Ethical Issues

Ethics committee approval was waived because of the retrospective analysis of the study according to national laws regulating observational retrospective studies. However, all patients provided informed consent to access their data for scientific purposes.

Subjects

The study population consisted of 391 consecutive patients with CIMR who survived combined coronary artery bypass grafting and UMRA performed at three institutions (Careggi Hospital, Florence, Italy; Civic Hospital, Brescia, Italy; and University Hospital, Maastricht, The Netherlands) between October 2008 and April 2010. CIMR was defined as the association of mild to severe MR with all the following features: (1) prior myocardial infarction > 16 days, (2) ≥75% stenosis of at least one coronary vessel, (3) a corresponding regional wall motion abnormality, and (4) type IIIb leaflet dysfunction following Carpentier’s classification, with or without annular dilatation.

Twenty-nine patients were excluded: two had intraoperative annuloplasty failure, 12 showed residual MR (≥2+ at discharge), and 15 had incomplete echocardiographic studies. Therefore, the final study population consisted of 362 patients. Other exclusion criteria were 1) degenerative or other nonischemic etiology, (2) ischemic isolated type I or type II dysfunction, (3) additional mitral valve repair procedures, (4) other valvular or congenital heart diseases, (5) previous cardiac surgery or percutaneous transluminal coronary angioplasty, (6) atrial fibrillation, and (7) sinus rhythm with heart rate at rest 100 beats/min.

One-hundred normal healthy subjects with no histories of cardiovascular disease, with normal Doppler echocardiographic findings and a gender distribution, ages, and average body surface areas similar to the study patients, served as controls. The median follow-up time was 14.3 months (interquartile range, 9.3–19.1).

Surgery

Patients with moderate or severe CIMR (effective regurgitant orifice area > 20 mm ² and regurgitant volume > 30 mL) were scheduled for operation. When MR was 2/4, surgery was indicated (1) in the presence of a dilated left ventricle (end-diastolic volume > 110 mL/m ² ) or a low LV ejection fraction (<0.35), as in the case of dilated cardiomyopathy; (2) in patients with increases in effective regurgitant orifice area > 13 mm ² on transthoracic echocardiographic exercise testing; and (3) in ischemic patients with fluctuating MR of grade ≥ 3 after intraoperative loading testing.

All patients underwent associated coronary artery bypass grafting. For the purposes of this study, complete revascularization was accomplished when at least one graft was placed distal to an approximately 50% diameter narrowing in each of the three major vascular system in which arterial narrowing of this severity was noted in a vessel ≥1.5 mm in diameter. It was not considered necessary to bypass all obstructed diagonal branches of the anterior descending or marginal branches of the circumflex coronary arteries for a classification of complete revascularization. Following this definition, 100% of patients underwent complete revascularization. The ring size was determined by standard measurements of the intertrigonal distance and anterior leaflet height. Downsizing by two ring sizes was performed in all patients.

Echocardiographic Measurements

Echocardiographic examinations were performed using a commercially available system (iE33; Philips Medical Systems, Best, The Netherlands). The clinical echocardiographic evaluation was as follows: transthoracic echocardiography and transesophageal echocardiography were performed <5 days before surgery, and serial transthoracic echocardiography was performed annually thereafter. Echocardiographic examinations were carried out by experienced echocardiographers (S.C., E.V., and E.C.) and stored on a magneto-optical disk for offline analysis. Measurements and calculations were made offline by two cardiologists (F.L. and C.M.R.) blinded to the aims of the study. The reliability of echocardiographic measurements was assessed by calculating interobserver and intraobserver intervals of agreement of main direct measures used in this study in 20 subjects randomly chosen among the study patients ( Table 1 ).

MR Assessment

The following quantitative measurements were simultaneously used to grade the severity of MR: (1) pulsed-wave Doppler and (2) proximal isovelocity surface area (PISA). When the evidence from different parameters was congruent, the measurements were averaged, allowing the calculation of effective regurgitant orifice area, regurgitant volume, and regurgitant fraction.

When different parameters were contradictory, PISA was chosen in case of a central jet or in the presence of a calcific mitral valve or mitral annulus, whereas pulsed-wave Doppler was preferred when the jet was eccentric or multiple. For each measurement, a minimum of three cardiac cycles were averaged. In patients with no or trivial MR by color Doppler, regurgitant volume and regurgitant fraction were used as calculated, and effective regurgitant orifice area was assumed as null. The respective thresholds for mild, moderate, and severe MR followed American Society of Echocardiography recommendations.

Recurrent MR at latest follow-up was defined as insufficiency ≥ 2+ in patients with no or trivial MR at discharge.

Measurement of Leaflet Tethering

Mitral valve configuration was assessed in midsystole using the parasternal long-axis and four-chamber views. The AML tethering angle, α′ ( Figure 1 A), the posterior mitral leaflet (PML) tethering angle, β′ ( Figure 1 B), and the bending angle ( Figure 1 C) were directly measured with specific software (Philips DICOM Viewer; Philips Medical System). The AML and PML excursion angles were calculated as the difference between AML and PML angles in systole and diastole. The ratio of α′ to β′ was a quantitative measurement of tethering: the closer the ratio was to 1, the more symmetric was the tethering.

