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Functional Significance of Elevated Mitral Gradients Following Repair for

Degenerative Mitral Regurgitation

Chan et al: Mitral Stenosis After Mitral Valve Repair

Kwan Leung Chan, MD, FRCPC*; Shin-Yee Chen, MD, FRCPC*;

Vincent Chan, MD, FRCSC*; Karen Hay, RDCS*; Thierry Mesana, MD, FRCSC*;

Buu Khanh Lam, MD, FRCSC*

*University of Ottawa Heart Institute

Correspondence to Kwan Leung Chan, MD FRCP University of Ottawa Heart Institute 40 Ruskin Street, H3412 Ottawa, ON K1Y 4W7 Tel: 613-761-4189 Fax: 613-761-4170 Email: [email protected]

DOI: 10.1161/CIRCIMAGING.112.000688

Journal Subject Codes: Cardiovascular (CV) surgery:[38] CV surgery: valvular disease,

Diagnostic testing:[125] Exercise testing, Diagnostic testing:[31] Echocardiography

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Abstract

Background—We have observed that elevated mitral gradients (EMG) can develop in some

patients following mitral valve repair for degenerative mitral regurgitation.

Methods and Results—We screened 275 patients who had mitral valve repair involving more

than one leaflet scallop between October 2001 and July 2010. Mitral valve hemodynamics were

assessed at rest and at peak exercise using the cycle ergometer. B-type natriuretic peptide (BNP)

levels were measured at rest and after exercise. The patients also performed a 6 minute walk test

and SF36 questionnaire. We enrolled 110 patients, with resting mean mitral diastolic gradient

3 mm Hg in 35 patients (Group 1), and > 3 mm Hg indicative of EMG in 75 patients (Group 2).

Posterior mitral leaflet plication (P=0.04) and the use of a complete mitral annuloplasty ring

(P<0.0001) were associated with EMG. Group 2 patients had larger left atrial volume (P=0.02),

higher mitral gradients at peak exercise and higher pulmonary artery systolic pressure at rest and

peak exercise, and lower exercise capacity (101±40 Watts versus 122 51 Watts, P=0.02). Group

2 patients also had higher BNP levels, and lower scores in 3 SF36 health concepts. Multivariate

regression analyses showed that mitral valve area was an independent predictor of maximum

exercise capacity (P=0.003).

Conclusions—Following mitral valve repair for degenerative mitral regurgitation EMG is not

uncommon, and is associated with worse intracardiac hemodynamics, higher BNP levels, lower

exercise capacity and poorer quality of life. Further refinement in the surgical technique may

reduce the incidence of this complication.

Key Words: mitral regurgitation, mitral valve repair, mitral stenosis, exercise capacity, quality

of life

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Mitral regurgitation (MR) is the most common valvular dysfunction affecting the general

population and its prevalence increases with age.1 The most common cause for primary MR is

degenerative/myxomatous mitral valve (MV) disease.2 In patients with severe MR due to

degenerative MV disease, the treatment of choice is MV repair which avoids the complications

associated with prosthetic valves and may provide a better long term survival compared to mitral

valve replacement.3-9 The procedure of MV repair consists of correction of the specific

component of the MV apparatus responsible for the abnormal coaptation leading to MR, and

remodeling of the mitral annulus by an annular ring or band. Resection of redundant leaflet

tissue particularly involving the posterior mitral leaflet can involve more than one third of the

leaflet, resulting in a significant reduction of the leaflet area and restricted excursion of the

posterior mitral leaflet.9-12

We hypothesize that MV repair involving more extensive tissue resection could result in elevated

mitral gradients (EMG) consistent with functional mitral stenosis (MS) which in turn could

affect the patient’s functional capacity and quality of life. The objectives of the present study

were to assess the prevalence and functional significance of EMG following MV repair for

degenerative MR by a comprehensive evaluation of resting and exercise MV hemodynamics,

exercise capacity and personal well being.

Methods

Patient Population:

From October 2001 to July 2010, MV repair was performed in 455 patients by a single surgeon

for severe MR due to myxomatous degeneration of the MV. Of these patients, 275 patients

(60%) had excess of MV tissue involving more than one leaflet scallop and were screened for

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enrolment into the study, as it was our hypothesis that functional MS may be more prevalent in

this subset of patients who required more aggressive tissue resection. The patients were

recruited and studied between December 2009 and April 2011. Patients who had residual MR

greater than mild in severity following MV repair were excluded. We also excluded hospitalized

patients, patients with prior myocardial infarction, left ventricular dysfunctionl with ejection

fraction < 40%, concomitant aortic valve disease with > mild stenosis or regurgitation, and

inability to perform bicycle exercise test. The patients underwent exercise echocardiography

using the supine bicycle protocol to assess exercise capacity and intracardiac hemodynamics

including MV diastolic gradients, severity of MR, and pulmonary artery systolic pressure at rest

and peak exercise. The 6 minute walk test was performed to provide an additional assessment of

the functional capacity.13,14 B-type natriuretic peptide (BNP) levels at rest and following

exercise were measured. The SF36 questionnaire was completed by all patients to measure their

functional health status. The study protocol was reviewed and approved by the Research Ethics

Board, and informed consent was obtained from all patients.

