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Ann Thorac Surg 2007;83:1691-1695
© 2007 The Society of Thoracic Surgeons
a Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
b Institute of Medical Immunology, Charité University Medicine Berlin, Berlin, Germany
Accepted for publication January 11, 2007.
* Address correspondence to Dr Knosalla, Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, D-13353 Berlin, Germany (Email: knosalla{at}dhzb.de).
Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30 – Feb 1, 2006.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Methods: Ten patients with Marfan syndrome (median age 36, range 19 to 56 years) underwent HTx between March 1986 and December 2005. The primary vascular manifestation of Marfan syndrome was type-A aortic dissection in three patients and ascending aortic aneurysm in seven patients. All patients had undergone cardiovascular operations prior to transplantation. All had refractory heart failure (New York Heart Association class IV) before transplantation. Three patients underwent transplantation after ventricular assist device (VAD) support (left VAD, n = 2; biventricular assist device, n = 1).
Results: There were no perioperative deaths. Two patients died of causes unrelated to Marfan disease (pneumonia on day 27, n = 1; stroke on day 102, n = 1). One patient died due to type-B dissection 3.8 years posttransplantation and one due to rupture of an aortic arch aneurysm after 12.1 years. Two patients underwent thoracoabdominal aortic replacement for chronic dissection 14 and 20 months posttransplantation, respectively. Kaplan-Meier survival rate was 80% at 1 year and 64% at 10 years. The Kaplan-Meier freedom from reoperation was 100% at 1 year and 62.5% at 10 years.
Conclusions: Heart transplantation in patients with Marfan syndrome results in good long-term survival, similar to that of patients without Marfan syndrome. Close follow-up and timely operation of aortic pathologies is mandatory. Reluctance to place these patients on a heart transplant waiting list appears not to be justified.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Patients with a form fruste of the syndrome or related connective-tissue disorders were not included in this study, nor was one patient who is currently still waiting with a CardioWest total artificial heart (SynCardia Systems, Inc, Tucson, AZ) for an appropriate donor heart. There were seven men and three women with a median age of 36 years (range, 19 to 56 years) (Table 1). The primary vascular manifestation of Marfan syndrome was type-A aortic dissection in three patients, ascending aortic aneurysm in six, and an ascending aortic aneurysm in combination with type-B aortic dissection in one (Fig 1). All patients had undergone cardiovascular operations prior to transplantation with a mean of 2.4 procedures per patient (range, 1 to 5): ascending aortic replacement (n = 9) with two redo operations; mitral valve replacement or repair (n = 5); aortic (hemi-) arch replacement (n = 2); descending aortic replacement (n = 2); thoracoabdominal aortic replacement (n = 2); and fenestration of type-B dissection (n = 1). All had refractory heart failure (New York Heart Association class IV) before transplantation. Three patients underwent transplantation after mechanical circulatory support with the Berlin Heart Excor (Berlin Heart AG, Berlin, Germany) (as left ventricular assist device, n = 2; biventricular assist device, n = 1). One patient with terminal heart failure and chronic type-B aortic dissection, who had a history of multiple aortic and cardiac procedures and underwent combined aortic surgery and implantation of a left ventricular assist device, has been reported on previously [10]. The waiting interval for transplantation was between 1 and 398 days (median, 29.5 days); there were no deaths on the waiting list. Organs were procured using standard technique allowing excess length of the donor aorta in order to reconstruct the ascending aorta and, if required, the proximal part of the aortic arch of the recipient after ascending aortic replacement without the use of any prosthetic material. Orthotopic implantation of the donor heart was carried out using the Lower and Shumway technique modified by Cooley and Barnard [11]. In two cases deep hypothermia with circulatory arrest and selective retrograde cerebral perfusion was required to replace the ascending aorta and the proximal aortic arch.
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3,500/µL) or azathioprine (1 to 5 mg/kg; white blood cell count not 3,500/µL). All patients received prednisolone in a tapering regimen with a target dose of 0.15 mg/kg after two months. Follow-up of aortic pathologies were performed by computer tomography with contrast enhancement and transthoracic echocardiography every six months.
Morbidity and Mortality
The timing and cause of complications and death were identified. Early death was defined as death before discharge from hospital.
Statistical Methods
Survival and event-free survival curves were calculated by the Kaplan-Meier method. Data were analyzed using SPSS for Windows, version 11.01 (SPSS Inc, Chicago, IL).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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The pathogenesis of left ventricular dysfunction in patients with Marfan syndrome remains elusive [13]. Impairment of left ventricular function may occur as a consequence of long-standing valvular disease, but recent evidence suggests that it may also occur in the absence of valvular pathology, as expressed by increased left ventricular diameters in a small subset of patients [14, 15]. Although all our patients had aortic valve disease, some in combination with mitral valve regurgitation, factors independent of valvular disease may have contributed to the progression of congestive heart failure.
