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J. Maxwell Chamberlain Memorial Paper for Adult Cardiac Surgery

Aortic Root Replacement in 372 Marfan Patients: Evolution of Operative Repair Over 30 Years

Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Accepted for publication January 30, 2009.

^_* Address correspondence to Dr Cameron, Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287 (Email: dcameron{at}jhmi.edu).

Presented at the Forty-fourth Annual Meeting of The Society for Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008. Winner of the J. Maxwell Chamberlain Memorial Paper for Adult Cardiac Surgery.

ADULT CARDIAC SURGERY: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.

 

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Discussion Acknowledgments References

 
Background: We reviewed the evolution of practice and late results of aortic root replacement (ARR) in Marfan syndrome patients at our institution.

Methods: A retrospective clinical review of Marfan patients undergoing ARR at our institution was performed. Follow-up data were obtained from hospital and office records and from telephone contact with patients or their physicians.

Results: Between September 1976 and September 2006, 372 Marfan syndrome patients underwent ARR: 269 had a Bentall composite graft, 85 had valve-sparing ARR, 16 had ARR with homografts, and 2 had ARR with porcine xenografts. In the first 24 years of the study, 85% received a Bentall graft; during the last 8 years, 61% had a valve-sparing procedure. There was no operative or hospital mortality among the 327 patients who underwent elective repair; there were 2 deaths among the 45 patients (4.4%) who underwent emergent or urgent operative repair. There were 74 late deaths (70 Bentalls, 2 homograft, and 2 valve-sparing ARRs). The most frequent causes of late death were dissection or rupture of the residual aorta (10 of 74) and arrhythmia (9 of 74). Of the 85 patients who had a valve-sparing procedure, 40 had a David II remodeling operation; there was 1 late death in this group, and 5 patients required late aortic valve replacement for aortic insufficiency. A David I reimplantation procedure using the De Paulis Valsalva graft has been used exclusively since May 2002. All 44 patients in this last group have 0 to 1+ aortic insufficiency.

Conclusions: Prophylactic surgical replacement of the ascending aorta in patients with Marfan syndrome has low operative risk and can prevent aortic catastrophe in most patients. Valve-sparing procedures, particularly using the reimplantation technique with the Valsalva graft, show promise but have not yet proven as durable as the Bentall.

Forty years ago, Hugh Bentall and Anthony DeBono [1] published an article in the journal Thorax describing a new surgical technique of aortic root replacement for aortic root aneurysm. This procedure gave new hope to Marfan syndrome (MFS) patients, for whom rupture of the ascending aorta is the leading cause of premature death, typically in the third decade of life [2]. Before the introduction of the Bentall composite graft procedure, MFS patients were usually operated on for aortic catastrophe or end-stage heart failure. At our own institution, only 5 MFS patients were operated on between 1965 and 1976; 4 required emergent operation for acute dissection of the ascending aorta, and the fifth patient had an elective operation for end-stage left ventricular failure caused by aortic insufficiency. Three of these patients died in the early postoperative period, a 60% mortality rate.

The report from Bentall and DeBono [1] encouraged us to begin a program of prophylactic aortic root replacement in MFS patients with root aneurysms. Our first composite graft operation was performed in September 1976. During the next 30 years, 12 surgeons performed aortic root replacement in 372 Marfan patients. In this report, we present the early and late results of those 372 patients.

	Patients and Methods

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Patient Selection
Three hundred seventy-two patients underwent aortic root replacement between September 1976 and September 2006. Two hundred sixty-nine patients had a composite graft repair, 85 had a valve-sparing aortic root replacement, 16 had aortic root replacement with a homograft, and 2 had replacements with porcine xenografts. All patient data were entered into a computerized patient registry; late follow-up data were obtained from clinical records and direct contact with patients and their primary physicians.

Approval to conduct this retrospective study without individual patient consent was provided by our institutional review board.

Operative Technique
Two hundred sixty-nine patients underwent aortic root replacement with a composite graft. Our current operative technique has evolved from the original Bentall procedure and has been described in detail in several publications [3, 4]. Eighty-five patients had valve-sparing aortic root replacement using techniques modified from Sarzsan and Yacoub [5] and David and Feindel [6]. Since May 2002, our procedure of choice has been a modified reimplantation technique using the De Paulis Valsalva graft [7, 8].

