Clinical material and methods. Fukui Cardiovascular Center, Fukui, Japan

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1 Mitral Valve Regurgitation after Atrial Septal Defect Repair in Adults Shohei Yoshida, Satoshi Numata, Yasushi Tsutsumi, Osamu Monta, Sachiko Yamazaki, Hiroyuki Seo, Takaaki Samura, Hirokazu Ohashi Fukui Cardiovascular Center, Fukui, Japan Background and aim of the study: Mitral valve regurgitation (MR) is known to deteriorate following adult atrial septal defect (ASD) repair in the mid to long term. The study aim was to identify the risk factors for this deterioration. Methods: Between 1995 and 2011, a total of 93 consecutive patients (aged 18 years) underwent ASD repair at the authors institution. Patients who underwent concomitant procedures, other than tricuspid annuloplasty or maze procedure, were excluded; hence, 74 patients were enrolled in the study. MR was evaluated by transthoracic echocardiography shortly after surgery and subsequently on a regular basis in the outpatient clinic. Risk factors for the deterioration of MR were estimated using Cox proportional hazards regression. Results: The mean patient age at surgery was 48.0 ± 17.1 years, and 20 patients (27%) had atrial fibrillation (AF) preoperatively. The mean follow up was 6.9 ± 5.5 years. The degree of MR was not unchanged or not improved in 54 patients (73.0%) (group 1), but was increased by one grade in 12 patients (16.2%) (group 2), and by two or more grades in eight patients (10.8%) (group 3). At surgery, all patients in group 3 were aged >50 years. In group 3, on echocardiography, the average end-diastolic left ventricular dimension was increased from 41.8 mm to 51.8 mm (p = 0.027), and enlargement of the mitral annulus was noted in seven patients. Four of the group 3 patients required reoperation for MR after ASD repair. The Cox proportional hazards model revealed preoperative AF (p = 0.045, hazard ratio (HR): 11.68, 95% confidence interval (95%CI): ) and Qp/Qs 2.8 (p = 0.015, HR: 9.19, 95%CI : ) to be independent risk factors of new-onset or aggravated MR (by two or more grades) after ASD repair. Conclusion: An earlier repair of ASD would be preferable in terms of MR aggravated after ASD repair. For elderly patients with a preoperative high Qp/Qs and AF, mitral valve annuloplasty with ASD repair should considered. The Journal of Heart Valve Disease 2014;23: It has been well recognized that new-onset mitral valve regurgitation (MR) or an aggravation of preexisting MR occasionally occurred after atrial septal defect (ASD) repair in adults. Previously, Park et al. (1) reported that 29% of adult patients who underwent ASD repair showed aggravated or new-onset MR, including 18 patients in whom the degree of MR was increased by two grades or more. At present, very little is known of the risk factors of MR deterioration and Presented at the Seventh Biennial Congress of the Society for Heart Valve Disease and Heart Valve Society of America, 22nd-25th June 2013, Palazzo del Casinò, Venice, Italy Address for correspondence: Dr. S. Yoshida, Fukui Cardiovascular Center, Shinbo 2-228, Fukui, Japan the impact of MR after ASD repair in the mid to long term. Hence, the study aim was to evaluate the preoperative risk factors for the postoperative deterioration of MR after ASD repair in adults. Clinical material and methods Patients Following institutional review board approval and informed consent being acquired from the patients, data were collected for this retrospective study. Between January 1995 and December 2011, a total of 93 consecutive patients (age 18 years) underwent ASD repair at the authors institution. To assess the net effects of ASD repair on mitral valve competence, any Copyright by ICR Publishers 2014

