Mitral Valve Area During Exercise After Restrictive Mitral Valve Annuloplasty

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 5, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2014.11.037

Mitral Valve Area During Exercise After Restrictive 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,y Lars Grieten, PHD, MSC,*y Wilfried Mullens, MD, PHD,*y Herbert Gutermann, MD,z Robert A. Dion, MD, PHD,z Robert A. Levine, MD,x Pieter M. Vandervoort, MD*y

ABSTRACT 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 pressure were assessed at different stages of exercise. AL opening angles were measured at rest and peak 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 ischemic

mitral valve annuloplasty (RMA) has evolved as the

and/or dilated heart disease is associated

gold standard treatment for severe secondary MR

with an unfavorable prognosis (1,2). Restrictive

(3–6); however, recurrence of MR after RMA has an

From the *Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; yFaculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; zDepartment of Cardiac Surgery, Ziekenhuis Oost-Limburg, Genk, Belgium; and the xCardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Dr. Bertrand is supported by a grant of the Research Foundation–Flanders (FWO, 11N7214N). Dr. Bertrand, Dr. Verbrugge, Mr. Smeets, Dr. Grieten, Dr. Mullens, and Dr. Vandervoort are researchers for the Limburg Clinical Research Program UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk, Hasselt University, Ziekenhuis Oost-Limburg, and Jessa Hospital. Dr. Dion has received consulting fees from Edwards Lifesciences, Johnson & Johnson, Sorin Biomedica, Medtronic, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received September 14, 2014; revised manuscript received October 27, 2014, accepted November 4, 2014.

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Mitral Valve Area After Restrictive Annuloplasty

incidence of approximately 30% (7), and mitral valve

commercially available system (Philips Med-

ABBREVIATIONS

replacement (MVR) has been proposed as a potential

ical Systems, IE33, Andover, Massachusetts).

AND ACRONYMS

alternative in selected patients (8–11). In addition,

Standard 2-dimensional and Doppler images

several studies have demonstrated the occurrence of

were acquired in the left lateral decubitus

moderate mitral stenosis (defined as mean transmi-

position and stored digitally for offline analysis in the CardioView software (TomTec Im-

SEE PAGE 462

aging Systems, Unterschleissheim, Germany).

tral pressure gradient [TMG] >5 mm Hg or mitral 2

valve area <1.5 cm ) after RMA (12–16). Functional mitral stenosis after RMA is generally attributed to

All measurements were averaged over 3 consecutive cardiac cycles for patients in sinus rhythm and 5 consecutive cycles for patients

undersizing of the annular ring, yet the subvalvular

with atrial fibrillation according to the guide-

apparatus might play a role as well. Importantly, the

lines of the American Society of Echocardiog-

impact of such functional mitral stenosis on exercise

raphy.

capacity and clinical outcome remains unclear,

method was used to calculate ejection fraction

mainly because most studies have based stenosis

at rest and peak exercise (20). Peak and mean

grading on the mean TMG at rest (13,14,16–19). How-

TMG were calculated using the modified

ever, this parameter is certainly flow dependent,

Bernoulli equation on the continuous-wave

The

modified

Simpson’s

biplane

453

AL = anterior (mitral) leaflet AR = aortic regurgitation 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

potentially masking severe stenosis in low-flow pa-

transmitral Doppler signal, with EOA calcu-

VO2max = maximal oxygen

tients (15). There are currently few data on the use

lated by the continuity equation (21). Systolic

uptake

of less flow-dependent parameters such as the effec-

pulmonary artery pressure (sPAP) was calculated us-

tive orifice area (EOA) to quantify stenosis in RMA

ing the modified Bernoulli equation on the trans-

patients.

tricuspid continuous-wave signal, while adding an

The aim of this study was to investigate the

estimate of right atrial pressure (22). Because patients

hemodynamic, functional, and clinical impact of

with more than mild MR and AR were excluded, mean

EOA after RMA and its relationship with diastolic

transmitral flow rate was defined as the ratio of left

anterior leaflet (AL) tethering at rest and during

ventricular (LV) stroke volume (measured from pulsed wave Doppler in the LV outflow tract) over diastolic

exercise.

filling time. During each stage of exercise, LV stroke

METHODS

volume, transmitral flow rate, peak and mean TMG, sPAP, and EOA were assessed. The mitral AL opening

STUDY

DESIGN

AND

STUDY

POPULATION. We

angle was measured on 2-dimensional TTE in an apical

included consecutive patients who underwent RMA

long-axis view, both at rest and at peak exercise.

with a complete semirigid Physio ring (Edwards Life-

Measures were taken at peak E-wave, and the angle of

sciences, Irvine, California), undersized by 1 or 2 sizes

the maximal excursion of the AL was measured with

to obtain a minimal coaptation length of 8 mm in the

respect to the plane of the prosthetic annular ring

A2-P2 segment, for secondary MR (Carpentier class

(Central Illustration).