Actuarial survival analyses were determined using the Kaplan-Meier method; in addition, freedom from thromboembolism, freedom from endocarditis, and freedom from reoperation on the residual aorta were calculated. A univariate analysis was performed using the Mantel-Cox method, and multivariate analysis was determined by the Cox proportional hazards method. Statistical computations were made using STATA version 9.0 (StatCorp, College Station, TX).

	Results

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Preoperative Patient Characteristics
Of the 372 MFS patients, 265 were men (71%) and 107 were women (29%; Table 1). Mean patient age was 32.9 years (range, 1.5 to 73 years). Fifty-nine (16%) had dissection of the ascending aorta at operation; 27 were acute dissections and 34 were chronic (more than 14 days old). Mean diameter of the ascending aorta in 315 adult patients in whom this dimension was noted in the hospital chart was 6.35 cm (range, 4 to 13 cm). Among patients with dissection, mean aortic diameter was 7.2 cm. Twenty-three patients had dissection in an aorta 6.5 cm or smaller.

There were 2 late deaths among the 85 patients undergoing a valve-sparing operation (Table 5). One patient status post–David II remodeling procedure died 9 years after surgery of multisystem organ failure after repair of dissection of a thoracoabdominal aortic aneurysm. The second patient died of biventricular failure while awaiting a heart transplant 10 years after a David I reimplantation procedure. There have been no late deaths among the 44 patients who have David I reimplantation procedures with the Valsalva graft.

Late mortality among the 73 mitral valve procedure patients was 26% (Table 3).

Multiple patient- and procedure-related variables were screened by univariate and subsequent multivariate analysis as potential risk factors for early or late death (Table 6). These variables included preoperative age, mitral valve surgery, preoperative dissection, New York Heart Association (NYHA) functional class III or IV, urgent operation, and male sex. Age, preoperative dissection, NYHA class III or IV, and urgent surgery were significant independent predictors of early or late death. In the multivariate analysis, age and mitral valve surgery emerged as significant independent predictors of mortality. Actuarial survival (Fig 1) among the 372 Marfan patients after aortic root replacement was 91.9%, 85.5%, 81.0%, and 75.6% at 5, 10, 15, and 20 years, respectively. Actuarial survival for patients with and without preoperative dissection is also depicted.

View larger version (11K): [in this window] [in a new window]   Fig 1. Actuarial survival of 372 Marfan patients after aortic root replacement was 91.9%, 85.5%, 81.0%, and 75.6% at 5, 10, 15, and 20 years, respectively. Effect of dissection present at root operation is also depicted.

View larger version (7K): [in this window] [in a new window]   Fig 2. Freedom from thromboembolic events in patients with composite grafts was 97.4%, 95.8%, 92.8% and 91.5% at 5, 10, 15, and 20 years, respectively.

View larger version (7K): [in this window] [in a new window]   Fig 3. Freedom from endocarditis was 97.2%, 95.1%, 94.2%, and 91.7% at 5, 10, 15, and 20 years, respectively.

Ten of 370 patients discharged from the hospital (2.7%) died of late dissection or rupture of the residual aorta. Four of these patients had emergent repair for acute dissection. Forty-nine of the 370 patients (13.2%) discharged from the hospital had late aortic procedures (aortic arch and beyond) for progressive aneurysm disease or dissection. Thirty-one patients (63%) were alive at last follow up. Freedom from reoperation on the residual aorta was 95.6%, 88.8%, 82.2%, and 72.1% at 5, 10, 15, and 20 years, respectively (Fig 4). The presence of dissection at the original operation had a profound effect on late survival and freedom from reoperation on the distal aorta. Of patients with dissection, survival at 10 and 20 years was 65% and 53%, respectively, versus 87% and 76% for patients without dissection. Freedom from reoperation on the residual aorta (arch and beyond) among patients with dissection was 67% at 10 years and 43% at 20 years, versus 92% at 10 years and 77% at 20 years in patients without dissection.

View larger version (9K): [in this window] [in a new window]   Fig 4. Freedom from reoperation on the residual aorta was 95.6%, 88.8%, 82.2%, and 72.1% at 5, 10, 15, and 20 years, respectively. Preoperative dissection versus no dissection is also depicted.

