Midterm Outcome of Valve-Sparing Aortic Root Replacement in Inherited Connective Tissue Disorders. Patients

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1 Midterm Outcome of Valve-Sparing Aortic Root Replacement in Inherited Connective Tissue Disorders Hiroshi Tanaka, MD, PhD, Hitoshi Ogino, MD, PhD, Hitoshi Matsuda, MD, PhD, Kenji Minatoya, MD, PhD, Hiroaki Sasaki, MD, PhD, and Yutaka Iba, MD Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan Background. This study determined the midterm outcome of valve-sparing aortic root replacement for patients with inherited connective tissue disorders. Methods. From 1993 to 2008, 94 patients underwent valve-sparing aortic root replacement. Sixty patients (64%), average age 33 years (range, 15 to 61 years), had inherited connective tissue disorders: Marfan syndrome, 54 (92%); Loeys-Dietz syndrome, 5 (8%); and smooth muscle -actin (ACTA2) mutation in 1. Median preoperative sinus diameter was 52 mm (range, 42 to 76 mm ), and moderate/severe aortic regurgitation was present in 14 (23%). Seven (12%, 1993 to 1999) underwent remodeling procedures, and 53 had reimplantation procedures. Cusp repair was performed in 4. Median follow-up was 55 months (range, 1 to 149 months). There were 15 patients in the early term (1993 to 2000) and 45 in the late term (2001 to 2008). Results. Four late deaths occurred (cardiac, 3; aortic, 1), with 10-year survival of 86%. Rates of freedom from aortic valve replacement at 5 and 10 years were 85% and 58% in remodeling and 96% and 58% in reimplantation. Risk factors for reoperations were postprocedure intraoperative aortic insufficiency greater than mild (p 0.046), remodeling procedure (p 0.016), and early term (p ). One patient (2%) with none/trivial postprocedure aortic insufficiency required aortic valve replacement. Freedom from reoperation in patients with none/ trivial postprocedure aortic insufficiency at 5 and 10 years was 100% and 67%. Conclusions. Meticulous control of aortic insufficiency during operation would bring favorable midterm durability in valve-sparing aortic root replacement using a reimplantation technique, even in patients with inherited connective tissue disorders. (Ann Thorac Surg 2011;92: ) 2011 by The Society of Thoracic Surgeons The life expectancy of patients with Marfan syndrome has improved since a composite valve-graft replacement procedure was introduced by Bentall and DeBono in 1968 [1]. However, valve-sparing aortic root replacement was first introduced in 1970 by Senning and popularized by Yacoub and David in recent years. Since then, excellent long-term results have been reported [2, 3]. Aortic cusp repair combined with root replacement brings a better long-term outcome [4], and the reimplantation technique has a better long-term durability than the remodeling technique [5]. Some surgeons, however, consider that Marfan syndrome is a contraindication for valve-sparing operations because of concern about the possibility of dilatation of the aortic annulus after the procedure. The long-term outcome of these procedures in connective tissue disorders such as Marfan syndrome remains unclear. We believe there is a role for valve-sparing procedures in Marfan syndrome and have performed these procedures Accepted for publication June 22, Presented at the Forty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31 Feb 2, Address correspondence to Dr Tanaka, Department of Cardiovascular Surgery, National Cardiovascular Center, 5 7-1, Fujishirodai, Suita, Osaka , Japan; hirtanak@hsp.ncvc.go.jp. since We reviewed our experience of aortic valvesparing procedures in patients who had connective tissue disorders and determined the midterm results. Material and Methods The Review Ethics Board of the National Cardiovascular Center, Osaka, approved this study, and the need for individual consent for the study was waived. Patients From 