Resting Echocardiographic Measurements:

The echocardiographic measurements were obtained in accordance with the guidelines of the

American Society of Echocardiography.15 The left ventricular ejection fraction was calculated

using the modified Simpson’s rule.

Supine Bicycle Exercise Echocardiography:

The patients were securely positioned on a supine tilting cycle ergometer table that allowed up to

40 tilt. The patient pedaled at a steady state against a fixed resistance. After an initial workload

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of 25 Watts maintained for two minutes, the workload was stepwisely increased by 25 Watts

every two minutes. This was a symptom-limited exercise test and the patients were encouraged

to exercise to exhaustion.

Mitral Valve Hemodynamics:

The MV hemodynamics were measured by Doppler at rest and peak exercise. The peak and

mean transmitral pressure gradients were calculated using the modified Bernoulli equation, and

the MV area was calculated by the continuity equation by dividing the left ventricular outflow

tract stroke volume by the integral of the diastolic mitral transvalvular velocity.16 The

pulmonary systolic pressure was calculated based on the tricuspid regurgitant velocity and the

estimated right atrial pressure.17 Severity of MR was assessed according to the published

guidelines.18

We studied 20 patients with no structural heart disease who were referred for echocardiograms.

None had > mild MR. They were matched for age (60.0 4.3 years) and sex (14 men and 6

women), and they also had similar resting heart rate (72.0±12.5 beats per minute) compared to

the study patients. The resting mitral mean diastolic gradient was 1.24 0.52 mm Hg (range 0.62

to 2.70 mm Hg). Thus, in the analysis of MV repair patients, a resting mitral diastolic gradient >

3 mm Hg was used to indicate the presence of EMG.

6-minute Walk Test:

The 6-minute walk test was performed on the same day as the exercise echocardiogram, after the

patients rested for at least one hour.13,14

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B-type Natriuretic Peptide:

Fasting blood samples were drawn to measure B-type natriuretic peptide (BNP) on the day of the

exercise echocardiogram. The measurement was based on the rapid enzyme-linked

immunosorbent assay using the Biosite Triage kits. To assess the effect of exercise on BNP, a

second blood level was measured 15 minutes after the exercise echocardiogram.

SF-36 Questionnaire:

Health-related quality of life assessment was performed using the Medical Outcome Trust short

form 36 Item Health Survey (SF36), which has well established psychometric properties and has

been shown to have high reliability and validity.19

Statistical Analysis:

Descriptive statistics were used to summarize data: categorical data were described using

frequencies and percentages with comparative evaluations carried out via the chi-square test, or

Fisher’s exact test for frequency <5; continuous variables were presented as mean + standard

deviation, and comparisons of continuous variables were performed using the Student’s t-test for

normally distributed data and the Wilcoxon rank-sum test to adjust for skewed distributions. In

addition, when applicable, one-way ANOVA testing were used to assess inter-group variations

with the maximum experimentwise error rate (MEER) being controlled by a t-test with

Bonferroni correction or the Kruskal-Wallis nonparametric analogue test when the assumption of

normality for an ANOVA was not met. All exploratory correlation analyses were performed

using the Pearson (r) and Spearman (rs) correlation coefficients. In addition to hypothesis-

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generating exploratory correlations to determine the interaction of patient characteristics and

exercise capacity, multivariable regression models were constructed, while controlling for EMG

functional MS, to explore possible factorial associations. All significant covariates were entered

into a multivariable logistic regression model in a forward stepwise manner with a liberal entry

criterion of P<0.15 and a stay criterion of P<0.05. Model goodness of fit was assessed using

chi-square statistics and the Hosmer-Lemeshow test. Statistical significance was set at P < 0.05.

All analyses were performed using the SAS statistical software (SAS v9.1; SAS, Cary, NC).