2 J Heart Valve Dis MR after ASD repair 311 Figure 1: Patient characteristics. patients who underwent concomitant procedures other than tricuspid annuloplasty or a maze procedure, such as mitral valve repair (n = 9), mitral valve replacement (n = 4), aortic valve replacement (n = 1) and coronary artery bypass grafting (n = 5), were excluded from the study (see Fig. 1). Consequently, 74 patients were enrolled into the study. The mean patient age at surgery was 48.0 ± 17.1 years, and 35 patients (47%) were males. Among the patients, 54 were in NYHA functional class I, and 20 in class II. Patients presented with hypertension (n = 15; 20.3%), hyperlipidemia (n = 4; 5.4%), diabetes mellitus (n = 6; 8.1%) and atrial fibrillation (AF; n = 20; 27.0%). Congenital malformations other than ASD included pulmonary stenosis in four cases (5.4%), and single coronary artery, Holt-Oram syndrome and partial anomalous pulmonary venous return in one case each (1.4%). Preoperative transthoracic echocardiography (TTE) and cardiac catheterization were performed in all patients; MR was evaluated using TTE shortly after surgery and on a regular basis at the outpatient clinic. Preoperatively, older patients at surgery had a higher probability of AF and severe tricuspid regurgitation (TR) (Fig. 2A and B). The preoperative MR grade was 0 in 53 patients, I in 19 patients, and II in two patients. None of the patients had mitral valve congenital abnormalities such as mitral cleft, or prolapse of the leaflet. The probability of preoperative MR was dependent on age at surgery (Fig. 2C and D). On echocardiography, the average preoperative left ventricular end-diastolic dimension (LVEDd) and left ventricular end-systolic dimension (LVESd) were 41.1 ± 4.9 mm and 26.7 ± 5.0 mm, respectively, while the average preoperative fractional shortening (FS) and left atrial size were 35.1 ± 6.9% and 34.7 ± 5.6 mm, respectively. Mitral annular dilatation was defined as a mitral annulus >28 mm. Preoperative catheter investigations showed the average Qp/Qs to be 2.6 ± 0.8, the pulmonary capillary wedge pressure (PCWP) 8. 9± 3.6 mmhg, and the systolic pulmonary artery pressure (SPAP) 33.0 ± 11.0 mmhg. Figure 2: A) Probability of preoperative atrial fibrillation versus age. B) Probability of preoperative severe TR versus age. C) Probability of preoperative MR versus age at operation. D) Preoperative MR grades.

3 312 MR after ASD repair J Heart Valve Dis Figure 3: A) Kaplan-Meier curves. Freedom from aggravation of MR by grade 2 at five, 10 and 15 years after surgery. B) Kaplan-Meier curve showing freedom from reoperation for MR at five, 10 and 15 years after surgery. Surgical procedure All operations were performed using cardiopulmonary bypass (CPB) and hypothermia of between C. Following the institution of CPB, cold crystalloid cardioplegic solution was administered antegradely through the root of the aorta. The method used to repair the defect depended on the size and anatomic type of the latter. The mean ASD size was 23.6 ± 9.4 mm. A primum type ASD was found in two patients, a secundum type in 72, and sinus venosus type in three. Three patients had a mixture of two types. None of the patients had concomitant mitral valve disease such as anterior mitral leaflet cleft. Fourteen patients (18.9%) underwent direct closure, while 60 (81.1%) required patch closure. Concomitant procedures performed included tricuspid annuloplasty in 20 cases (27.0%) and a maze procedure in eight (10.8%). Statistical analysis Data were displayed as frequencies or mean ± SD. Freedom from MR aggravation and from reoperation Figure 4: Changes in degree of MR in group 3. MR was aggravated shortly after ASD repair in one patient, but gradually over several years in the other patients. for MR were estimated using the method of Kaplan and Meier. Risk factors for deterioration of MR were estimated by Cox proportional hazards regression. The preoperative and intraoperative variables included in the analysis were age at surgery, gender, NYHA class, hypertension, hyperlipidemia, diabetes mellitus, AF, MR, severe TR, left atrial size, LVEDd, LVESd, FS, Qp/Qs, PCWP, SPAP, ASD diameter, type of ASD, ASD repair technique, associated tricuspid annuloplasty, and associated maze procedure. Statistical analyses were performed using commercial software (Ekuseru-Toukei 2012; Social Survey Research Information Co., Ltd.). A p-value <0.05 was considered to be statistically significant. Results There was no mortality among the patients during a mean follow up of 6.9 ± 5.5 years. The degree of MR was unchanged or improved in 54 patients (73.0%; group 1), while 20 patients (27.0%) showed aggravated or new-onset MR. The degree of MR was increased by one grade in 12 patients (16.2%; group 2), and by two or more grades in eight patients (10.8%; group 3). The Kaplan-Meier curve showed the freedom rate from MR aggravation to be 92.2%, 77.6% and 69.0% at one, five and 10 years after surgery (Fig. 3A). The changes of MR degree in group 3 are shown in Figure 4. The aggravation of MR occurred soon after ASD repair in one patient, but gradually over several years in the other patients. Following ASD repair, the average LVEDd was increased from 41.1 to 45.1 mm in group 1, from 40.3 to 44.5 mm in group 2, and from 41.8 to 51.8 mm in group 3 (Fig. 5A). The increase in LVEDd in group 3 was significantly greater than in groups 1 and 2 (p = 0.004). In group 3, the increases in LVEDd and LVESd occurred gradually over several years in almost all patients (Fig. 6).