IIIb, i.e., systolic leaflet restriction) between July 2007 and September 2012 at a single tertiary care center

EXERCISE TEST. All participating patients underwent

(Ziekenhuis Oost-Limburg, Genk, Belgium). Exclusion

a symptom-limited graded bicycle test in the semi-

criteria were structural leaflet abnormalities at surgical

supine position on a tilting exercise table. Workload

inspection, inability to undergo a supine bicycle ex-

was initiated at 20 W, with increments of 20 W every 3

ercise test, more than mild aortic regurgitation (AR)

min. In patients with poor general condition, an

(vena contracta width >3 mm), and more than mild

adjusted protocol was applied with 10 W of initial

MR recurrence (vena contracta width >3 mm) at rest

workload and increments of 10 W every 3 min.

or during exercise. Eligible patients underwent a

Blood pressure, a 12-lead electrocardiogram, ergo-

comprehensive resting transthoracic echocardiogra-

spirometry (Jaeger, Würzburg, Germany), and echo-

phy (TTE) examination, followed by a semisupine

cardiography measurements were recorded at each

symptom-limited bicycle exercise test with concomi-

stage.

tantly performed TTE. The study complied with the

CLINICAL ENDPOINTS. All-cause mortality and heart

Declaration of Helsinki, the protocol was approved by

failure admissions (defined as hospitalization because

the local ethics committee, and written informed

of signs or symptoms of congestion that warranted

consent was obtained from all participating patients.

treatment with parenteral drugs) were registered in

ECHOCARDIOGRAPHIC MEASUREMENTS. Resting and

all study patients from the day of surgery until

exercise echocardiography was performed with a

July 31, 2014, which yielded a follow-up of at least

454

Bertrand et al.

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C EN T RA L ILL USTRA T IO N

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 associated with improved clinical outcome, as shown by the KaplanMeier 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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Mitral Valve Area After Restrictive Annuloplasty

20 months after surgery for every patient. This follow-up included retrospective clinical data col-

T A B L E 1 Baseline Characteristics

RMA Patients (n ¼ 39)

lected during the postoperative period before the study visit, as well as prospective data from the study visit until July 31, 2014. STATISTICAL ANALYSIS. Results of continuous var-

iables were expressed as mean  SD if normally

63  11

Age at surgery, yrs Male

30 (77) 1.88  0.17

Body surface area, m2 Pre-operative NYHA functional class, I/II/III/IV, n

1/12/21/5

Pre-operative LV ejection fraction, %

40  12

distributed or otherwise by median and interquartile

Pre-operative LV end-diastolic volume, ml

153  57

range. Normality was assessed by the Shapiro-Wilk

Pre-operative LV end-systolic volume, ml

93  48

statistic. The paired or unpaired Student t test and

Pre-operative sPAP, mm Hg

50  12

Wilcoxon signed rank test were used whenever

Diabetes mellitus

appropriate. Categorical variables were expressed as

Pathogenesis of functional MR

percents and compared with Fisher exact test. Linear regression models were used to assess the

12 (31)

Ischemic

34 (87)

Nonischemic dilated

5 (13)

Operative data

correlation between TMG, EOA, and the square of

Aortic clamp time, min

transmitral flow rate. Predictors of maximal oxygen

Physio ring size, measured, 28/30/32/34/36/38

4/15/9/6/4/1

160  46

uptake (VO2 max) and EOA with a p value <0.1 at

Physio ring size, implanted, 24/26/28/30/32/34

3/10/12/7/5/2

univariate analysis were entered in multiple linear

Postoperative A2-P2 coaptation length, mm

8.6 (7.7–9.0)

regression models. Cox proportional hazards regres-

Concomitant TVA

19 (49)

Concomitant CABG

29 (74)

sion was used to assess variables associated with freedom from all-cause mortality or heart failure readmission since surgery, and variables with p < 0.1 were entered in a multivariate Cox regression model.