Results

Baseline Patient Characteristics

We screened 275 patients and enrolled 110 (40.0%) patients into the study. The reasons for

exclusions are shown on Table 1. One main reason for exclusion was that our institute is a

tertiary referral centre and many patients did not reside in our region. Resting mitral mean

diastolic gradient 3 mm Hg was present in 35 patients (Group 1) and > 3 mm Hg in 75 patients

(Group 2). The time interval since surgery was 4.2 ± 2.3 and was shorter in Group 1 patients (P

= 0.0002). There were no statistically significant differences between the 2 groups in

demographics including age, sex distribution, and body mass index.(Table 2). Prolapse or flail

involving the posterior mitral leaflet was the most common leaflet abnormality in both groups,

whereas isolated anterior mitral leaflet abnormality was uncommon.

Techniques of MV Repair

The details of the repair are presented in Table 3. Plication of the posterior mitral leaflet was

performed in 8 Group 2 patients (11%) but none in Group 1 patient; (P=0.04). All but 3 patients

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(97%) had annuloplasty with a posterior band or ring. Annular ring (mean size 30.5 ± 2.1 mm)

was implanted in 41(55%) of the Group 2 patients, but in only 1 Group 1 patient (3%) (P<0.001),

whereas annular band was used in 32 Group 1 patients and 33 Group 2 patients with a trend for a

smaller band size in Group 2 (31.3 ±2.9 mm versus 30.0 ± 2.5 mm, P = 0.07). The Cox Maze

procedure, tricuspid valve annuloplasty and concomitant coronary bypass surgery were

performed with similar frequencies in both groups.

Resting Echocardiographic Data

The left ventricular dimensions and ejection fraction were normal and similar in both groups of

patients (Table 4). Not surprisingly, the indexed left atrial volume was greater in Group 2

patients than in Group 1 patients (P=0.02).

Mitral Valve Hemodynamics:

The resting heart rate was higher in patients in Group 2, but the heart rates at peak exercise were

similar between the two groups. The calculated mitral valve area was smaller in patients in

Group 2 (Table 4). There were no statistically significant correlations between resting

hemodynamics and clinical characteristics including age, sex and time duration since surgery.

There were 29 patients with resting mean mitral gradient 5-10 mm Hg, and 3 patients with

resting gradient > 10 mm Hg. The differences between the 2 groups in diastolic mitral gradients

were magnified at peak exercise (P<0.0001). Mild MR was present in 20 patients (6 in Group 1

and 14 in Group 2, P=0.85), and only 4 patients in Group 2 had an increase in MR severity by

one grade from rest to peak exercise, including 3 patients from none to mild, and one patient

from mild to moderate MR. No patients had > 1 grade increase in MR during exercise. The

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pulmonary artery systolic pressure remained higher in Group 2 patients at rest and at peak

exercise (P=0.02), and correlated with resting mean diastolic MV gradient (r=0.47, P<0.0001;

r=0.46, P<0.0001 respectively).

Functional Assessment

The bicycle exercise test showed that Group 2 patients had lower exercise capacity with shorter

exercise durations and lower Watts and METS (Table 5). However, there was no significant

difference between the two groups in the 6-minute walk distance which is a submaximal exercise

test.

Both the baseline and post exercise BNP levels were higher in Group 2 patients.

The SF36 questionnaire showed significant differences between the 2 groups in three of the eight

domains: Physical Functioning, Vitality and General Health (Table 5).

Maximum exercise capacity in Watts correlated with age (r=-0.51, P<0.0001), MV mean

diastolic gradient at rest (r=-0.23, P=0.015) and at peak exercise (r=-0.22, P=0.02), MV area

(r=0.48, P<0.001), pulmonary artery systolic pressure at rest (r=-0.48, P<0.0001) and at peak

exercise (r=-0.21, P=0.03), and BNP at rest (r=-0.54, P<0.0001) and post exercise (r=-0.45,

P<0.0001). There was also association between maximum exercise capacity with gender

(125 28 Watts in men and 68 40 Watts in women, P=<0.0001) and 2 of the SF36 component

scales which were Physical Functioning (r=0.58, P<0.0001) and Vitality (r=0.31, P=0.0001).

Using multivariable regression analysis, we identified young age (P<0.0001), male gender

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(P<0.0001), MV area (P=0.003), BNP at rest (P=0.02) and SF36’s Physical Functioning

(P=0.015) as independent predictors of better exercise capacity. Additional exploratory models

controlling for EMG did not identify any additional clinical factors associated with exercise

capacity.