4 J Heart Valve Dis MR after ASD repair 313 Figure 5: Changes in (A) end-diastolic left ventricular dimension and (B) fractional shortening on echocardiography between preoperative and postoperative states. After ASD repair, the average FS was changed from 35.5% to 36.4% in group 1, from 35.3% to 36.8% in group 2, and from 32.4% to 28.5% in group 3 (Fig. 5B). The average FS was decreased only in group 3 patients, all of whom were aged >50 years at surgery (Table I). Enlargement of the mitral annulus was found in seven patients (87.5%) in group 3, whereas only a total of four patients (6.1%) showed enlargement of the mitral annulus in groups 1 and 2. Four of the group 3 patients (50%) required reoperation for MR after ASD repair. The Kaplan-Meier curves showed freedom from reoperation for MR to be 100% at five years after surgery, 93.9% at 10 years, and 83.1% at 15 years (Fig. 3B). The multivariate Cox proportional hazards regression analysis revealed preoperative AF (p = 0.045; hazard ratio (HR) 11.68; 95% confidence interval (CI): ) and Qp/Qs 2.8 (p = 0.015, HR 9.19, 95% CI: ) to be independent risk factors of new-onset or aggravated MR (by two or more grades) after ASD repair (Table II). Figure 6: Increases in LVEDd in group 3 versus postoperative time. Discussion It is well known that, in 35-50% of ASD patients, mitral valve prolapse may occur with or without significant mitral valve regurgitation (2-5). Preoperatively, a reduced left ventricular end-diastolic volume and an abnormality of septal configuration could serve as one mechanism of mitral valve prolapse (2,6). Following repair of the defect, the ventricular septum is shifted towards the right side of the heart and, as a consequence, such rightward deviation might cause MR. In children, the mitral valve leaflet can adapt to this deviation and therefore MR is rarely worsened after ASD. However, in adults some patients will require mitral annuloplasty at the time of surgical repair of the ASD. In one report, 29% of patients were shown to have aggravated or new-onset MR after surgical closure of an ASD (1). Older age and indexed ASD size were also shown to be independent risk factors for new-onset or aggravated MR on multivariate analysis. Other reports showed that postoperative MR aggravation occurred in 20 patients among 227 following the transcatheter repair of an ASD (7). According to these reports, the pathogenesis of MR after ASD repair might be a failure to adapt to a new rightward convex septum caused by an increased LVEDd, since in older patients the mitral valve leaflet may undergo histologic changes for septal configuration. Although these studies described only short-term results after surgical repair, the present study evaluated the mid- to long-term results after surgical ASD repair. Most of the patients had no aggravation of MR after ASD repair during the follow up period and, indeed, the pre-existing MR was improved in 50 patients. However, in eight patients the MR was aggravated by two or more grades. The pathogenesis of worsening MR in the mid to long term after ASD repair is unclear, although the

5 314 MR after ASD repair J Heart Valve Dis Table I: Profiles of patients with MR aggravation by two or more grades. Age Gender Qp/Qs ASD ASD Other Preoperative Postoperative Enlargement Reoperation (mm) closure procedure MR MR of mitral for MR annulus 72 F Patch TAP F Patch TAP F Patch TAP F Direct M Patch M Patch M Patch TAP M Patch Maze ASD: Atrial septal defect; MR: Mitral regurgitation; TAP: Tricuspid annuloplasty. Table II: Multivariate Cox proportional hazards regression analysis. Parameter ΔMR <2 ΔMR 2 p-value (U) p-value (M) Hazard 95% CI (n = 66) (n = 8) ratio Male gender Age (years) * 46.3 ± ± LAD (mm) * 34.0 ± ± LVEDd (mm) * 41.0 ± ± LVESd (m) * 26.4 ± ± FS (%) 35.5 ± ± MR grade TR grade HT HL DM AF NYHA class Qp/Qs PCWP (mmhg) * 8.6 ± ± SPAP (mmhg) * 31.3 ± ± ASD type Primum Secundum Sinus venosus ASD (mm) * 23.3 ± ± Direct closure TAP Maze * Values are mean ± SD. AF: Atrial fibrillation; ASD: Atrial septal defect; DM: Diabetes mellitus; FS: Fractional shortening; HL: Hyperlipidemia; HT: Hypertension; LAD: Left atrial diameter; LVEDd: Left ventricular end-diastolic diameter; LVESd: Left ventricular end-systolic diameter; MR: Mitral regurgitation; PCWP: Pulmonary capillary wedge pressure; SPAP: End-systolic pulmonary artery pressure; TAP: Tricuspid annuloplasty; TR: Tricuspid regurgitation.

