EVOLUTION OF CONCOMITANT MODERATE AND MODERATE TO SEVERE FUNCTIONAL MITRAL REGURGITATION, FOLLOWING AORTIC VALVE SURGERY FOR SEVERE AORTIC STENOSIS EVOLUCIJA KONKOMITANTNE UMERENE I UMERENE DO TEŠKE FUNKCIONALNE MITRALNE REGURGITACIJE, NAKON OPERACIJE TEŠKE

Background/Aim. Functional mitral regurgitation (FMR) is a common entity in patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR). The aim of this study was to examine evolution of moderate and moderate to severe FMR after an isolated AVR, to identify prognostic indicators for persistent MR postoperatively, and to offer the recommendation regarding surgical intervention for moderate and moderate to severe FMR at the time of AVR for AS. Methods. We retrospectively reviewed 39 consecutive patients with moderate and moderate to severe FMR at the time of isolated AVR from January 2007 to December 2013. We collected preoperative and postoperative echocardiographic data to determine the evolution of FMR after AVR. Patients were divided into the persistent (n = 14) and improved FMR group (n = 25). Secondary division was into the prosthesis-patient mismatch (PPM, n = 7) and non prosthesis-patient mismatch group (non PPM, n = 32 patients). Late follow-up echocardiography was completed in 100% (39/39) of patients. Results. FMR improved postoperatively (MR ? 2+) in 64% (25/39) of patients, while 36% (14/39) of patients had persistent MR ? 2). In comparison to the persistent group, the patient with improved FMR had significant decrease in the left ventricular enddiastolic diameter, left ventricular end-systolic diameter, posterior wall and septum thickness postoperatively. The same indicators of reverse remodeling were found in the non PPM group in comparison to the PPM group. The incidence of postoperative FMR improvement was higher in the non PPM group (65.6%, p = 0.001) in comparison to the PPM group (42.9%, p = 0.125). The mean follow-up duration was 39.5 ? 23.5 months. Conclusion. In accordance with previous studies, this study also showed improvement in FMR following AVR surgery. Improvement in MR degree was associated with echocardiographic parameters of reverse left ventricular remodeling. Conservative approach is advisable in patients with moderate and moderate to severe FMR, believing that repair or replacement is unnecessary at the time of AVR for severe AS. PPM could prevent downgrading of FMR, stressing out the importance of choosing the prosthesis of adequate size.


Mitral regurgitation (MR) is a frequent coexisting dysfunction in patients with
severe aortic valve stenosis (AS).Some degree of MR is found in as much as 61% to 90% of patients undergoing aortic valve replacement (AVR) for AS 1 .
The etiology of MR in patients with AS is usually functional, secondary to the chronic pressure overload that promotes left ventricular remodeling.Functional mitral regurgitation (FMR) has been reported in as high as 75% of patients who undergo AVR 2 .
According to the guidelines, mitral valve (MV) surgery is reasonable for patients with chronic severe secondary MR who are undergoing AVR, and MV repair may be considered for patients with chronic moderate secondary MR who are undergoing other cardiac surgery 3 .As long as there are no morphological leaflet abnormalities, mitral annulus dilatation or marked abnormalities of LV geometry, surgical intervention on the MV is in general not necessary and non-severe secondary MR usually improves after the aortic valve is treated 4 .
Although mitral valve surgery at the time of AVR may increase perioperative mortality and morbidity, the effect of residual MR on survival, quality of life and development of heart failure is important too.Data from the Society for Thoracic Surgery (STS) database (2002-2006) reports an overall unadjusted mortality of 3.2% following AVR in a population of 67.292 patients at 809 centers worldwide.Double valve replacement is, as expected, associated with a significantly higher operative risk with a postoperative mortality at 11-12%, emphasizing that careful patient selection is imperative 5 .Gillinov et al. suggested that mitral valve repair during double valve surgery might be beneficial compared to mitral replacement, with a long-term reduction in mortality (34% versus 46%), without increased perioperative mortality.Talwar et al. reported that mitral valve repair with AVR provided significantly better event-free survival than double valve replacement 5 , 6 .Schubert et al. emphasized that in patients whose MR improved postoperatively, 5year survival was 73.5%, compared with 65.4% in patients whose MR did not improve (p=0.06).Survival was worse in patients whose MR worsened (46.7%; p<0.01) 7 .Barreiro et al found that patients with persistent or worsening MR after AVR tended to have a lower 5-year survival 8 .Vanden Eynden et al found a trend towards better 10-year survival in patients with improved postoperative MR 9 .
The aim of this study was to examine evolution of moderate and moderate to severe functional MR after isolated AVR, and to identify prognostic indicators for persistent MR postoperatively.Also, we intended to set a recommendation -should FMR be operated simultaneously with AVR.