Study visit 33  17

Time since surgery, months Atrial fibrillation

4 (10)

NYHA functional class, I/II/III/IV

18/17/4/0

An assumption was made that hemodynamic data at the time of study were representative for the entire follow-up period. Cumulative survival rates were calculated according to the Kaplan–Meier method,

Values are mean  SD, n (%) or n. CABG ¼ coronary artery bypass graft; LV ¼ left ventricular; MR ¼ mitral regurgitation; NYHA ¼ New York Heart Association; RMA ¼ restrictive mitral annuloplasty; sPAP ¼ systolic pulmonary artery pressure; TVA ¼ tricuspid valve annuloplasty.

and groups were compared with the log-rank test. Receiver operating characteristic curves were used to determine area under the curve, sensitivity and specificity of different parameters, and cutoffs for the

there were no new ischemic alterations on the 12-lead

prediction of impaired exercise capacity (VO2max <15

electrocardiogram monitoring during exercise, and

ml/kg/min). Statistical significance was always set

no obvious new wall motion abnormalities were

at a 2-tailed probability of p < 0.05. All statistical

observed at peak exercise in standard apical views.

analyses were performed with the Statistical Package

TRANSMITRAL PRESSURE-FLOW RELATIONSHIP AT

for Social Sciences version 20.0 (SPSS Inc., Chicago,

REST AND DURING EXERCISE. Echocardiographic

Illinois).

measures at rest and at maximal exercise for all

RESULTS

are presented in Table 2. Mean and peak TMG, cardiac

39 patients after mean follow-up of 33  17 months output, and sPAP increased significantly during exPATIENT POPULATION. Of 103 screened patients,

ercise. The evolution of the mean TMG with respect to

27 patients had died. Nine were excluded because of

cardiac output at each stage of exercise is displayed in

structural leaflet abnormalities at surgical inspection,

Figure 1A. There was a strong and significant corre-

and 24 patients did not perform an exercise test

lation between the mean TMG and the square of

for various reasons (orthopedic or neurological

the cardiac output (r ¼ 0.81; p < 0.001), as well as

limitations, n ¼ 9; distance to hospital, n ¼ 3; and

the square of the transmitral flow rate (r ¼ 0.81;

refusal to participate, n ¼ 12). Four patients were

p < 0.001) (Figure 1B). This quadratic relationship is in

excluded from the analyses because they had recur-

agreement

rent MR or AR at rest or during exercise at the time of

derived from the Bernoulli equation and the principle

with

fundamental

hydraulic

notions

the study visit. Accordingly, the final study popula-

of continuity, in which the pressure gradient DP

tion consisted of 39 patients. Table 1 summarizes their

across a stenotic orifice EOA is known to be a function

baseline characteristics. None of the study patients

of the flow rate F squared (23,24), as displayed in

had angina pectoris at rest or during the exercise test,

Equations 1 and 2:

455

456

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multivariate model, AL opening angle at peak exer-

T A B L E 2 Resting and Exercise Doppler Echocardiography

Heart rate, beats/min

cise (p ¼ 0.037) remained the strongest determinant

Resting

Peak Exercise

p Value

of EOAi, independent of ring size (p ¼ 0.087) and

64  11

101  21

<0.001

peak cardiac output (p ¼ 0.137).

64  12

72  18

<0.001

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

analysis, patient age (p ¼ 0.004) and exercise EOAi

Mean transmitral flow rate, ml/s

132  41

263  99

<0.001

(p ¼ 0.004) emerged as independent predictors of

Stroke volume, ml/beat Cardiac output, l/min

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 Indexed EOA, cm2/m2 sPAP, mm Hg*

1.5  0.4

2.0  0.5

<0.001

0.8  0.2

1.0  0.3

<0.001

40  15

54  16

<0.001

Values are mean  SD. *Echocardiographic assessment of sPAP during exercise only successful in n 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.

IMPACT OF EOAI ON EXERCISE CAPACITY AND CLINICAL OUTCOME. VO 2 max was 15.2  4.3 ml$ kg 1

$min 1 in the population overall. In multivariate

VO2 max. At a cutoff value of 0.9 cm2 /m 2, exercise EOAi (area under the curve 0.750) had 86% sensitivity and 62% specificity to predict an exercise capacity lower than 15 ml/kg/min. During the entire follow-up period (55  16 months), 11 patients were admitted to the hospital for decompensated heart failure, and 2 patients died. In a multivariate Cox regression model to assess freedom from all-cause mortality or heart failure admission (Table 3) exercise EOAi (p ¼ 0.034) and age (p ¼ 0.008) were independently associated with outcome. Patients with exercise EOAi below the

F pffiffiffiffiffiffiffi EOA ¼ 50:4 DP 2  F DP ¼ 50:4 EOA

(Equation 1)

(Equation 2)

A display of this theoretical hydraulic relationship for various EOA orifices ranging from 0.5 to 3.5 cm 2 is

above-mentioned cutoff of 0.9 cm2 /m 2 (n ¼ 14) had significantly worse outcome than patients with higher exercise EOAi (n ¼ 25), as shown in the Central Illustration.

