Midterm Results of David Reimplantation in Patients With Connective Tissue Disorder

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1 Midterm Results of David Reimplantation in Patients With Connective Tissue Disorder Lars G. Svensson, MD, PhD, Eugene H. Blackstone, MD, Mazin Alsalihi, FICMS, PhD, Lillian H. Batizy, MS, Eric E. Roselli, MD, Rebecca McCullough, RN, BSN, Alessandro Vivacqua, MD, Rocio T. Moran, MD, A. Marc Gillinov, MD, Maran Thamilarasan, MD, Brian Griffin, MD, Donald F. Hammer, MD, William J. Stewart, MD, Joseph F. Sabik, III, MD, and Bruce W. Lytle, MD Marfan Syndrome and Connective Tissue Disorder Clinic, Departments of Thoracic and Cardiovascular Surgery and Cardiovascular Medicine, Heart and Vascular Institute, Department of Quantitative Health Sciences, Research Institute, and Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio Background. Few series have examined follow-up risks of the David reimplantation operation in patients with connective tissue disorder. Hence, we assessed its midterm safety and effectiveness for Marfan syndrome and other connective tissue disorders, such as Ehlers-Danlos, Loeys-Dietz, and marfanoid syndromes. Methods. Of 313 patients who underwent modified David reimplantation, 178 identified as having connective tissue disorders underwent operation from January 1, 1991, to December 31, These disorders included Marfan (84%), marfanoid (8.4%), Loeys-Dietz (5.6%), Ehlers-Danlos (1.1%), and other syndromes (1.1%). Concomitant procedures included mitral valve repair in 7.3% and an atrial fibrillation procedure in 3.4%. Results. There were no operative or 30-day deaths. Complications included prolonged ventilation (3%), renal failure (3%), reoperation for bleeding (2.2%), and permanent stroke (0.56%). Eight-year survival was 94% and freedom from aortic valve reoperation at 6 years was 92%. Of the 7 aortic valve reoperations, 3 were attributable to endocarditis and 3 to technical failure. One reoperation was performed at another hospital, and the reason could not be determined. There were no late strokes or hemorrhagic events. At 4 years, approximately 70% of patients had no aortic valve regurgitation, and 18% were in grade 1. Conclusions. Prophylactic root and valve preservation using David reimplantation is safe and provides excellent midterm effectiveness and low risk of late events except for endocarditis. (Ann Thorac Surg 2013;95:555 62) 2013 by The Society of Thoracic Surgeons Patients with connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, bicuspid aortic valves, and other less welldefined entities, are prone to aortic dissection, aneurysms, and aortic rupture [1 5]. With occurrence of an acute aortic catastrophic event, some 40% die immediately, with 1% to 3% dying every hour during the first 24 hours. Emergency surgery carries a 5% to 25% mortality risk, and 5-year survival is only 50% to 70% [6, 7]. These grim statistics have led to various attempts to reduce mortality. Among these is prophylactic repair of aortic root aneurysms, which reduces risk of late death, ideally with operative death of less than 1% to justify the risk. However, mechanical valve composite grafts are associated with morbid events. Only 40% of patients are alive and event free at 10 years [8 32]. Recently, the David reimplantation operation has been shown to be associated with low operative risk, excellent late survival, and low risk for late aortic valve replacement Accepted for publication Aug 1, Presented at the Poster Session of the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 Feb 1, Address correspondence to Dr Svensson, Cleveland Clinic, 9500 Euclid Ave, Desk J4-1, Cleveland, OH 44195; svenssl@ccf.org. [8 32]. In our previous report, no patient died after surgery, and 99% were 10-year survivors (100% for those with Marfan syndrome) [30]. Freedom from reoperation was 97% at 9 years and 94% at 10 years. However, because myxomatous changes remain in the aortic cusps of patients with Marfan syndrome, concern has been expressed about late durability with valve reimplantation. Few series have examined late risks of the David reimplantation operation