6 J Heart Valve Dis MR after ASD repair 315 large majority of group 3 patients (87.5%) showed enlargement of the mitral annulus, while in groups 1 and 2 such enlargement occurred in only four patients (6.1%). In addition, greater postoperative increases in LVEDd and LVESd were observed in group 3 compared to groups 1 and 2. Consequently, enlargement of the mitral annulus might play a significant role in MR aggravation by two or more grades in the mid to long term. When Ohashi et al. (8) investigated left ventricular function after ASD repair, they demonstrated - postoperatively - a significant negative correlation between age and stroke volume of left ventricle, and age and left ventricular stroke work index, respectively. These findings suggest that, in older patients with ASD, left ventricular dysfunction is more common than in younger patients. Postoperative left ventricular dysfunction could cause mitral annular dilatation and mitral valve regurgitation. In the present study, Cox regression analysis showed AF and Qp/Qs 2.8 to be independent risk factors for new-onset or aggravated MR after ASD repair in the mid to long term. It was assumed that the presence of preoperative AF formed part of the pathogenesis of enlargement of the mitral annulus. Because older patients at surgery had a higher probability of preoperative AF, the age of patients in whom MR was aggravated MR was typically >50 years. A higher Qp/Qs may suggest dramatic changes of rightward shifting of the ventricular septum postoperatively. The importance of the present study was to clarify that some patients might require mitral valve intervention at the time of ASD repair. In the present authors experience, between January 1995 and December 2011, eight patients (aged 18 years) underwent ASD repair and mitral annuloplasty simultaneously, but failed to show any MR aggravation, except for one patient with a torn chorda. Thus, mitral annuloplasty at the time of ASD repair might be beneficial in preventing MR aggravation. As the latter condition was also observed after transcatheter repair of ASD, mitral annuloplasty should be considered when effecting ASD repair in patients at high risk of MR aggravation. Study limitations The main limitations of the study were its retrospective nature and the small number of cases examined, such that the statistical impact of the Cox regression analysis might have been limited. In conclusion, based on the study results, a preoperative high Qp/Qs and AF were seen as independent risk factors for the recurrence of MR after isolated ASD repair. In addition, elder patients had a tendency for MR to be aggravated after ASD repair. Taken together, these factors might suggest that an earlier surgical intervention in patients (aged <50 years) would be preferable in terms of MR occurrence after ASD repair. For elder patients with a high Qp/Qs and AF preoperatively, mitral valve annuloplasty with ASD repair should be taken into consideration. References 1. Park JJ, Lee SC, Kim JB, et al. Deterioration of mitral valve competence after the repair of atrial septal defect in adults. Ann Thorac Surg 2011;92: Toyono M, Pettersson GB, Matsumura Y, et al. Preoperative and postoperative mitral valve prolapsed and regurgitation in adult patients with secundum atrial septal defects. Echocardiography 2008;25: Angel J, Soler-Soler J, Garcia del Castillo H, et al. The role of reduced left ventricular end-diastolic volume in the apparently high prevalence of mitral valve prolapsed in atrial septal defect. Eur J Cardiol 1980;11: Joy J, Kartha CC, Balakrishnan KG, et al. Structural basis for mitral valve dysfunction associated with ostium secundum atrial septal defects. Cardiology 1993;82: Suchon E, Podolec P, Plazak W, et al. Mitral valve prolapsed associated with ostium secundum atrial septal defect - a functional disorder. Acta Cardiol 2004;59: Nagata S, Nimura Y, Sakakibara H, et al. Mitral valve lesion associated with secundum atrial septal defect: Analysis by real time two dimensional echocardiography. Br Heart J 1983;49: Wilson NJ, Smith J, Prommete B, O Donnell C, Gentles TL, Ruygrok PN. Transcatheter closure of secundum atrial septal defects with the Amplatzer septal occlude in adults and children: Follow up closure rates, degree of mitral regurgitation and evolution of arrhythmias. Heart Lung Circ 2008;17: Ohashi H, Mitamoto T, Shimizu Y, et al. Left ventricular function in ostium secundum type atrial septal defect. Nihon Kyobu Geka Gakkai Zasshi 1980;28:

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