Discussion

In the past three decades, MV repair has become the preferred surgical procedure in the

treatment of patients with severe degenerative MR.5-7,20-22 The procedure frequently involves

resection of a portion of the posterior mitral leaflet and some form of mitral annuloplasty to

remodel the annulus and to support the leaflet repair.10-12 These anatomic alterations suggest that

some degree of MS may be a sequela following MV repair. The present study is the first study

to systematically assess patients with more extensive myxomatous changes following MV repair

for the development of EMG, and showed a varying degree of MS ranging from mild to severe in

many of these patients. Whether EMG of the magnitude reported in this study is indicative of

MS may be controversial. On the other hand, EMG of similar magnitude following MV

annuloplasty for ischemic MR has been reported in several recent studies.23-26 In 123 such

patients Williams et al reported mean diastolic MV gradient > 5 mm Hg in 54% and > 8 mm Hg

in 13% of patients, with only about 10% of these patients having moderate or severe MR.24 The

term “functional MS” was introduced in studies of patients who underwent surgical annuloplasty

for ischemic MR.23-26 Kainuma et al reported the presence of functional MS in 58 patients post

surgical annuloplasty for ischemic MR and the mean diastolic mitral gradient was 2.9 +/- 1.1 mm

Hg in their patients.26 Magne et al and Kubota et al also reported the ubiquitous presence of

functional MS in similar patients and both studies included a controlled group.23, 25 In the study

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by Magne et al, the 20 controls were patients with coronary artery disease and left ventricular

dysfunction and the mean mitral gradient was 2 +/- 1 mm Hg whereas the controls in the study

by Kubota et al were healthy individuals with normal left ventricular function and a mean mitral

gradient of 0.6 +/- 0.2 mm Hg, in comparison to 6 +/- 2 mm Hg and 3.5 +/- 2.7 mm Hg in the

annuloplasty patients in the two studies respectively. Complete rings were used with the average

size being 24.7 mm in the study by Magne et al and 28.0 mm in the study by Kubota et al.23,25

The mitral gradients in our controls are similar to that reported by Kubota et al.25

Magne et al reported that functional MS diagnosed by the presence of this low magnitude of

EMG was associated with elevated pulmonary pressures and worse functional capacity.23 It is

noteworthy that functional MS evidenced by EMG was present in the absence of leaflet

abnormalities and even when the annuloplasty ring was not undersized.25

Although MS in our patients was generally mild, moderate to severe MS can occur in some

patients. The development of MS appears intrinsic to the repair procedure, as the increased

mitral gradients are observed shortly following the procedure. This is different from the late and

unusual occurrence of MS years after MV repair due to excessive fibrous tissue at the annular

ring extending onto the leaflets.27-29

As there are no prior studies on EMG in patients with MV repair for degenerative MR, we

included a control group to establish the normal limits of mitral valve gradients, even though the

concept of functional MS has been developed in patients with surgical annuloplasty for ischemic

MR showing that a mean diastolic mitral gradient > 3 mm Hg was likely abnormal.23-26 The data

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in our controls provided further evidence that mean diastolic mitral gradient > 3 mm Hg was

abnormal and indicative of MS.

Clinical Significance of EMG

The functional significance of EMG in these patients has not been well recognized.4,5,11 Before

MV repair, many patients may have poor exercise endurance due to occult or overt heart failure

as a result of severe MR. They would experience improvement in their symptoms following MV

repair which drastically reduce MR, and thus may not recognize mild persistent limitation due to

the presence of MS which is mild in most instances. Furthermore, some of the patients are

elderly or sedentary, such that a mild or even moderate degree of limitation to their exercise

endurance may not be recognized. Without comprehensive assessment, mild limitation due to

incomplete recovery would be difficult to recognize by the patient or the physician.

Despite only mild EMG consistent with mild MS in the majority of cases, there was functional

and physiologic impact on the patients. Patients with functional MS had larger left atrial

volumes, and MV area was an independent predictor of exercise capacity. The physiological

importance of EMG is further supported by the higher levels of BNP indicative of elevated

intracardiac pressures, and higher pulmonary artery systolic pressures both at rest and at peak

exercise, consistent with the presence of functional MS in these patients. The adverse impact of

functional MS was further evidenced by the reduced exercise capacity demonstrated by the

exercise bicycle test, which is a better test for maximum exercise capacity than the 6-minute

walk test.

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Patients with EMG had a poorer quality of life, with lower scores in three of the SF36

component scales indicating that they were more limited in physical activities, had less energy,

and perceived their personal health less favourably. Thus EMG should be looked for in patients

who remain limited despite apparently successful MV repair.

Implications for MV repair:

The present study showed a high prevalence of EMG following MV repair in patients with

myxomatous changes involving more than one leaflet scallop. Though largely mild in severity

EMG clearly had physiological and functional significance. Furthermore, EMG can be more

severe in some patients. Thus, avoiding EMG should be an objective of a successful MV repair.