(A) Tethering of the AML was assessed by measuring the angle between the annular plane (AP) and the AML, α′. (B) Tethering of the PML was assessed by measuring the angle between the annular plane (AP) and the PML, β′. (C) The bending angle, γ, was measured as the angle between the bending distance, line AB (from the anterior annulus to the bending point, B, created by the tethering of intermediate or strut chordae in the body of the anterior leaflet), and the distance, line BC, from the bending point to the coaptation point, C .

The tenting area was measured by the area enclosed between the annular plane and the mitral leaflets from the parasternal long-axis view at midsystole. The coaptation height was measured as the perpendicular distance between the coaptation point of the mitral leaflets and the line connecting the annular hinge points in the long-axis view at end-systole. The coaptation length was measured as the length of apposition of the AML and PML. The coaptation distance was measured (along the annular plane) from the anterior leaflet attachment to the point of coaptation.

LV Remodeling and LV Function

LV volumes and LV ejection fraction were assessed using the biapical Simpson disk method. LVRR was defined as a reduction in end-systolic volume index (ESVI) > 15% at the latest echocardiographic study compared with baseline volume. Sphericity indexes were obtained at end-diastole and end-systole as the volume of the left ventricle divided by the volume of a sphere with a diameter equal to the longest axis of the left ventricle measured in the apical view. LVGRR was defined as a reduction in end-systolic sphericity index to a value < 0.72 (the mean value in healthy controls) at the latest echocardiographic study in patients with altered baseline geometry. The myocardial performance index was measured using the method described by Tei et al.

Papillary Muscle (PM) Displacement

The displacement of PMs was quantified as the distances from well-defined anatomic landmarks at early and end-systole. From the parasternal short-axis view, the geometric chord defined by the intersection of the right and left ventricles (“septal insertions”) and the midseptal perpendicular line were used as references. Lateral and inferior displacements of anterior and posterior PMs were measured as distances from these fixed references ( Figures 2 A and 2 B). Separation between PMs was directly measured.

(A) Measurement of posterior dislocation of PMs. From the parasternal short-axis view, the geometric chord defined by the intersection of the right and left ventricles ( line AB ) and the midseptal perpendicular line ( line CD ) were used as references. Posterior displacements of anterior and posterior PMs were measured as the distances from line AB ( dashed lines a, a′ ). (B) Measurement of lateral dislocation of PMs. From the parasternal short-axis view, the geometric chord defined by the intersection of the right and left ventricles ( line AB ) and the midseptal perpendicular line ( line CD ) were used as references. Lateral displacements of anterior and posterior PMs were measured as distances from line CD ( dashed lines b, b′ ). (C) Measurement of the length, l ₁ , between ALPM and contralateral anterior mitral annulus. (D) Measurement of the length, l ₂ , between PMPM and anterior mitral annulus (see text).

The lengths between the anterolateral PM (ALPM) and posteromedial PM (PMPM) tips and contralateral anterior mitral annulus were also measured in midsystole in the apical four-chamber and two-chamber views using the anterior mitral annulus as a reference point to estimate outward PM displacement ( Figures 2 B and 2 C).

Patient Classification

Patients were divided by baseline measurements of α′ into two groups: group 1, α′ < 39.5° (less than severe AML tethering; n = 196), and group 2, α′ ≥ 39.5° (severe or greater AML tethering; n = 166). The cutoff was chosen on the basis of our previous experience. For comparisons, a β′ cutoff of ≥45° was chosen.

Patient characteristics are summarized in Table 2 . Patients in group 2 had larger LV diameters and volumes, more spherical ventricles, and lower LV ejection fractions. No other differences were found in baseline demographics and operative variables between groups.

Statistical Analysis

Variables were tested for normal distribution using the Kolmogorov-Smirnov test. Continuous data are expressed as mean ± SD; data not normally distributed are presented as medians and interquartile ranges and frequencies as proportions. Variables were compared using t tests, Mann-Whitney U tests, and χ ² tests as appropriate.

Multivariate logistic regression analysis was performed to assess the effect of preoperative AML tethering on end points. Forty demographic, clinical, and echocardiographic parameters were investigated for their predictive value. To enhance the accuracy of the model, the number of variables was reduced using variable clustering until the number of variables to use as candidates in the regression analysis was ≤ m /10, where for binary outcomes m is the number of patients in the less frequent outcome category. Model fit for logistic regression was assessed using the Hosmer-Lemeshow statistic, and predictive accuracy was assessed using the concordance index, c .

The model adjusted for variables that were recognized as key factors of MR recurrence. Internal validation of predictors generated by multivariate logistic regression was performed by means of bootstrapping techniques, with 1,000 cycles and the generation of odds ratio and bias-corrected 95% confidence intervals.