DISCUSSION

superposed in Figure 1B. RELATIONSHIP

BETWEEN

TRANSMITRAL

FLOW

RATE AND EOA. The mean EOA at rest was 1.5  2

0.4 cm (EOA indexed for body surface area, or EOAi, 2

2

0.8  0.2 cm /m ) in RMA patients. On the basis of this resting value and assuming a constant EOA, the expected mean TMG at maximal flow rate would be much higher than the observed mean gradient at maximal flow rate. During exercise, however, an increase in EOA was observed with increasing flow rate (quadratic correlation: r ¼ 0.78; p < 0.001) (Figure 2). EOA at maximal exercise was 2.0  2

2

2

0.5 cm (EOAi 1.0  0.3 cm /m , p < 0.001 for the change from rest).

This study quantified the transmitral pressure-flow relationship in patients with secondary MR treated with RMA and demonstrated an increase in EOA during exercise. Exercise EOAi was independently associated with outcome and was a stronger predictor of exercise capacity than was EOAi at rest, which stresses the importance of exercise echocardiography in this patient population. In addition, our findings challenge the concept that functional mitral stenosis from RMA for secondary MR solely results from a small annular size. If that were the case, the stenotic valve area would be fixed and less responsive to exercise. Instead, our findings suggest that the observed stenosis after RMA has an important subvalvular

DIASTOLIC AL OPENING ANGLE. The AL opening

component as well (in addition to ring size), dictated

angle at rest (68  10 ) showed a moderate correla-

by the diastolic restriction of anterior leaflet opening,

tion with EOA at rest (r ¼ 0.4; p ¼ 0.014). However,

likely caused by diastolic leaflet tethering.

exercise EOA was much better correlated to AL

DIASTOLIC LEAFLET TETHERING: PATHOPHYSIOLOGICAL

opening angle at peak exercise (r ¼ 0.6; p < 0.001).

INSIGHTS. Secondary MR results from LV motion ab-

Larger increases in AL opening angle during exercise

normalities or dilation, causing an imbalance between

were associated with higher relative increases in EOA

closing forces and papillary muscle tethering, thereby

(r ¼ 0.42; p ¼ 0.001). Univariate linear regression

interfering with normal systolic coaptation (25). These

identified annuloplasty ring size (r ¼ 0.4; p ¼ 0.007),

“culprit” LV abnormalities have diastolic implications

AL opening angle at peak exercise (r ¼ 0.6; p < 0.001),

as well, not only impairing LV relaxation but also

and peak cardiac output (r ¼ 0.5; p ¼ 0.002) as

inhibiting diastolic leaflet opening caused by severe

determinants of EOAi at peak exercise. In the

leaflet tethering. This phenomenon can be aggravated

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Mitral Valve Area After Restrictive Annuloplasty

F I G U R E 1 Transmitral Pressure-Flow Relationship During Exercise

B 25.0

25.0

20.0

20.0

Mean TMG (mmHg)

Mean TMG (mmHg)

A

15.0

10.0

5.0

0.5cm2

1.0cm2

1.5cm2

2.0cm2

2

m

2.5c

15.0

3.0cm2

10.0 3.5cm2

5.0 r2 = 0.65

0.0 2.5

5.0 7.5 10.0 Cardiac Output (L/min)

12.5

r2 = 0,66

0.0 0

100

200 300 400 Transmitral Flow (mL/s)

500

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.

by insertion of a prosthetic ring, anteriorly displacing

caused by papillary muscle displacement decreases

the posterior annulus and increasing the importance

the opening angle of this lid and obstructs inflow

of the AL during diastole (which then acts like the

(Figure 3). During exercise, increasing flow and left

lid of a pedal-operated waste bin). AL tethering

atrial pressure might (in part) overcome the tethering force and increase the opening angle to some extent. Importantly, however, the AL “opening reserve”

F I G U R E 2 EOA as a Function of Transmitral Flow Rate

might also be determined by the LV response to exercise (17). In patients with a positive LV response (i.e., a significant decrease in LV end-systolic vol-

3.5

ume), papillary muscle tethering decreases and AL opening and EOA increase (Central Illustration).