The use of a complete ring was associated with a higher incidence of EMG, suggesting that a

band or an incomplete ring should be considered and undersizing with an annular band should be

avoided to reduce the risk of EMG. Minimizing the amount of mitral leaflet resection and leaflet

plication may also be useful. It is interesting that EMG has also been described in patients who

undergo restrictive annuloplasty for ischemic MR, highlighting that EMG can occur in the

setting of an undersize annular ring without leaflet resection and may even be present with a

properly sized ring.23-26

The mechanism of EMG in these patients require further study. Obstruction can occur at the

annulus and the leaflet level.25 The placement of an annular ring not only alters the antero-

posterior and transverse diameters of the annulus, but it also limits the expansion of the annulus

which is essential to the opening of MV orifice.30 In patients following MV annuloplasty for

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ischemic MR, Kubota et al observed a substantial difference between the calculated MV area

using the continuity equation and the calculated geometric MV annular area (1.6 +/- 0.2 cm2

versus 3.3 +/- 0.5 cm2, p < 0.01), even though the MV leaflets were normal without thickening or

commissural fusion. They proposed that MS in their patients was largely due to restricted

diastolic leaflet excursion.25 This may also be the case in our patients whose posterior MV

leaflet frequently showed restricted excursion. Geometric measures such as the MV annular area

can be misleading and should not be used to assess stenosis severity, because it does not take into

consideration the flow properties.31 Serial obstruction at both the MV annulus and the leaflets is

plausible. Real time 3-dimensional echocardiography appears to be a promising imaging

modality in assessing the mechanism of EMG in these patients.32

Limitations

The patients were recruited from a large series of MV repair by a single surgeon with a

recognized expertise in this procedure.33 We enrolled patients with more severe myxomatous

changes requiring more extensive tissue resection, which made up 60% of our MV repair

population and may partly explain the high prevalence of EMG in the study. Future studies

should include patients with limited focal MV involvement to have a better perspective of the

prevalence of EMG in MV repair population as a whole. The surgical techniques employed in

the present study are widely used, but have been evolving such that the use of an incomplete ring

or band had become more common in the more recent cases. It is possible that our findings may

not be applicable to other surgical centers, particularly if different techniques are used for MV

repair. We included only ambulatory patients such that patients with severe EMG may be under-

represented as they would be more likely to have heart failure and be hospitalized. Group 2

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patients had higher resting heart rates which may have contributed to the increased MV

gradients. The MV area which is independent of heart rate was significantly different between

the 2 groups. At peak exercise with similar heart rates in both groups the MV gradients

remained significantly higher in patients in Group 2, indicating that the difference in resting

heart rate likely had a small role in accounting for the differences in MV gradients between the

two groups. It can be argued that the definition of EMG is too liberal resulting in a high

prevalence but this definition was based on the findings in matched controls and supported by

the findings in studies on MV annuloplasty for ischemic MR. Furthermore the validity of this

definition was supported by the exercise data and the functional questionnaire, both of which

showed that EMG with mitral diastolic gradient > 3 mm Hg had physiologic and functional

importance. Even with a more restrictive definition such as mean mitral gradient > 5 mm Hg, 32

patients (29%) following MV repair would be considered to have EMG. The 6-minute walk test

is a sub-maximal exercise test and provides a useful indication of functional capacity in patients

with more advanced heart conditions such as pulmonary hypertension and severe heart failure,

but it is not an appropriate test to assess maximum exercise capacity in patients with less

advanced diseases.13,14 The sample size was modest and the findings may be subject to type I

and type II errors. Further studies to validate our findings will be beneficial.

Conclusion

Following MV repair for degenerative MR, EMG can develop in many of these patients. The

development of EMG has an adverse effect on the exercise mitral hemodynamics, exercise

capacity, BNP levels and the patient’s perception of well being. Further refinement in the

questionnaire, , ,, ,, , bbbbbbb

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surgical technique such as the avoidance of a complete ring may decrease the incidence of EMG

following MV repair.

Sources of Funding

Supported in part by the University of Ottawa Heart Institute Academic Medical Organization

Innovation Fund.

Disclosures

None.

References

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G zheart diseases: a population-based study Lancet 2006;368:1

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9. Lawrie GM. Mitral valve repair vs replacement. Current recommendations and long-term results. Cardiol Clin. 1998 ;16:437-48. 10. Carpentier A. Cardiac valve surgery: the French correction. J Thorac Cardiovasc Surg. 1983;86:323-337. 11. David TE, Ivanov J, Armstrong S, Rakowski H. Late outcomes of mitral valve repair for floppy valves: Implications for asymptomatic patients. J Thorac Cardiovasc Surg. 2003;125:1143-52. 12. Mesana T, Ibrahim M, Hynes M. A technique for annular plication to facilitate sliding plasty after extensive mitral valve posterior leaflet resection. Ann Thorac Surg. 2005;79:720-2.