	Comment

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Our experience with bioprostheses was disappointing because of poor durability, particularly in the patients most likely to benefit from avoidance of anticoagulants: children and young adults. We now use bioprostheses only in the treatment of prosthetic valve endocarditis, for which the most successful and reliable treatment has been total excision of the Bentall graft and re-replacement with a cryopreserved aortic homograft root.

Encouraged by the reports from Sarzsan and Yacoub [5] and David and Feindel [6] on valve-sparing operations, we began a program of selective use of valve sparing procedures in 1993. Initially, we used the remodeling method because we believed it was technically more straightforward and that preservation of sinuses was important for long-term valve integrity. The observation that some patients experienced anular dilation and valve incompetence after remodeling led to adoption of the reimplantation procedure, which stabilizes the annulus and is more hemostatic. Coincident with this change, we used the Valsalva Dacron graft, with preformed sinuses, which simplified construction of the prosthetic root and combined the "best of both worlds" of the reimplantation and remodeling procedures: annular stabilization and preservation of sinuses. The reimplantation operation with a Valsalva graft has been our preferred operation for both children and adults since 2002, and durability of this prosthesis has been excellent. The promise of a lower risk of thromboembolism, lower risk of endocarditis, and avoidance of anticoagulation has also been satisfied. Long-term durability (>10 years) is still unknown, so its role vis-à-vis the Bentall procedure must await further follow-up. Furthermore, not all patients are candidates for valve-sparing procedures. In our practice, 10% to 20% of patients who choose a valve-sparing operation are deemed intraoperatively to have leaflet abnormalities that portend poor long-term results and thus undergo valve replacement. Severely stretched or thinned leaflets, and leaflets with multiple fenestrations, in our view should not be preserved. Valve repair has been infrequent and limited to mid-leaflet plication.

Long-term survival is still compromised in MFS patients after root replacement; the two major causes of late death are distal aortic catastrophe and arrhythmia. The entire Marfan aorta is abnormal and remains at risk for dissection and aneurysm, so it deserves close monitoring and antihypertensive medical control, usually with a β-blocker. Some authors have even suggested that a rigid noncompliant Dacron graft in the ascending aorta increases the risk of distal aortic disruption. It is thus important to excise as much of the ascending aorta as possible, although hemiarch replacement is rarely needed. Further improvements in long-term survival will require better understanding of the factors leading to distal aortic disease, and the means of prevention. Similarly, arrhythmia remains poorly described and poorly understood in the older Marfan patient; this study raises the question whether implantable defibrillators or antiarrhythmic medication should be considered for the postoperative MFS patient.

The study also demonstrates the profound effect of dissection on late survival and need for reoperation on the distal aorta, emphasizing the importance of root intervention before dissection occurs. Identification of patient subgroups at greater risk of dissection or lowering of the threshold for intervention are goals to pursue to reduce the rate of dissection.

Our current indications for aortic root replacement in MFS are (1) aortic sinus diameter 5 cm or greater, or 4.5 cm among patients with family history of rupture or dissection, (2) ascending aortic dissection, whether acute or chronic, (3) aneurysm growth more than 1 cm/year, and (4) worsening aortic regurgitation in a dilated root when a valve-sparing procedure is desired. The last two indications are particularly relevant to MFS children with dilated roots, in whom guidelines based on indexed aortic size are still not established. Nearly 90% of our patients in the last 5 years have requested and received valve-sparing procedures, a situation that is the reverse from the first 20 years when Bentall procedures were the rule. However, this must be regarded with some caution, as the Bentall remains the established therapy with known long-term and highly reproducible results.

	Discussion

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DR JOSEPH E. BAVARIA (Philadelphia, PA): I congratulate Drs Cameron and Gott on their report of aortic root surgery in Marfan's patients. This is the world's most complete series and represents a 31-year evolution since their first implant in 1976. The short- and long-term results are outstanding, and the fundamental concept of aortic root reconstruction on an elective basis is firmly established as there is a dramatic impact on survival compared to the natural history of the disease.