1993 to 2008, 94 patients underwent valve-sparing aortic root replacement at the National Cardiovascular Center, Osaka. Of them, 60 patients (64%), with an average age of 33 years (range, 15 to 61 years), had inherited connective tissue disorders: Marfan syndrome in 54 (92%), Loeys-Dietz syndrome in 5 (8%), and smooth muscle -actin (ACTA2) mutation in 1. Marfan syndrome was diagnosed in accordance with Ghent nosology. Loeys-Dietz syndrome was diagnosed by genetic analysis of transforming growth factor- (TGFB) mutation. Four patients had acute aortic dissection and another 4 had chronic aortic dissection. Median preoperative sinus diameter was 52 mm (range, 42 to 76 mm), and moderate/ severe aortic regurgitation was present in 14 (23%). There 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg TANAKA ET AL 2011;92: MIDTERM OUTCOME OF AORTIC VALVE-SPARING PROCEDURES were 15 patients in the early period (1993 to 2000) and 45 in the late period (2001 to 2008). Operative Procedures Seven patients (12%, 1993 to 1999) underwent the remodeling procedure, and 53 underwent the reimplantation procedure. Cusp repair was performed in 4, comprising annuloplasty band with remodeling in 2, central plication in 1, and commissural plication in 1. There were three types of modification of the reimplantation: an original technique using a tube graft in 28, the technique using a tube graft with creation of neosinuses in 12, and Valsalva graft in 13. All grafts were woven Dacron (DuPont, Wilmington, DE). Patient characteristics and operative procedures are reported in Table ADULT CARDIAC Follow-Up Patients were routinely followed up annually, and computed tomography of the entire aorta and echocardiography were performed at each assessment. Telephone interviews were used to obtain data for 9 patients whose follow-up occurred at other institutions. No patients were lost in these follow-up data. Median follow-up was 55 months (range, 1 to 149 months). Table 1. Patient Characteristics and Operative Procedures Variable Median (Range) No. (%) Age, years 33 (15 61) Male sex 50 (83) Etiology Marfan syndrome 54 (92) Loeys-Dietz syndrome 5 (8) ACTA2 mutation 1 (1) Aortic pathology No dissection 52 (87) Chronic type A dissection 4 (6) Acute type A dissection 4 (6) Emergency presentation 4 (6) Sinus diameter, mm 52 (42 76) AI moderate/severe 14 (23) Procedure Remodeling ( ) 7 (12) Cusp repair 3 Reimplantation 53 (88) Tube graft 28 Tube graft with neosinus 12 Valsalva graft 13 Cusp repair 1 Concomitant procedure Hemiarch replacement 1 Total arch replacement 4 Mitral valve repair 2 Total arch mitral valve repair 2 Postprocedure intra-op AI 2 6 (10) ACTA2 gene encoding smooth muscle -actin; AI aortic insufficiency. Fig 1. Survival after operation. Statistical Analysis Demographic and other patient-related data were obtained from National Cardiovascular Center medical records. Data are expressed as the median value with the range. Survival and freedom from reoperation were determined by Kaplan-Meier analysis. The risk for reoperation was determined using the Cox regression model. Results There were no hospital deaths and 4 late deaths. The cause of late death was cardiac in 3 and aortic in 1, comprising cardiac failure, death at reoperation, arrhythmia, and aortic dissection. Survival is shown in Figure 1 and was 95% at 10 years. Freedom from reoperation is shown in Figure 2. The cause of reoperation was recurrent aortic insufficiency (AI) in all patients. The rates of freedom from reoperation were 95% at 5 years and 59% at 10 years. The results of the analysis of the risk for reoperation using the Cox regression model are reported in Table 2. Procedures performed in the early period (1993 to 2000), sinus diameter greater than 60 mm, remodeling procedure, and postprocedure intraoperative AI greater than Fig 2. Freedom from reoperation for aortic insufficiency (AI).