in patients with connective tissue disorders [21]. Hence, we examined early and midterm safety and clinical effectiveness of this operation in this patient population, with particular focus on repair durability. Patients and Methods Patients Of 313 patients who underwent modified David reimplantation, 178 identified as having connective tissue disorders underwent operation from January 1, 1991, to Dr Sabik discloses financial relationships with Medtronic, Edwards Lifesciences, and Abbott Vascular by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 556 SVENSSON ET AL Ann Thorac Surg DAVID REIMPLANTATION 2013;95: June 1, 2011, at Cleveland Clinic. Patients with solely bicuspid valves were excluded because David reimplantation is not the usual choice for these patients, and they Table 1. Patient Characteristics and Procedural Details Variable n a Mean SD No. (%) or Demographics Age (y) Weight (kg) Height (cm) Body surface area (m 2 ) NYHA class 155 I 84 (54) II 53 (34) III 17 (11) IV 1 (0.65) Noncardiac morbidity Connective tissue disorder 178 Marfan syndrome 149 (84) Loeys-Dietz syndrome 10 (4.6) Marfanoid 15 (8.4) Ehler-Danlos syndrome 2 (1.1) Probable Loeys-Dietz syndrome 2 (1.1) Not otherwise specified 2 (1.1) Hypertension (49) COPD (13) Smoking (44) Pharmacologically treated diabetes (1.1) Carotid disease (14) Prior stroke (2.2) Renal dialysis (1.2) Creatinine (mg/dl) Total cholesterol (mg/dl) Hematocrit (%) Cardiac morbidity Aortic valve regurgitation (68) Grade (31) 1 18 (11) 2 44 (26) 3 32 (19) 4 23 (14) Aortic valve stenosis (1.7) Mitral valve regurgitation (37) Tricuspid valve regurgitation (29) Atrial fibrillation/flutter (0.60) Ventricular arrhythmia (5.4) Prior cardiac operation (2.8) Concomitant procedures Coronary artery bypass grafting (7.9) Mitral valve repair (7.3) Ablation for atrial fibrillation (3.4) Support Myocardial ischemic time (min) Cardiopulmonary bypass (min) Table 1. Continued Variable n a Mean SD No. (%) or Circulatory arrest (16) Circulatory arrest time (min) a Patients with data available. COPD chronic obstructive pulmonary disease; Heart Association; SD standard deviation. NYHA New York are not typically considered as having a generalized connective tissue disorder. Nevertheless, patients with a bicuspid valve associated with Marfan syndrome or Loeys-Dietz syndrome were included; the latter may have a higher prevalence of bicuspid valves. Also excluded were 27 patients with Marfan syndrome who underwent a composite root replacement (Bentall) during this period. Of the 178 patients, 149 (84%) had Marfan syndrome, 10 (5.6%) had Loeys-Dietz syndrome, and 2 (1.1%) had Ehlers-Danlos syndrome; 132 (74%) were men, the average age was years, and the average height was cm. Of note, 15 (8.4%) had the features of Marfan syndrome but did not meet complete clinical criteria for diagnosis and had a poorly defined connective tissue disorder. Of the 178 patients, 5 (2.8%) had undergone previous cardiac surgery, 2 had endocarditis (1.1%), 23 (13%) had chronic obstructive pulmonary disease in keeping with connective tissue disorders, 2 (1.2%) were on dialysis (1.2%), and 4 (2.2%) had a history of stroke. Of interest, 49% (n 87) were hypertensive and 5.4% (n 9) had malignant ventricular arrhythmias. Only 14 had coronary artery disease. Fifty-one patients (29%) also had tricuspid valve regurgitation (Table 1). Data were retrieved from the Cardiovascular Information Registry, a prospective registry of all cardiac operations maintained concurrent with patient care. Use of data from this registry for research was approved by Cleveland Clinic s Institutional Review Board, with patient consent waived. Operation Patients underwent surgery for aneurysmal roots (n 169; 98%), severe (3 /4 ) aortic valve regurgitation (n 55; 33%), severe mitral valve regurgitation (n 10; 6.6%), or heart failure (n 9; 5.1%). In patients who had either root aneurysms without symptoms (New York Heart Association [NYHA] class I: n 84; 54%) or important valvular disease, timing of surgery was determined by aortic diameter greater than 5.0 cm or root cross-sectional area to height ratio greater than 10 cm 2 /m. For Loeys- Dietz syndrome patients, a size greater than 4.2 cm was used as per the American Heart Association/American College of Cardiology/Society of Thoracic Surgeons/ American Association for Thoracic Surgery thoracicaorta disease guidelines [1]. The David reimplantation operation was either as described by David [11, 12, 21, 24] or our modification of that operation (n 108; 61%) using a Hegar dilator in the annulus to downsize it to a normal expected diameter