Patient Selection
From January 2007 to December 2013, a total of 1104 patients underwent isolated AVR for sever AS, at the Dedinje Cardiovascular Institute, Belgrade, Serbia.From this group we excluded patients with: morphologic abnormalities of the mitral apparatus, calcification or fibrosis of leaflets, chordae rupture, leaflet prolaps, significant coronary artery stenosis, aortic disease, previous open heart procedures, and congenital disease.
After these exclusions, 39 patients were enrolled in our study.
We conducted a retrospective study of 39 consecutive patients.Patient's demographics, clinical characteristics and preoperative and postoperative echocardiographic data were collected in a retrospective manner for the entire cohort.
Primarily, patients were stratified into 2 groups based on improvement or no improvement of their FMR at the last follow-up echocardiogram after AVR.Persistent FMR group (14 patients, 36%) remained in moderate and moderate to severe grade (2+ and 3+) after AVR.Improved FMR group (25 patients, 64%) had a reduction in MR grade (less than 2+) after AVR.
Secondarily, we formed additional 2 groups of patients, based on the value of indexed Effective Orifice Area (EOAi), of the implanted aortic prosthesis.The EOA was derived from the manufacturer's published values of projected in vivo EOA.This value was indexed to body surface area to yield the indexed effective orifice area of the valve.
Prosthesis-patient mismatch group (PPM) (7 patients, 18%) had EOAi ≤0.85 cm 2 /m 2 .Non prosthesis-patient mismatch group (non PPM) (32 patients, 82%) had EOAi >0.85 The values, distributions and frequencies of preoperative and postoperative variables between groups were compared, to determine if any significant differences were associated with postoperative improvement or worsening of functional MR.
AVR was performed using mechanical St. Jude Medical™ Hemodynamic Plus Aortic Valve in 36 patients, and St. Jude Medical™ Biocor™ Pericardial Stented Tissue Valve in 3 patients.
Our study was approved by the institutional review board of Dedinje Cardiovascular Institute, with a waiver of the requirement for individual patient consent.

Echocardiography and Grading of Mitral Regurgitation
All studied patients went through preoperative and postoperative transthoracic echocardiography, a complete M-mode, bidimensional and Doppler echocardiographic assessment according to the European Association of Echocardiography and American Society of Echocardiography guidelines 10 .
The diagnosis of a severe AV stenosis was established by preoperative echocardiography.
Grading of MR was as follows: 0 for no regurgitation, 0.5 for trace, 1+ for mild, 2+ for moderate, 3+ for moderate-severe, and 4+ for severe, as defined by the American Society of Echocardiography.Grading was done by preoperative transtoracic echocardiography 7,10 .

Follow-Up
Postoperative echocardiography was routinely performed before discharge.Late follow-up echocardiograms were obtained on the patients at variable intervals and at the discretion of the patients' individual cardiologists.Late follow-up echocardiographic data were obtained for 100% (39/39) of patients.We use the latest echocardiography findings for the comparison.

Statistical Analysis
All data are expressed as mean ± standard deviation (SD) or as absolute values and percentages.Statistical analysis was done using the Student's independent t-test, pairedsamples t-test, χ 2 or Fisher's exact test and Wilcoxon signed-rank test.Statistical significance was defined as a two-tailed p value less than 0.05.SPSS for Windows, version 20.0 (SPSS Inc, Chicago, IL) was used for statistical analysis.

Improved FMR group versus persistent FMR group
In the cohort of 39 patients, 25 improved FMR postoperatively, and

Persistent FMR groupbefore versus after AVR
Following aortic valve replacement, peak and mean transvalvular pressure gradients reduced significantly.Gradients measured across aortic prostheses were significantly lower than gradients measured across severely stenosed native valve.The remaining echocardiographic parameters did not change significantly (Table 2).

Improved FMR groupbefore versus after AVR
Following aortic valve replacement, peak and mean transvalvular pressure gradients reduced significantly.Gradients measured across aortic prostheses were significantly lower than gradients measured across severely stenosed native valve.In addition, LVEDD, LVESD, septum thickness, left ventricular posterior wall thickness, also reduced significantly (Table 3).In other words, there is a significant reverse remodeling of the left ventricle in this group of patients.