3 1648 TANAKA ET AL Ann Thorac Surg MIDTERM OUTCOME OF AORTIC VALVE-SPARING PROCEDURES 2011;92: Table 2. Proportional Hazard Analysis for Reoperation Variable mild were all associated with an increased risk of reoperation in univariate analysis. In the final multivariate analysis, sinus diameter greater than 60 mm was not a predictor of reoperation. In the patients who underwent the reimplantation procedure, 5 patients required reoperation for recurrent AI. Of these 5 patients, 2 underwent reoperation within 1 year after the initial operation, and 4 patients had postprocedure intraoperative AI greater than mild. Figure 3 shows freedom from reoperation in the patients with the reimplantation procedure stratified according to the presence of postprocedure intraoperative AI. Comment Univariate Multivariate HR p Value HR p Value Early period a Preop AI moderate/severe Sinus ( 60 mm) Remodeling procedure Postprocedure AI a Early period: ; late period, AI aortic insufficiency; HR hazard ratio. Although excellent long-term results of aortic valvesparing procedures have been reported, the results in connective tissue disorders, such as Marfan syndrome, remain unclear. The possibility of continuing rapid postprocedural degeneration of the aortic root components (aortic annulus and cusps) after the procedures is a concern. Although remodeling is a physiologically superior operation to reimplantation [6], it does not correct the problem of dilation of the aortic annulus. Modifications of this technique with an annuloplasty have been reported [7]; however, the important fact is that the native tissue between the annuloplasty band and the supraannular graft in Marfan syndrome may dilate with time [8]. Two of our patients who underwent remodeling with annuloplasty in 1996 still have native cusps, but AI is moderate and dilated the residual native tissue like spraying in both patients. In our current practice, even with physiologic superiority, the remodeling technique would have no role in connective tissue disorders. A reimplantation technique that can fix the aortic annulus is widely used for aortic root aneurysm in connective tissue disorders. Restoration of normal aortic cusp geometry is the most important technical aspect of this operation. Thus, we carefully determine the position of the commissures with confirmation of the cusp coaptation and create the neosinus hemisphere using the 6 stitches to fix the subcommissural portion to prevent distortion of the suture line to obtain good neosinus configuration. According to the results in this study, only a trivial central AI jet seen by transesophageal echocardiography is currently regarded as acceptable; otherwise, we reclamp the aorta and repair the cusp. We performed cusp repairs in only one of the reimplantation cases in this study and obtained a good result; therefore, cusp degeneration due to connective tissue disorders would be durable, at least for midterm follow-up, if the patient were to leave the operating room without a greater than 1 residual AI. Two of 5 patients who underwent the reimplantation procedure and had early reoperation (within 1 year) for recurrent AI had postprocedural intraoperative AI greater than mild. This observation was also supported by data from Kallenbach and colleagues [9] and De Paulis and colleagues [10]. None of the patients with postprocedural intraoperative none/trivial AI in this study had moderate/severe AI at the latest follow-up. The problem of this procedure is correction of coexistent aortic regurgitation, which requires cusp repairs for long-term durability because the main cause of reoperation was recurrent AI. In connective tissue disorders, AI is caused by shallow coaptation brought about by root dilatation [11], and then the cusps become thinner and stretched, finally prolapsed, and thicken and shorten. The preoperative risk factors for reoperation in this study were a large sinus ( 60 mm) and more than moderate AI, which reflect an advanced stage. Our current indication of reimplantation in connective tissue disorders is a sinus diameter exceeding 45 mm, and most patients do not require cusp repair. In the advanced stage with cusp prolapse, we also applied reimplantations with cusp repair within 2 years in patients who wished to have a valve-sparing operation despite the possibility of early failure. Although David and colleagues [12] reported good results of these procedures, with 30% cusp repair in patients with Marfan syndrome, manipulation of thin cusps would be challenging. The histologic studies by Fleischer and colleagues [13] revealed a high degree of structural deterioration of aortic cusp excised from patients with Marfan syndrome at the time of root replacement. They showed fragmen- Fig 3. Freedom from reoperation in reimplantation according to postprocedure aortic insufficiency (AI; blue line) and postoperative AI (red line).