13. American Thoracic Society Statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-117. 14. Cahalin LP, Mathier MA, Semigran MJ, Dec GW, DiSalvo TG. The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure. Chest. 1996;110:325-32. 15. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellika PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Soloman SD, Spencer KT, Sutton MS, Stewart WJ; Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiograph. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18:1440-63. 16. Quinones MA, Otto CM, Stoddard M,Waggoner A, ZoghbiWA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr. 2002;15:167-84. 17. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. . Guidelines for the Echocardiographic Assessment of the Right Heart in Adults: A Report from the American Society of Echocardiography Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23:685-713. 18. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003;16:777-802. 19. Beaton DE, Hogg-Johnson S, Bombardier C, Evaluating changes in health status: reliability and responsiveness of five generic health status measures in workers with musculoskeletal disorders. J Clin Epidemiol. 1997;50:79–93. 20. Van Rijk-Zwikker G. Delemarre B, Husmans H. Mitral valve anatomy and morphology: Relevance to mitral valve replacement and valve reconstruction. J Card Surg. 1994;9:255. 21. Malkowski MJ, Boudoulas H, Wooley CF, Guo R, Pearson AC, Gray PG. Spectrum of structural abnormalities in floppy mitral valve echocardiographic evaluation. Am Heart J. 1996;132:145-151.

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e and the Chamber Quantifi ation Writing Group, developeds oc

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22. Gillonov AM, Blackstone EH, Nowicki ER, Slisatkorn W, Al-Dossari G, Johnston DR, George KM, Houghtaling PL, Griffin B, Sabik JF 3rd, Svensson LG. Valve repair versus valve replacement for degenerative mitral valve disease. J Thorac Cardiovasc Surg. 2008;135:885-93, 893. 23. Magne J, Senechal M, Mathieu P, Dumesnil JG, Dagenais F, Pibarot P. Restrictive annuloplasty for ischemic mitral regurgitation may induce function mitral stenosis. J Am Coll Cardiol. 2008;51:1692-701. 24. Williams ML, Daneshmand MA, Jollis JG Horton JR, Shaw LK, Swaminathan M, Davis RD, Glower DD, Smith PK, Milano CA. Mitral gradients and frequency of recurrence of mitral regurgitation after ring annuloplasty for ischemic mitral regurgitation. Ann Thorac Surg. 2009;88:1197-201. 25. Kubota K, Otsuji Y, Ueno T, Koriyama C, Levine RA, Sakata R, Tei C.. Functional mitral stenosis after surgical annuloplasty for ischemic mitral regurgitaton : importance of subvalvular tethering in the mechanism and dynamic deterioration during exertion. J Thorac Cardiovasc Surg. 2010;140:617-623. 26. Kainuma S, Taniguchi K, Daimon T, Sakaguchi T, Funatsu T, Kondoh H, Miyagawa S, Takeda K, Shudo Y, Masai T, Fujita S, Nishino M, Sawa Y; Osaka Cardiovascular Surgery Research (OSCAR) Group. Does stringent restrictive annuloplasty for functional mitral regurgitation cause functional mitral stenosis and pulmonary hypertension? Circulation. 2011;124 (suppl1):S97-106. 27. Tanaka K, Makuuchi H, Naruse Y, Kobayashi T, Hayashi I, Takayama T, Namifusa Y. Mitral stenosis due to fibrous tissue overgrowth after mitral valve repair. J Cardiovasc Surg. (Torino). 2003;44:59-60. 28. Nishida H, Takahara Y, Takeuchi S, Mogi K. Mitral stenosis after mitral valve repair using the duran flexible annuloplasty ring for degenerative mitral regurgitation. J Heart Valve Dis. 2005;14:563-4. 29. Ibrahim MF, David TE. Mitral stenosis after mitral valve repair for non-rheumatic mitral regurgitation. Ann Thorac Surg. 2002 ;73:34-6. 30. Okada Y, Shomura T, Yamaura Y, Yoshikawa J. Comparison of the Carpentier and Duran prosthetic rings used in mitral reconstruction. Ann Thorac Surg. 1995;59:658-62. 31. Garcia D, Kadem L. What do you mean by aortic valve area: geometric orifice area, effective orifice area, or Gorlin area? J Heart Valve Dis. 2006;15:601-8. 32. Hung J, Lang R, Flachskampf F, Shernan SK, McCulloch ML, Adams DB, Thomas J, Vannan M, Ryan T; ASE. 3D echocardiography: a review of the current status and future directions. J Am Soc Echocardiogr. 2007;20:213-233. 33. Verma S, Mesana TG. Mitral-valve repair for mitral valve prolapse. N Engl J Med. 2009;361:2261-9.