Finally, to assess whether the predictive value of α′ was secondary to other factors, such as abnormal LV function and geometry, we estimated the effects of α′ and β′ in subgroups that included systolic sphericity index (cutoff, 0.8), ESVI (cutoff, 45 mL/m ² ), myocardial performance index (cutoff, 0.9), wall motion score index (cutoff, 1.5), and coaptation height (cutoff, 11 mm). First, we estimated the effect of AML tethering in each of the subgroups. Then we tested for interactions between α′ and subgroup variables using multivariate general linear modeling.

SPSS version 12.0 (SPSS, Inc., Chicago, IL) and Stats Direct version 2.5.7 (Stats Direct, Sale, United Kingdom) were used for these calculations.

Recurrent MR and Leaflet Tethering

Data for MR are shown in Table 3 . Patients in group 1 showed a more asymmetric pattern with eccentric jet directions in most patients, whereas in group 2, preoperative jet directions were central in the majority of patients. At latest follow-up, 91 patients (25.1%) showed recurrent MR; it occurred more frequently in patients in group 2 ( Figures 3 A– 3 D).

Table 3

MR ( n = 362)

		Group 1 (α′ < 39.5°) ( n = 196)			Group 2 (α′ ≥ 39.5°) ( n = 166)
Variable	Controls ( n = 100)	Preoperative	Follow-up	P	Preoperative	Follow-up	P
MR
Grade	0 (0–1)	3 (3–4) ∗	0 (0–1)	<.001	3 (3–4) ∗	2 (1–2) ∗,†	.002
None	62 (62.0%)	—	161 (82.1%)		—	25 (15.1%)
1+	38 (38.0%)	—	16 (8.2%)		—	69 (41.5%)
2+	—	29 (14.7%)	16 (8.2%)		26 (15.7%)	52 (31.4%)
3+	—	122 (62.4%)	3 (1.5%)		100 (60.7%)	11 (6.6%)
4+	—	45 (22.9%)	—		40 (24.0%)	9 (5.4%)
Direction of regurgitant jet
Central	—	17 (8.7%)	—	<.001	104 (62.7%) †	1 (1.4%)
Anterior	—	21 (10.7%)	—		15 (9.0%)	1 (1.4%)	<.001
Posterior	—	131 (66.8%)	17 (89.4%)		21(12.7%) †	68 (94.4%)
Complex	—	27 (13.8%)	2 (10.6%)		26 (15.6%)	2 (2.8%)
EROA (mm )	—	35.3 ± 10.2	—	—	39.4 ± 11.7	27.7 ± 10.3	.05
RF (%)	—	43.3 ± 9.4	—	—	46.6 ± 13.4	32.4 ± 12.6	.04
RV (mL/beat)	—	54.9 ± 11.7	—	—	57.1 ± 14.6	38.2 ± 13.4	.02
TA (cm )	0.8 ± 0.2	3.2 ± 1.1 ∗	1.9 ± 0.3 ∗	<.001	4.2 ± 1.1 ∗,†	2.8 ± 1 ∗,†	<.001
CL (mm)	8.2 ± 0.3	4.0 ± 0.6 ∗	8.6 ± 0.3	<.001	3.2 ± 0.3 ∗,†	4.0 ± 0.3 ∗,†	.8
Coaptation distance (mm)	28.2 ± 7.0	35.4 ± 7.3 ∗	31.4 ± 5.6 ∗	.43	36.8 ± 6.1 ∗	38.7 ± 8.4 ∗,†	.65
Coaptation height (mm)	7.0 ± 3.1	10.0 ± 1.9 ∗	8.3 ± 0.8	.03	13.2 ± 2.2 ∗,†	11.7 ± 1.6 ∗,†	.2
Mitral leaflet tethering
β′ (°)	34.2 ± 6.2	52.0 ± 10.1 ∗	60.3 ± 12.1 ∗	<.001	50.6 ± 12.2 ∗	60.1 ± 14.4 ∗	<.001
α′(°)	23.9 ± 3.1	33.8 ± 4.4 ∗	26.1 ± 3.5 ∗	<.006	40.4 ± 6.0 ∗	33.0 ± 4.4	.01
α′/β′	0.70 ± 0.4	0.65 ± 0.1 ∗	0.50 ± 0.1 ∗	<.001	0.80 ± 0.1 ∗,†	0.55 ± 0.2 ∗	<.001
γ (°)	152.1 ± 13.2	140.2 ± 10.3 ∗	151.1 ± 11.4	.02	129.3 ± 6.4 ∗,†	121.5 ± 5.3 ∗,†	.08
α′ ex (°)	42.4 ± 4.3	36.6 ± 4.2 ∗	43.5 ± 4.9	.02	27.2 ± 3.3 ∗,†	38.9 ± 5.2 ∗,†	.007
β′ ex (°)	24.9 ± 3.3	14.2 ± 2.7 ∗	8.9 ± 1.2 ∗	.004	13.9 ± 4.3 ∗	9.2 ± 1.7 ∗	.01

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