4 Ann Thorac Surg TANAKA ET AL 2011;92: MIDTERM OUTCOME OF AORTIC VALVE-SPARING PROCEDURES tation and scarcity of fibrillin in the aortic cusps. Two unknowns are whether this structural deterioration of the cusps is primarily due to connective tissue disorders or secondary to the annulus dilation and whether the deterioration decelerates after the reimplantation procedure. Indeed, the mode of failure in reimplantation was fibrosis and shortening of the cusps in all cases, which was not compatible with the degeneration caused by connective tissue disorders. Similar findings were obtained in the failure cases in patients without connective tissue disorders; therefore, the main cause may be mechanical stress on the cusps due to the lack of sinuses after the procedure. According to the theory of the important role of the neosinuses in the reimplantation technique [14], we have used the graft with neosinus since 2006, have not experienced reoperations, and further follow-up would be needed. The rate of freedom from reoperation was different between the early (1993 to 2000) and late (2001 to 2008) periods. The two reasons for this are patient selection and the technical learning curve. Preoperative median sinus diameter was 59 mm in the early period and 49 mm in the late period, and preoperative median AI grades were 2.7 (range, 0 to 4) in the early period and 1.7 in the late period; consequently, postprocedure intraoperative AI grades were 1.5 and 0.6, respectively. This means that we currently select patients in the early stage of disease. During the technical learning curve, 6 surgeons performed 15 valve-sparing procedures in the early period; in contrast, 4 surgeons performed 38 reimplantation procedures under the control of 1 surgeon (H.O.) in the late period. Given the need for standardization and reproducibility of the procedure, we have been using the Valsalva graft (Vascutek, Renfrewshire, Scotland, United Kingdom) exclusively since In the 34 patients who did not have genetic etiologies, the rates of freedom from reoperation were 68% at 5 years and 48% at 10 years, which were similar to those of the patients who had genetic etiologies (log-rank, p 0.344). Although the reoperation rate was significantly high, even in this patient group, 22 of 34 patients underwent the operation before Thus, this significantly high rate of reoperation would be related to patient selection and the technical learning curve. In conclusion, valve-sparing aortic root replacement brings acceptable long-term durability, even in patients with inherited connective tissue disorders; however, surgeons need patient selection and will experience a learning curve for this complicated procedure. Early surgical intervention is needed for long-term durability. References Gott VL, Greene PS, Alejo DE, et al. Replacement of the aortic root in patients with Marfan s syndrome. N Engl J Med 1999;340: Yacoub MH, Gehle P, Chandrasekaran V, Birks EJ, Child A, Radley-Smith R. J Late results of a valve-preserving operation in patients with aneurysms of the ascending aorta and root. Thorac Cardiovasc Surg 1998;115: David TE, Ivanov J, Armstrong S, Feindel CM, Webb GD. Aortic valve-sparing operations in patients with aneurysms of the aortic root or ascending aorta. Ann Thorac Surg 2002;74:S Langer F, Aicher D, Kissinger A, et al. Aortic valve repair using a differentiated surgical strategy Circulation 2004;110 (11 suppl 1):II de Oliveira NC, David TE, Ivanov J, et al. Results of surgery for aortic root aneurysm in patients with Marfan syndrome. J Thorac Cardiovasc Surg 2003;125: Leyh RG, Schmidtke C, Sievers HH, Yacoub MH. Opening and closing characteristics of the aortic valve after different types of valve-preserving surgery. Circulation 1999;100: Lansac E, Di Centa I, Sleilaty G, et al. An aortic ring: from physiologic reconstruction of the root to a standardized approach for aortic valve repair. Thorac Cardiovasc Surg 2010;140 (6 suppl):s28 35; discussion S David TE, Maganti M, Armstrong S. Aortic root aneurysm: principles of repair and long-term follow-up. J Thorac Cardiovasc Surg 2010;140 (6 suppl):s14 9; discussion S Kallenbach