtethering might therefore increase repair durability,reduce the degree of undersizing needed to obtainthe target coaptation length, and reduce the func-tional stenosis after surgery. Importantly, the in-crease in EOA tended to reach a plateau (2.0 to 2.5cm2) at higher flow rates. We hypothesize thisplateau is influenced by the effective orifice of thering in the absence of leaflet tethering. Indeed, inmultivariate analysis, ring size remained associatedwith exercise EOA, independent of leaflet angle.Therefore, all efforts to ensure a durable repair whilerelieving tethering and increasing annuloplasty ringsize should be subject to further research.

STUDY LIMITATIONS. This was a single-center studywith limited sample size and a small endpoint count(i.e., there was a risk of overfitting the Cox regressionmodel). Therefore, our results should be con-sidered hypothesis generating. Clinical follow-up foroutcome analysis started immediately after surgeryand thus preceded the exercise study visit. Weassumed the hemodynamic and functional measuresat the study visit were representative for the entirepostoperative follow-up period. This assumption ison the basis of prior RMA studies demonstrating sta-ble hemodynamics (mean transmitral gradient at rest)from early after surgery until 18-month follow-up (3),as well as evidence of early postoperative improve-ment in New York Heart Association functional classthat remained stable for up to 7 years of follow-up inpatients undergoing coronary artery bypass graftingwith mitral valve annuloplasty for secondary MR (35).

Finally, patients with recurrent MR after RMA at restor during exercise were excluded from analysisto ensure the validity of the continuity equation.Because the mechanism of MR recurrence is com-monly related to ongoing leaflet tethering (33) andrestricted leaflet motion (34), one could hypothesizethat the change in EOA and AL opening angle withincreasing flow would be more limited or even nega-tive in these excluded patients.

CONCLUSIONS

This study demonstrated that in patients with sec-ondary MR after RMA, the EOA increases withincreasing transmitral flow rate despite fixed annularsize. Diastolic AL tethering plays a key role in thisdynamic process, with increasing AL opening duringexercise being associated with higher exercise EOA.EOAi at peak exercise is a strong and independentpredictor of exercise capacity and is independentlyassociated with outcome. Our findings stress theimportance of maximizing AL mobility by targetingthe subvalvular apparatus in future repair algorithmsfor secondary MR.

ACKNOWLEDGMENTS The authors thank the tech-nicians and nursing staff of the cardiac ultrasoundlaboratory (R. Reyskens, K. Cuyvers, K. Machiels, andL. Jacobs) for their excellent support in the datacollection.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Pieter M. Vandervoort, Department of Cardiology,Ziekenhuis Oost-Limburg, Schiepse Bos 6, Genk 3600,Belgium. E-mail: pieter.vandervoort@zol.be.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Ongo-

ing leaflet tethering after mitral valve repair in pa-

tients with secondary MR contributes both to recurrent

MR and to diastolic inflow obstruction post-

operatively.

TRANSLATIONAL OUTLOOK: Further studies are

needed to determine whether relief of leaflet tethering in

patients undergoing repair of secondary MR improves the

durability of repair, increases diastolic orifice area, and is

associated with better long-term clinical outcomes.

Bertrand et al. J A C C V O L . 6 5 , N O . 5 , 2 0 1 5

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KEY WORDS exercise echocardiography,heart failure, mitral valve, valvuloplasty