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Table 1. Reasons for Exclusion

Reason for Exclusion N (%)

Mitral valve replacement 11 (6.7)

Moderate or severe MR 8 (4.8)

Left ventricular dysfunction* 18 (10.9)

Unable to exercise 13 (7.9)

Refused to participate 18 (10.9)

Lived too far away 27 (16.4)

Unable to contact 36 (21.8)

Deceased 25 (15.2)

Others 4 (2.4)

Total 165 (100)

* left ventricular ejection fraction < 40%.

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Table 2. Patient Characteristics

All

(N=110)

Group1

Mean MV Grad

< 3mm Hg

(N=35)

Group 2

Mean MV Grad

> 3mm Hg

(N=75)

P

Age (yrs) 60 +/- 11.9 61 +/- 12.3 60 +/- 11.7 0.71

Male (%) 78 (71) 27 (77) 51 (68) 0.33

Hypertension (%) 34 (31) 9 (25) 25 (34) 0.35

Chronic renal

failure (%)

12 (11) 4 (12) 8 (10) 0.76

Smoking (%) 60 (55) 18 (51) 42 (56) 0.65

Atrial fibrillation

pre-op (%)

18 (17) 5 (15) 13 (17) 0.84

Body mass index

(kg/m2)

26.1 +/- 3.6 26.3 +/- 3.8 25.9 +/- 3.5 0.56

Blood pressure

(mm Hg)

Systolic 132 +/- 17 131 +/- 20 132 +/- 16 0.62

Diastolic 82 +/- 10 83 +/- 11 81 +/- 9 0.21

Mitral leaflet

pathology (%)

Anterior 2 (2) 1 (3) 1 (1) 0.56

25 ((34) )

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Posterior 60 (54) 19 (54) 41 (55) 0.58

Both 48 (44) 15 (43) 33 (44) 0.29

Time interval since

surgery (years)

4.2 +/- 2.3 3.1 +/- 1.5 4.8 +/- 2.4 0.0002

NYHA at follow-

up (%)

0.13

I 67 (61) 26 (74) 41 (55)

II 33 (30) 6 (17) 27 (36)

III 10 (9) 3 (9) 7 (9)

Atrial fibrillation

at follow-up

30 (27) 6 (17) 24 (32) 0.10

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Table 3. Surgical Characteristics

All

(N=110)

Group1

Mean MV Grad

< 3mm Hg

(N=35)

Group 2

Mean MV Grad

> 3mm Hg

(N=75)

P

Posterior mitral

leaflet

Resection 79 (72) 25 (71) 54 (72) 0.95

Plication 8 (7) 0 8 (11) 0.04

Sliding plasty 65 (59) 22 (63) 43 (57) 0.58

Anterior mitral leaflet

A1 repair 11 (10) 3 (9) 8 (11) 0.73

A2 repair 43 (39) 11 (31) 32 (43) 0.26

A3 repair 23 (21) 7 (20) 16 (21) 0.87

Commissuroplasty

Anterolateral 4 (4) 1 (3) 3 (4) 0.77

Posteromedial 5 (5) 2 (6) 3 (4) 0.69

MV Annuloplasty 107 (97) 33 (94) 74 (99)

Band 65 (59) 32 (91) 33 (44) <0.0001

Ring 42 (38) 1 (3) 41 (55) <0.0001

Tricuspid

annuloplasty

10 (9) 3 (9) 7 (9) 0.89

Cox maze 13 (12) 3 (9) 7 (9) 0.90

8 (1( 1))

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procedure

Coronary bypass

surgery

14 (13) 6 (14) 8 (11) 0.34

A1, A2 and A3 refer to the lateral, mid and medial scallops of the anterior mitral leaflet.