They describe the evolution of their procedural treatment strategy from mechanical composite grafts, to bioroots, to the remodeling style aortic root procedure, to their present algorithm since 2002, which is performing a reimplantation valve-sparing operation with a Valsalva Dacron conduit, if possible, but, importantly, to realize, as highlighted in this report, that a mechanical composite graft is a very satisfactory plan B.

On examination of the data, and I had the privilege of having the manuscript, at least in the intermediate term the reimplantation valve-sparing operation using the De Paulis Valsalva graft has performed well. There have been no failures, no endocarditis, and no late mortality out to 5 years in 44 patients. Additionally, all patients with a thromboembolic event were in the mechanical composite group.

(Slide) This corroborates our initial series reported at the Griepp New York Aortic Surgery Meeting in 2006 by Settepani in 35 Marfan's patients treated with valve-sparing root reconstruction using a De Paulis graft with a freedom from structural valve deterioration at 5 years of 93.5%.

I would like to ask the authors some questions that may be of interest to the audience. Number one, actuarial survival for the whole cohort was 75.6% at 20 years. In a subgroup analysis, what was the 20-year survival of the 59 patients who presented with dissection versus the 313 who were operated on for nondissection?

Two, related to this question, what was the freedom of distal aortic late reoperation in the same dissection versus nondissection subgroup? I am willing to bet that it was quite different.

Three, you report freedom from thromboembolism of 91% at 20 years, but also report zero TE (thromboembolic) events in your biological root cases. What is the freedom from thromboembolism in the mechanical composite subgroup?

And I would like your editorial opinion, because I think the audience would all value this; you report an elegant evolution of procedural therapeutics. Was there also an evolution in your thinking about when and at what diameters to operate on a Marfan's root?

And lastly, why do you think that the concomitant mitral valve surgery subgroup did so much worse long term with the highest multivariate hazard ratio?

Again, I congratulate Drs Cameron and Vincent Gott for being the guiding light for all of us who perform these operations on Marfan's patients on a regular basis. Thank you.

DR CAMERON: Thank you very much, Dr Bavaria, for your kind remarks and insightful comments about our manuscript. I will try to answer the five questions that you raised.

First regarding survival, and importantly, the impact of dissection present at the time of the initial operation on survival, this was not presented in the talk in the interest of time, but we do have those data, and the impact on dissection, as you might expect, is profound. At 20 years after operation the survival of the dissected group is 50% compared to 75% in the nondissected group. So survival is compromised by a third at 20 years when dissection is present, and of course this is an additional argument for doing everything we can with this disease to prevent dissection. Once dissection occurs, the cat is out of the bag. So the effect of dissection is profound on survival even though the mortality rate is low for the initial operation.

Similarly, dissection has a profound effect on the late reoperation rate. At 20 years, patients who had a dissection at the first operation had freedom from reoperation of 40% at 20 years versus 77%. So in terms of reoperation, the presence of a dissection will actually double the risk that a patient will need another operation at 20 years.

As for freedom from thromboembolism, it is true that we grouped all patients, and perhaps it would be a more telling analysis to focus specifically on the composite graft patients, because the absolute freedom from endocarditis and thromboembolism in the valve-sparing procedures perhaps gave a more optimistic picture of thromboembolism in composite grafts. However, the rate of thromboembolism with composite grafts was low, and in the first 10 years of follow-up they are low in both groups. After 10 years they begin to diverge a bit, and freedom from thromboembolism for just the mechanical valves is about 89% at 20 years and 67% at 25.

The question of when to operate is controversial. When you have a prophylactic operation which has a near zero operative mortality, one is tempted to employ it earlier and earlier, but I think some caution needs to be exerted here. This is not always a reproducible result at other institutions, and I would agree that we clearly need to intervene early enough to prevent dissection, but that is not always possible, even when operating at 4.5 cm. I would agree we need to find better ways to identify patients who are at particular risk for dissection and perhaps not use size of the aorta as the deciding variable. For now we continue to use 5 cm as our threshold for intervention, but I will admit that many patients, having read the Internet information available to them and who are particularly interested in valve-sparing operations, are coming to us sooner and we are being compelled to operate below 5 cm.

I think the reason mitral patients do less well is because of the effect of mitral surgery and in fact mitral disease on the left ventricular myocardium, and I suspect that the presence of mitral disease is also a marker for more severe affliction with Marfan syndrome.