PPM group versus non PPM group
In the cohort of 39 patients, 32 were in non PPM group (EOAi >0.85 cm 2 /m 2 ), and  5).

Non PPM groupbefore versus after AVR
Following aortic valve replacement, peak and mean transvalvular pressure gradients reduced significantly.Gradients measured across aortic prostheses were significantly lower than gradients measured across severely stenosed native valve.In addition, LVEDD, LVESD, septum thickness, left ventricular posterior wall thickness, also reduced significantly.In other words, there is a significant reverse remodeling of the left ventricle in this group of patients.Another important finding was that MR grade reduced below 2+ in the majority of patients (65.6%) (p=0.001)(Table 6).Harling and colleagues quantitatively demonstrated within their review, the structural remodeling resulting from severe AS regresses following AVR, as demonstrated by a reduction in LV mass and LVED diameter 11 .Several studies identified factors associated with evidence of ventricular remodeling, such as higher preoperative LV mass, larger LV diastolic diameter and enddiastolic volume to be independent predictors of improvement in MR following AVR.They suggest that, where there is potential for reverse remodeling to occur, a more significant improvement in MR will be seen following AVR 12,13,14 .
The similar effect was observed in cardiac resynchronization therapy (CRT).Previous studies have reported that more than mild PPM, defined as an indexed EOA ≤0.85 cm2/m2, is associated with less symptomatic improvement, worse hemodynamics at rest and during exercise, less regression of left ventricular hypertrophy, and more cardiac events after AVR 21 .The impact of aortic prosthesis size, and thus of patient/prosthesis mismatch, on the evolution of FMR was addressed in our study.In addition to postoperative peak and mean gradient reduction, LVEDD, LVESD, septum thickness, left ventricular posterior wall thickness, also reduced significantly in patients without PPM.In other words, there is a significant reverse remodeling of the left ventricle in patients without PPM.Also, FMR grade reduced below 2+ in 65.6% of non PPM patients, in comparison to 42.9% in PPM group.It is worth of mentioning that we used the identical model of mechanical and tissue prostheses in all patients, eliminating the influence of different manufacturer design.In contrary, Waisbren et al. reported that there was no independent relation of aortic prosthesis size with the change in MR 22 .
Our patient selection was guided by restrictive criteria, forming a homogeneous FMR group.Nevertheless, the small number of patients limits the impact of our results, especially in comparing non PPM and PPM groups (32 vs. 7).

Conclusion
In accordance with previous studies, our results also showed improvement in functional MR following AVR surgery, in majority of patients.The reverse remodeling of the LV positively correlates with postoperative FMR downgrading.PPM could be a condition that adversely affects reduction of FMR.We recommend conservative approach in patients with moderate and moderate to severe functional mitral regurgitation, believing that repair or replacement is unnecessary at the time of AVR for severe aortic stenosis.On the other hand, we strongly advocate against PPM in those patients, stressing out the importance of choosing the prosthesis of adequate size.

Table 1
).The mean late follow-up duration was 42.64 ± 20.72 months in the persistent FMR group, and 37.72 ± 25.13 months in the improved FMR group (p=0.537).
7 were in PPM group (EOAi ≤0.85 cm 2 /m 2 ).There was no difference in the preoperative demographic, clinical and echocardiographic parameters between groups, except the patient age.

Table 1
Comparison of the baseline patient characteristics in respect to FMR persistence

Table 2
Changes in echocardiographic data after AVR (Persistent FMR group) LVEDD -Left ventricular end-diastolic diameter; LVESD -Left ventricular end-systolic diameter; LAleft atrial diameter; LVEF -Left ventricular ejection fraction; TR -Tricuspid regurgitation.Results are presented as mean ± standard deviation or as absolute values (percentages).

Table 3
Changes in echocardiographic data after AVR (Improved FMR group) LVEDD -Left ventricular end-diastolic diameter; LVESD -Left ventricular end-systolic diameter; LAleft atrial diameter; LVEF -Left ventricular ejection fraction; TR -Tricuspid regurgitation.Results are presented as mean ± standard deviation or as absolute values (percentages).

Table 4
Comparison of the baseline patient characteristics in respect to EOAi

Table 6
Changes in echocardiographic data after AVR (EOAi >0.85 group) robust reduction in transvalular gradients in the improved FMR group.This finding could be partially explained by lower preoperative values of LVEF in the persistent FMR group (low flowlow gradient effect).