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24

Table 4. Echocardiographic Variables

All

(N=110)

Group1

Mean MV Grad

< 3mm Hg

(N=35)

Group 2

Mean MV

Grad

> 3mm Hg

(N=75)

P

Resting Measures

LVEDD, mm 47.7 +/- 4.2 47.9 +/- 3.8 47.6 +/- 4.5 0.75

LVESD, mm 29.6 +/- 4.6 29.4 +/- 3.9 29.7 +/- 4.9 0.71

LV EF, % 63.3 +/- 5.9 62.7 +/- 6.4 63.6 +/- 5.7 0.47

LA Volume Index, ml/m2 39.5 +/- 12.7 35.6 +/- 10.9 41.3 +/- 13.1 0.02

LV Stroke Volume 82.3 +/- 23.9 87.4 +/- 26.1 80 +/- 22.6 0.13

Cardiac Output, l/min 5.8 +/- 1.6 5.7 +/- 1.5 5.9 +/- 1.6 0.68

Heart Rate, bpm 72.3 +/- 10.8 67.1 +/- 8.5 74.7 +/- 10.9 0.0004

MV Peak Gradient, mm

Hg

10.0 +/- 4.4 6.5 +/- 1.2 11.7 +/- 4.5 <0.0001

MV Mean Gradient, mm

Hg

4.5 +/- 2.4 2.5 +/- 0.3 5.5 +/- 2.4

MV Area, cm2 2.1 +/- 0.6 2.4 +/- 0.5 1.9 +/- 0.6 0.0005

MR (%) 20 (18) 6 (17) 14 (19) 0.85

PASP, mm Hg 33.3 +/- 9.6 28.6 +/- 5.7 35.5 +/- 10.2 .0003

Peak Exercise Measures

Heart Rate, bpm 121 +/- 24 122 +/- 26 121 +/- 24 0.86

29.7 +/- 4.4.4.4.4...99 99999

63636363636363.6.6.6.6.6.6.6 +++++++/-/-/-/-/-/-/- 5555555.7.7.7.7.7

82.3 +/- 23.9 87.4 +/- 26.1 80 +/- 22.6

m

mmmmmll/l m2 39.9.99.9 55555 +/+/+/+/+/---- 1212121212.77777 35.5..6 +/+/+/++/----- 101010100.9999 444441.1111 33333 +/+/+/+/+/----- 1313131313.1

8882.2.22.33333 +/+/+///- 2223232 .999 8887.7.77.4444 4 +/+/+/+/+/- 22626262 11.11 888880000 /+//- 2222222222 66.666

imin 5.5.5.55 888 +/+/+/+/+/--- 1.1.1.11.66666 5.5.5.5.5 7 7 7 77 +/+/+/+/+ ----- 1.1.1.1 555 5.5.5.5.5.9 9 9 99 +/+/+++ - 111.666



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MV Peak Gradient, mm

Hg

21.9 +/- 10.1 15.6 +/- 6.4 24.8 +/- 10.2 <0.0001

MV Mean Gradient, mm

Hg

12.5 +/- 6.7 8.9 +/- 3.8 14.2 +/- 7.1 <0.0001

MR (%) 23 (21) 6 (17) 17 (23) 0.68

PASP, mm Hg 48.6 +/- 11.9 44.7 +/- 9.9 50.5 +/- 12.3 0.02

EF, ejection fraction; LA, left atrium; LVEDD, left ventricular end diastolic dimension; LVESD,

left ventricular end systolic dimension; MR, mitral regurgitation; MV, mitral valve; PASP,

pulmonary artery systolic pressure.



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Table 5. Functional Variables

All

(N=110)

Group1

Mean MV Grad

< 3mm Hg

(N=35)

Group 2

Mean MV Grad

> 3mm Hg

(N=75)

P

6-Minute Walk

distance, m

459 +/- 90 476 +/- 76 452 +/- 96 0.19

Cycle Ergometry

Exercise duration,

minutes

12.8 +/- 2.8 14.5 +/- 5.9 11.9 +/- 5.4 0.03

Exercise, Watts 108 +/- 45 122 +/- 51 101 +/- 40 0.02

Exercise, METS 5.8 +/- 1.7 6.3 +/- 2.0 5.6 +/- 1.5 0.04

BNP levels, pg/ml

Baseline 93.4 +/- 89 63.8 +/- 75.6 107.2 +/- 91.9 0.02

Post exercise 119 +/- 98 88.8 +/- 83.8 133 +/- 101 0.03

SF36

Physical Functioning 81.5 +/- 20.4 87.6 +/- 13.3 78.7 +/- 22.4 0.03

Vitality 61 +/- 21 68.3 +/- 17.6 57.5 +/- 21.7 0.01

General Health 69.2 +/- 18.5 77.7 +/- 13.0 65.2 +/- 19.4 0.0007

11.9 +/- 5.44

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Kwan Leung Chan, Shin-Yee Chen, Vincent Chan, Karen Hay, Thierry Mesana and Buu Khanh LamRegurgitation

Functional Significance of Elevated Mitral Gradients Following Repair for Degenerative Mitral

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