I thank you again for your kind comments, and I would be happy to entertain other questions from the floor.

DR THORALF SUNDT (Rochester, MN): Duke, you have got a remarkably high repair rate, an admirably high repair rate. My question is about the leaflets themselves. Are you ever dissuaded from doing a valve-sparing operation because of fenestrations in the leaflets? And have you noticed differences in the distensibility or stretchability of the leaflets? I have the sense that some have very stretchy leaflets and others have stiffer leaflets, and I have been concerned about whether those very stretchy leaflets will hold up in the long run. Thanks.

DR CAMERON: Thank you very much, Thor, and I share your concern. We make it very clear to patients who are coming to the operating room for valve-sparing operations that there is somewhere between a 10% and 20% chance that we will get to the operating room and not perform a valve-sparing operation, usually for the reasons you mention, that in Marfan syndrome in particular the leaflets are extraordinarily thin and often have fenestrations at the commissures. We believe these are stress fenestrations and may represent irreversibly damaged leaflets. In the Marfan syndrome we do not think that these leaflets are repairable. This is not true with other valve pathologies, but the aortic valve in Marfan syndrome is extraordinarily thin and I don't think it is amenable to repair.

DR CHARLES D. FRASER (Houston, TX): Duke, there are many of us here in the audience who were educated by you and Dr Gott and others here present from Johns Hopkins, and we are most grateful for your educational leadership. I wanted to comment or ask your thoughts about the fact that the majority of these cases, perhaps all of these cases, were done with a resident surgeon as the primary surgeon with the assistance of a staff attending surgeon. What is your insight about that and how are you able to accomplish such outstanding results in this paradigm?

DR CAMERON: Well, the paradigm of helping a resident do a case like this is something that I inherited from my mentors, Dr Gott and Dr Reitz. I thank them for that, and I think this is a very important message as we try to train residents. I will admit that the aortic root is a part of the chest that is particularly good for teaching. It is one of the few complex operations, where both the surgeon and the assistant can see well, and I think this helps a great deal. But thank you very much for your kind words.

	Acknowledgments

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This study was supported in part by the Dana and Albert "Cubby" Broccoli Center for Aortic Diseases, the Mildred and Carmont Blitz Cardiac Research Fund, The Joyce Koons Family Cardiac Endowment Fund, and the Smilow Family Foundation. Doctors Lois Nwakanma and Brian Bethea are Hugh R. Sharp, Jr. Research Fellows, and Drs Eric Weiss, Jason Williams, and Torin Fitton are Irene Piccinini Investigators.

	References

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1. Bentall HH, DeBono A. A technique for complete replacement of the ascending aorta Thorax 1968;23:338-339.[Abstract/Free Full Text]
2. Murdock JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome N Engl J Med 1972;286:804-808.[Medline]
3. Gott VL, Pyeritz RE, Cameron DE, et al. Composite graft repair of Marfan aneurysm of the ascending aorta Ann Thoracic Surg 1991;52:38-45.[Abstract]
4. Gott VL, Cameron DE, Pyeritz RE, et al. Composite graft repair of Marfan aneurysm of the ascending aorta: results in 150 patients J Card Surg 1994;9:482-489.[Medline]
5. Sarsan MAI, Yacoub M. Remodeling of the aortic valve annulus J Thorac Cardiovasc Surg 1993;105:435-438.[Abstract]
6. David TE, Feirdel CM. An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta J Thorac Cardiovasc Surg 1992;103:617-622.[Abstract]
7. De Paulis R, De Matteis GM, Nardi P, et al. A new aortic Dacron conduit for surgical treatment of aortic root pathology Ital Heart J 2000;1:457-463.[Medline]
8. De Paulis R, DeMatteis GM, Nardi P, et al. One-year appraisal of a new aortic root conduit with sinuses of Valsalva J Thorac Cardiovasc Surg 2002;123:33-39.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Duke E. Cameron Diane E. Alejo Nishant D. Patel Lois U. Nwakanma Luca A. Vricella Jason A. Williams Brian T. Bethea Torin P. Fitton Vincent L. Gott Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cameron, D. E. Articles by Gott, V. L. Search for Related Content PubMed Articles by Cameron, D. E. Articles by Gott, V. L. Related Collections Great vessels