K, Karck M, Pak D, et al. Decade of aortic valve sparing reimplantation: are we pushing the limits too far? Circulation 2005;112 (9 suppl):i De Paulis R, Scaffa R, Nardella S, et al. Use of the Valsalva graft and long-term follow-up. J Thorac Cardiovasc Surg 2010;140(6 suppl):s23 7; discussion S Bradley TJ, Potts JE, Potts MT, DeSouza AM, Sandor GG. Echocardiographic Doppler assessment of the biophysical properties of the aorta in pediatric patients with the Marfan syndrome. Am J Cardiol 2005;96: David TE, Armstrong S, Maganti M, Colman J, Bradley TJ. Long-term results of aortic valve-sparing operations in patients with Marfan syndrome. J Thorac Cardiovasc Surg 2009;138:859 64; discussion Fleischer KJ, Nousari HC, Anhalt GJ, Stone CD, Laschinger JC. Immunohistochemical abnormalities of fibrillin in cardiovascular tissues in Marfan s syndrome. Ann Thorac Surg 1997;63: Cochran RP, Kunzelman KS, Eddy AC, Hofer BO, Verrier ED. Modified conduit preparation creates a pseudosinus in an aortic valve-sparing procedure for aneurysm of the ascending aorta. J Thorac Cardiovasc Surg 1995;109: ADULT CARDIAC DISCUSSION DR GORAV AILAWADI (Charlottesville, VA): Did you also look at the preoperative aortic diameter at the level of the annulus and sinuses, and does that have any correlation with the ability to perform a valve-sparing procedure and with long-term durability? DR TANAKA: We saw the sinus diameter as a measure for the reoperation, but we couldn t find the other risk factor for sinus diameter. DR ERIC ROSELLI (Cleveland, OH): I think your study highlights a couple of important points. Number one is when you think you are done with the operation, if the patient has moderate aortic insufficiency (AI), you are not done with the operation. As you saw, I think you showed very clearly that the patients who left the operating room with 2 AI failed within 5 or 6 years and they are probably going to be better off with a valve replacement. And the other thing I think that you very clearly highlighted and congratulate you for is demonstrating that sizing of the graft

5 1650 TANAKA ET AL Ann Thorac Surg MIDTERM OUTCOME OF AORTIC VALVE-SPARING PROCEDURES 2011;92: seems to be very important. I noticed that all of the later reimplantation failures were in patients where there was a tube graft. The Valsalva graft, I think, is a nice addition to make this operation simpler, although I would like to highlight that our experience in Cleveland with over 200 patients with follow-up at 10 years, the freedom from reoperation is over 95%, and most of those patients received a tube graft. Very meticulous attention is paid to sizing those things, so that the tube graft is selected such that there is a large sinus there. So I think it is important that you highlighted that. What can you tell us about these patients who had aortic dissections? The hope is that when you treat these patients, you protect them from aortic dissection. Was there something that you learned that changed your technique to prevent dissection in these folks now? DR TANAKA: I mean new dissection, even after root replacement. Initially they had no dissection. DR ROSELLI: So how will you prevent that in the future? Is there something in particular about those 3 patients? DR TANAKA: What we can do, at the first operation we replace the ascending aorta as long as possible, but at the moment, that is all as a surgeon. DR ROSELLI: Did those patients have a dilated ascending aorta or was it a normal aorta? DR TANAKA: Normal aorta. DR TANAKA: In dissection cases, I think the technique is more difficult than the nondissection cases. DR ROSELLI: I am sorry. What I mean is that you showed 3 patients had reoperations because they had a dissection. You mean the reoperation, the indication was a new dissection, or that they had had initially the valve-sparing procedure for a dissection? DR RUGGERO DE PAULIS (Rome, Italy): I completely agree that a perfect intraoperative result is the key to a long-term good result. I was wondering if you have any data on the amount of coaptation you get after your operation. DR TANAKA: No, I am sorry. I don t have data about the coaptation.