Structural and functional abnormalities of the fibrillin-1 protein, as a result of the fibrillin-1 gene defect in Marfan patients, are likely to play a role in the observed myocardial dysfunction. Fibrillin-1 is a major protein component of extracellular matrix fibrils known as microfibrils. These are found primarily around the periphery of the amorphous elastin component of the elastic fibers [16]. Elastin has been shown to be important in mediating elastic recoil. Immunohistochemical studies of the myocardium with an anti-fibrillin-1 antibody showed that microfibrils form myofiber-collagen fiber linkages at sites where the power of myocardial contraction is transmitted to the extracellular connective tissue framework in the myocardium [17]. Mutations in the fibrillin-1 gene may cause structural and (or) functional abnormalities in the microfibrils, leading to impairment of myocardial contraction. Another pathway through which fibrillin-1 may interfere with myocardial function is the complex transforming growth factor-ß (TGF-ß) signaling process. This may be through a recently described mutation of the TGF-ß receptor type 2 [18]. Recent studies have also suggested that the amount of fibrillin-1 in the matrix may be one determinant of the reservoir for TGF-ß [2]. The elevated TGF-ß 1gene expression has been measured in ventricular biopsies from patients with hypertrophic or dilated cardiomyopathy [19, 20]; Leucin
Prolin (Leu10Pro) polymorphism in the TGF-ß 1 gene is associated with end-stage heart failure in dilated cardiomyopathy [21]. The linkage of these pathways to Marfan syndrome, however, still needs to be formally demonstrated.
The indication for heart transplantation in Marfan patients is a matter of debate. As stated above, many centers may refuse these patients because of concerns about future cardiovascular complications. On the basis of our experience reported here, we do not consider this reluctance to place Marfan patients on the waiting list for heart transplantation to be justified. The capacity of the transplanting center for appropriate surveillance and management of the vascular complications associated with the disease is important to obtain optimal results after transplantation. Marfan patients should therefore be referred to centers with extensive experience in both heart transplantation and surgery of the thoracic-abdominal aorta.
A particular clinical problem is the combination of a symptomatic aneurysm of the thoracic aorta and end-stage heart failure prior to transplantation. In a case published by our group, combined aortic surgery and implantation of a left ventricular assist device were successful in bridging the patient until heart transplantation 217 days later [10]. Two further patients have been successfully bridged to transplantation using an extracorporeal assist device system.
In terms of long-term survival, the International Society for Heart and Lung Transplantation registry reports 1-year and 10-year survival rates for adult heart transplantation of 80% and 49%, respectively, with a survival half-life of 9.6 years and a conditional half-life of 12 years for those surviving the first year [22]. The number of patients reported in this study is too small for statistical comparison but it is encouraging to see that our Marfan patients were able to achieve as good results as were patients without Marfan syndrome.
The use of immunosuppressive therapy in patients with cardiovascular manifestations of Marfan syndrome is a matter of controversy, as hypertension induced by calcineurin inhibitors and the long-term steroid therapy may reduce the integrity of aortic connective tissue and thereby increase the risk of vascular complications. However, this factor may be less relevant given the relatively long half-life of arterial collagen [23]. All our Marfan patients who underwent heart transplantation received exactly the same immunosuppressive therapy as heart transplant recipients without Marfan syndrome. Blood pressure was closely monitored and hypertension was carefully treated with antihypertensive drugs. During the follow-up, one patient died due to rupture of an acute type-B dissection 3.8 years after heart transplantation. This patient had been followed at another center close to his home town. In all other patients, we saw no new onset of acute aortic dissection but we did see progression of aortic dilatation. Two patients required thoracoabdominal aortic repair 14 and 20 months after heart transplantation.
It is to be acknowledged that the current study has certain limitations. First, by its nature it is subject to the restrictions of a retrospective study. Second, the study cohort is relatively small. However, to the best of our knowledge this study presents the largest single center experience of heart transplantation in Marfan patients reported so far.
In conclusion, the results of this series show that heart transplantation can be performed in patients with Marfan syndrome with good long-term survival, similar to that of patients without Marfan syndrome. Close follow-up and timely operation of aortic pathologies is mandatory, as vascular complications can occur even late after primary aortic operation. Reluctance to place these patients on a heart transplant waiting list appears not to be justified.
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Acknowledgments |
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