EOA (cm2)

3.0

Importantly, increasing the AL opening angle will not only increase the geometric orifice area at the tip

2.5

of the restricted leaflets but also has an impact on the coefficient of flow contraction. An alteration of the

2.0

inflow angulation during exercise, caused by a conformational change in the subvalvular apparatus,

1.5

is known to increase the coefficient of contraction (26). Thus, any exercise-induced increase in leaflet

1.0

angulation will result in both an increase in geometric R2 quadratic = 0.602

0.5 0

100

200 300 400 Transmitral Flow (ml/s)

500

orifice area and an increase in the coefficient of contraction, which compounds the effect on EOA. COMPARISON WITH PREVIOUS WORK. In a similar

RMA population, Magne et al. (12) also observed a Effective orifice area (EOA) as measured at each step of exercise

significant increase in EOA during exercise with a

with respect to the transmitral flow rate. A quadratic correlation

concomitant rise in LV ejection fraction (Table 4).

curve is superposed as a dashed line.

Kubota et al. (17), on the other hand, observed a significant decrease in EOA during exercise after

457

458

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found no exercise-induced increase in EOA in RMA

T A B L E 3 Predictors of Clinical Endpoint on Univariate and

patients despite an increase in ejection fraction.

Multivariate Cox Regression Analysis

Increasing ejection fraction during exercise, however, Univariate Analysis Parameter

Multivariate Analysis

might be characterized by increased LV end-diastolic

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

—

—

—

study by Magne et al. (12) and the present study.

Atrial fibrillation

0.89

0.11–6.90

0.908

—

—

—

Moreover, in the patient group in the study by Fino

LV end-diastolic volume

1.0

0.98–1.01

0.793

—

—

—

et al. (27), exercise EOAi was an independent pre-

LV end-systolic volume

1.0

0.99–1.02

0.944

—

—

—

dictor of exercise sPAP (as a surrogate of exercise

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

—

—

—

volume rather than a decrease in end-systolic volume. This might have caused a difference in exercise tethering in the patient group in the study by Fino et al. (27) compared with the RMA population in the

capacity). In MVR patients, severe valve prosthesis–patient

EOAi at peak exercise

0.11

0.01–1.36

0.086

0.08

0.01–0.84

0.034

mismatch (defined as EOAi <0.9 cm 2/m 2) is known to

Mean TMG at rest

0.80

0.56–1.14

0.211

—

—

—

be associated with postoperative pulmonary hyper-

Peak TMG at rest

0.95

0.82–1.10

0.492

—

—

—

tension and worse outcomes (28,29). Our findings indicate that similar mismatch hemodynamics and

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

physiology can also be observed in patients after RMA, with 2 important differences, however. First, EOAi was an independent predictor of outcome in

RMA. However, LV contractile reserve was severely

RMA patients not at rest but at peak exercise. We

impaired in this population, with the ejection fraction

hypothesize that in MVR patients, the EOA is fixed

decreasing during exercise. Moreover, the study by

during exercise and therefore is an identical predictor

Kubota et al. (17) suggested diastolic subvalvular

of outcome both at rest and peak exercise. Second,

tethering as an important contributor to functional

because the mechanism of inflow obstruction is

mitral stenosis after RMA. Finally, Fino et al. (27)

related to diastolic leaflet restriction, patients with adverse remodeling and LV dilation will have the

F I G U R E 3 Diastolic Leaflet Tethering After RMA on Echocardiography

lowest EOAi at peak exercise, further aggravating exercise capacity and outcome in a vicious circle. This might explain the independently strong association between exercise EOAi, exercise capacity, and outcome in this small sample population. CLINICAL IMPLICATIONS. The demonstration of a

dynamic mitral valve area in RMA patients because of diastolic leaflet restriction may add important insights with respect to functional capacity, exercise hemodynamics, and treatment options in this patient population. First, the increase in TMG during exercise is more attenuated in RMA patients than in patients with similar resting hemodynamics but with a more fixed orifice, as seen in organic mitral stenosis (30,31) and mechanical MVR (32). When describing and grading the degree of functional stenosis after RMA on the basis of resting data alone, it is important to realize the possible dynamic behavior of the EOA, especially in patients with beneficial LV remodeling. In case of doubt, exercise echocardiography with assessment of EOA at peak Transthoracic echocardiographic images in apical long-axis view show the typical diastolic inflow restriction in a patient who has undergone restrictive mitral valve annuloplasty (RMA), with and without color Doppler flow. Opening of the anterior (mitral) leaflet is

exercise should be applied. Second, our findings strongly support further research of concomitant

restricted because of diastolic papillary muscle tethering, which typically causes deviation

subvalvular procedures for patients with secondary

of blood inflow toward the inferolateral wall.