3 Ann Thorac Surg SVENSSON ET AL 2013;95: DAVID REIMPLANTATION 557 Table 2. Complications After David Reimplantation for Connective Tissue Disorder Complication n No. (%) 68% CL Hospital death (0) Permanent stroke (0.56) Prolonged ventilation ( 24 h) (3) Permanent pacemaker (3.9) Atrial fibrillation (25) Perioperative myocardial (1.7) infarction Reoperation for bleeding or (2.2) tamponade Reoperation for valve (0) dysfunction Renal failure requiring (0) dialysis Deep sternal wound infection (0) a Patients with data available. CL confidence limit. [16]. Early in our experience, neosinuses were not as well formed as at present. Concomitant operative procedures included mitral valve repair (n 13; 7.3%), ablation for atrial fibrillation (n 6; 3.4%), patent foramen ovale or atrial septal defect suture closure (n 3; 1.7%), coronary artery bypass grafting (n 14; 7.9%), and aortic arch repairs, including elephant trunk procedures (n 29; 16%) performed under circulatory arrest with a mean time of minutes. Average aortic cross-clamp time was minutes (range, 59 to 141 minutes) and cardiopulmonary bypass time was minutes. End Points Early safety end points included hospital mortality and postoperative stroke, myocardial infarction, reoperation for bleeding, prolonged ventilation, renal failure and dialysis, deep wound infection, pacemaker or implantable cardioverter-defibrillator requirement, and reoperation for valve dysfunction. These morbidities, all recorded prospectively, were defined according to The Society of Thoracic Surgeons National Adult Cardiac Database (see VendorsPGS.pdf). Clinical effectiveness was assessed by all-cause mortality, reoperation for aortic valve or thoracic-aorta disease or complications, infective endocarditis, stroke, and aortic valve regurgitation. Active follow-up was conducted yearly and included ascertaining additional cardiovascular interventions, occurrence of endocarditis, and stroke; a total of 485 patient-years of follow-up data was available for these analyses. For all-cause mortality, this follow-up was supplemented by information from the Social Security Master Death File, resulting in 904 patient-years of follow-up data available for analysis (median, 4.2 years), with 10% of patients followed more than 8 years. Postoperative aortic regurgitation severity grade was obtained by transthoracic echocardiograms. For the most part, the studies were performed at Cleveland Clinic, and results were recorded in the Echocardiography Database. However, patients were also requested to supply echocardiographic reports if they had not been seen at Cleveland Clinic. Data Analysis SAS version 9.1 was used for all analyses (SAS, Inc, Cary, NC). All probability values are two sided. Categorical variables were summarized by frequencies and percentages and compared with the 2 or Fisher s exact test. Continuous variables were summarized by mean and standard deviation unless their distribution was skewed, Fig 1. Survival after David reimplantation. Each symbol represents a death, and vertical bars are 68% confidence limits. Solid line enclosed within dashed 68% confidence bands represents parametric estimate. No. at risk

4 558 SVENSSON ET AL Ann Thorac Surg DAVID REIMPLANTATION 2013;95: in which case the 15th, 50th (median), and 85th percentiles are presented, equivalent to 1 standard deviation. Time-related estimates are accompanied by 68% confidence limits (CL) or bands. Nonparametric estimates of freedom from time-related events were estimated by the Kaplan-Meier method and hazard functions by a parametric multiphase method [33 35]. For 161 patients, 403 follow-up transthoracic echocardiograms were available. Repeated regurgitation grades were analyzed longitudinally across time. Because of its ordinal nature, grade of regurgitation was assumed to have come from a multinomial distribution. Using this assumption, a longitudinal cumulative logit model was used to model the temporal trend of regurgitation. Although aortic regurgitation severity ranged from 1 to 4, for analysis, grades 3 and 4 were combined because of sparse data. This resulted in four ordinal grades for analysis; 0 (none), 1 (mild), 2 (moderate), and 3 /4 (moderately severe/severe). Results Safety There were no operative deaths (0%; CL, 0% to 1.0%). Complications included 1 stroke (0.56%; CL, 0.10% to 1.8%), 3 myocardial infarctions (1.7%; CL, 0.77% to 3.3%), Fig 2. Aortic reoperations after David reimplantation. (A) Freedom from reoperation. Format is as in Figure 1. Note that early reoperations were for second-stage elephant trunk procedures. (B) Instantaneous risk (hazard function) of aortic reoperations. Solid line represents parametric estimates enclosed within dashed 68% confidence bands. No. at risk A B

5 Ann Thorac Surg SVENSSON ET AL 2013;95: DAVID REIMPLANTATION reoperations for bleeding (2.2%; CL, 1.2% to 4.0%), and 5 (2.8%; CL, 1.6% to 4.6%) each of renal failure (no dialysis) and prolonged ventilation (Table 2). No deep wound infections or reoperations for perioperative valve dysfunction occurred. Seven patients (3.9%; CL, 2.5% to 6.0%) required a pacemaker, and 1 required an implantable cardioverter-defibrillator (0.56%; CL, 0.10% to 1.8%). Clinical Effectiveness Survival was excellent at 96% and 94% at 5 and 8 years, respectively (Fig 1). Risk of reoperation on the aorta was low at 11% at 6 years, including elective second-stage operations (Fig 2A). Most aortic reoperations were planned second-stage elephant trunk procedures, with a peak hazard function at 3 to 4 months after the initial David reimplantation and first-stage elephant trunk procedure (Fig 2B). There were 7 late aortic valve reoperations, 3 attributable to endocarditis at 2.5 months, 3 years, and 4.5 years after surgery, and 3 technical failures at 9 months, 1.2 years, and 17 years; in 1 the left coronary cusp slipped below the graft, in 1 the cusps appeared to be thickening and scarring, and in 1 aortic valve stenosis of a bicuspid valve had occurred. In 1 patient the valve was replaced at another hospital for 2 to 3 regurgitation of uncertain cause. Five- and 6-year freedom from reoperation on the aortic valve was 93% and 92%, respectively Fig 3. Aortic valve reoperation after David reimplantation. (A) Freedom from reoperation. Format is as in Figure 1. (B) Instantaneous risk (hazard function). Depiction is as in Figure 2B. No. at risk A B

6 560 SVENSSON ET AL Ann Thorac Surg DAVID REIMPLANTATION 2013;95: Fig 4. Aortic regurgitation (AR) after David reimplantation. Parametric estimates of temporal average of patients in each grade of AR. Symbols represent data grouped without regard to repeated measurements within time frames to provide a crude verification of model fit. (echos echocardiograms.) Grade /4+ No. of echos No. of patients (Fig 3A). The hazard function remained consistent with time with approximately 1.5% annual risk (Fig 3B), whereas with replacement of a biologic valve it increased with time. Of note, there were no strokes, embolic events, or hemorrhagic events observed during follow-up, known risks for mechanical valves. Durability For grade 0 regurgitation (no regurgitation, including no trace regurgitation), temporal decomposition analysis showed an early decrease to 66% at 1.5 years, but thereafter prevalence was constant. Combined with trace or 1 regurgitation, after 1.5 years 83% of patients had no significant regurgitation, 9% had 2, and 7% had 3 /4 (Fig 4). These latter patients underwent reoperation because they developed symptoms or ventricular dysfunction as noted in the preceding text. Comment Composite valve grafts have been the gold standard for replacing the aortic root in patients with root dilatation and connective disorders [32, 36]. Although excellent survival has been reported with mechanical valve composite grafts, the downside