MR to relieve leaflet tethering. Prior studies have demonstrated

that

ongoing

leaflet

tethering

is

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Mitral Valve Area After Restrictive Annuloplasty

T A B L E 4 Comparison With Previous Exercise Studies After RMA Using Physio Ring I

First Author, Year (Ref. #)

n

Present study

Median Ring Size

Mean TMG (mm Hg)

Peak TMG (mm Hg)

CO (l/min)

EOA (cm2 )

sPAP (mm Hg)

LVEF (%)

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

62

13  4

4.6  1.2

1.5  0.3

42  13

43  11

DSE

24

83

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 in Tables 2 and 3.

involved in the mechanism of MR recurrence (33,34).

Finally, patients with recurrent MR after RMA at rest

Our study shows leaflet tethering probably plays a

or during exercise were excluded from analysis

role in diastolic inflow restriction as well. Relieving

to ensure the validity of the continuity equation.

tethering might therefore increase repair durability,

Because the mechanism of MR recurrence is com-

reduce the degree of undersizing needed to obtain

monly related to ongoing leaflet tethering (33) and

the target coaptation length, and reduce the func-

restricted leaflet motion (34), one could hypothesize

tional stenosis after surgery. Importantly, the in-

that the change in EOA and AL opening angle with

crease in EOA tended to reach a plateau (2.0 to 2.5

increasing flow would be more limited or even nega-

cm 2) at higher flow rates. We hypothesize this

tive in these excluded patients.

plateau is influenced by the effective orifice of the ring in the absence of leaflet tethering. Indeed, in

CONCLUSIONS

multivariate analysis, ring size remained associated with exercise EOA, independent of leaflet angle.

This study demonstrated that in patients with sec-

Therefore, all efforts to ensure a durable repair while

ondary MR after RMA, the EOA increases with

relieving tethering and increasing annuloplasty ring

increasing transmitral flow rate despite fixed annular

size should be subject to further research.

size. Diastolic AL tethering plays a key role in this dynamic process, with increasing AL opening during

STUDY LIMITATIONS. This was a single-center study

exercise being associated with higher exercise EOA.

with limited sample size and a small endpoint count

EOAi at peak exercise is a strong and independent

(i.e., there was a risk of overfitting the Cox regression

predictor of exercise capacity and is independently

model). Therefore, our results should be con-

associated with outcome. Our findings stress the

sidered hypothesis generating. Clinical follow-up for

importance of maximizing AL mobility by targeting

outcome analysis started immediately after surgery

the subvalvular apparatus in future repair algorithms

and thus preceded the exercise study visit. We

for secondary MR.

assumed the hemodynamic and functional measures at the study visit were representative for the entire postoperative follow-up period. This assumption is on the basis of prior RMA studies demonstrating stable hemodynamics (mean transmitral gradient at rest) from early after surgery until 18-month follow-up (3),

ACKNOWLEDGMENTS The authors thank the tech-

nicians and nursing staff of the cardiac ultrasound laboratory (R. Reyskens, K. Cuyvers, K. Machiels, and L. Jacobs) for their excellent support in the data collection.

as well as evidence of early postoperative improvement in New York Heart Association functional class

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

that remained stable for up to 7 years of follow-up in

Pieter M. Vandervoort, Department of Cardiology,

patients undergoing coronary artery bypass grafting

Ziekenhuis Oost-Limburg, Schiepse Bos 6, Genk 3600,

with mitral valve annuloplasty for secondary MR (35).

Belgium. E-mail: [email protected].

459

460

Bertrand et al.

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Mitral Valve Area After Restrictive Annuloplasty

FEBRUARY 10, 2015:452–61

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Ongo-

TRANSLATIONAL OUTLOOK: Further studies are

ing leaflet tethering after mitral valve repair in pa-

needed to determine whether relief of leaflet tethering in

tients with secondary MR contributes both to recurrent

patients undergoing repair of secondary MR improves the

MR and to diastolic inflow obstruction post-

durability of repair, increases diastolic orifice area, and is

operatively.

associated with better long-term clinical outcomes.

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

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