of anticoagulation with its attendant risk of bleeding or embolism, particularly stroke, has been a concern. Indeed, for both isolated mechanical valve replacement and mechanical composite valve grafts, event-free survival at 10 years has been reported to be only 40% [32]. In patients with connective tissue disorders, the cusps typically show evidence of myxomatous degeneration on histologic examination [1]. An early concern about using the David reimplantation operation in patients with connective tissue disorders was that the preservation of the cusps would result in early failure [8, 11, 15, 27, 29]. Previous reports on reimplantation of the aortic valve have included series of patients undergoing the procedure without focusing specifically on those with connective tissue disorders and long-term outcomes, with the exception of the study by David and colleagues [21]. The present study has shown that risk in patients with connective tissue disorder is small, with no operative deaths in this series and low risk of neurologic events. Indeed, we believe that routine use of antiplatelet agents for 30 days after surgery reduces risk of platelet aggregates forming on the raw surface areas and potentially causing platelet aggregate emboli [30, 31]. At 6 years, freedom from reoperation was a satisfactory 92%, and we expect that this will improve as our modification of the David reimplantation operation is improved by newer techniques [16, 30, 31]. Our previous report on patients with Marfan syndrome showed no failures with David reimplantation operations; with remodeling operations, failure was higher [2]. Hence, based on our experience and that of David and others [21], we believe that the recommendation from the Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease to perform the reimplantation operation in patients with connective tissue disorder is justified, using an aortic size of 5.0 cm, but 4.2 cm for patients with Loeys-Dietz syndrome [1]. Thus, with an approximate 94% 8-year survival and 92% freedom from reoperation, total event-free survival is about 88% and is likely to be considerably better than the 40% event-free survival at 10 years after composite valve graft surgery [32]. A quandary regarding preserving the aortic valve during reimplantation is determining which valves can be kept if regurgitation is severe and not solely caused by central tricuspid regurgitation. We recommend that the

7 Ann Thorac Surg SVENSSON ET AL 2013;95: DAVID REIMPLANTATION 561 cusps be carefully and systematically examined using the CLASS schema (Commissures, Leaflets, Annulus, Sinotubular junction, and Sinuses). If more than two cusps are prolapsing or have important perforations, we do not recommend preservation. Cusp repair techniques can be used to make most valves preservable, and a Hegar dilator can be used to reduce annular size to normal, potentially increasing cusp durability [16]. In this series, 29 patients (16%) had arch repairs mostly with elephant trunk procedures. Increasingly in patients with complex arch anatomy or chronic type B dissection, we perform concurrent elephant trunk procedures, sometimes with prophylactic frozen elephant trunks. Limitations This is a single-institution observational study with prospective data recording. Ideally, a prospective randomized trial would be done to compare composite valve grafts and the reimplantation operation, but based on our experience, we do not believe this would be justified nor do we have equipoise. We did not have access to aortic root measurements that may have informed the decision to perform a Bentall operation in a small number of patients with Marfan syndrome, and we have not used cusp height in our decision making. Conclusions We believe this study shows that the David reimplantation operation is the preferred procedure for preserving the aortic valve in patients with connective tissue disorder. This operation can be safely performed to justify this prophylactic procedure, and has a low follow-up event rate and risk of reoperation compared with mechanical valves. References 1. 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