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Ann Thorac Surg 2007;83:1067-1074
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Are Marfan Syndrome and Marfanoid Patients Distinguishable on Long-Term Follow-Up?

Lars G. Svensson, MD, PhDa,*, Eugene H. Blackstone, MDa,b, Jingyuan Feng, MSb, Daniel de Oliveira, MDa, A. Marc Gillinov, MDa, Maran Thamilarasan, MDc, Richard A. Grimm, DOc, Brian Griffin, MDc, Donald Hammer, MDc, Timothy Williams, MDc, Deborah H. Gladish, BAa, Bruce W. Lytle, MDa

a Center for Aortic Surgery, Marfan Syndrome, and Connective Tissue Disorders Clinic, Cleveland, Ohio
b Departments of Thoracic and Cardiovascular Surgery, Quantitative Health Sciences, The Cleveland Clinic, Cleveland, Ohio
c Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio

Accepted for publication October 23, 2006.

* Address correspondence to Dr Svensson, Center for Aortic Surgery, Marfan Syndrome, and Connective Tissue Disorders Clinic, The Cleveland Clinic, 9500 Euclid Ave, Desk F24, Cleveland, OH 44195 (Email: svenssl{at}ccf.org).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: It is unclear whether late outcome differs for Marfan syndrome and marfanoid patients. Thus, we compared characteristics of Marfan versus marfanoid patients and their survival and requirement for reoperation.

Methods: From 1978 to October 2003, 162 patients with a presumptive diagnosis of Marfan syndrome underwent operation. We recategorized them as confirmed Marfan (n = 122), marfanoid (n = 23), Ehlers-Danlos syndrome (n = 5), or other (n = 12). Patients categorized as marfanoid failed to meet the major criteria of Marfan syndrome. We compared characteristics of Marfan and marfanoid groups and assessed long-term survival and need for reoperation.

Results: Marfan and marfanoid patients had similar demographics (women, 33% versus 39%; age, 39 ± 13 versus 41 ± 12 years; height, 186 ± 12 cm versus 184 ± 9.6 cm), valve pathophysiology (aortic regurgitation, 66% versus 58%; mitral regurgitation, 58% versus 62%), and aortic pathology (dilated, 40% versus 39%; dissected, 17% versus 13%). Overall hospital survival was 99.3% (144/145), and 10-year survival was similar at 82% in the Marfan and 100% in marfanoid groups (p = 0.13). Patients with aortic dissection (p = 0.001) and mitral valve replacement (p = 0.003) were at higher risk of death. Reoperation was more frequent after separate aortic valve–ascending aorta graft operations (p = 0.04), and among taller patients (p = 0.005). Of 24 Marfan patients with David root reimplantations, none has required reoperation.

Conclusions: Marfan and marfanoid patients have similar physical characteristics and postoperative survival, although reoperation was more frequent in Marfan patients. Surgery before occurrence of aortic dissection or mitral valve repair should reduce the risk of reoperation, but taller patients, irrespective of Marfan or gender, are more likely to require reoperation.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Patients with Marfan syndrome must meet at least four broad diagnostic criteria to be classified as such: aortic involvement, dislocated eye lens, family history of Marfan syndrome, and marfanoid musculoskeletal body habitus [1–3]. Many patients with an aortic root aneurysm have a marfanoid appearance but do not meet those criteria. This may be because they are young and have not yet developed eye complications or because a detailed family history is not available; for example, because of adoption [1–27].

The objective of this study was to compare patient and clinical characteristics of true Marfan syndrome patients with those having a marfanoid appearance and to ascertain the association of these characteristics with long-term survival and risk of reoperation.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Between 1978 and October 2003, 162 patients with a presumptive diagnosis of Marfan syndrome who had undergone ascending or aortic arch surgery, or both, were identified from surgical registries, clinical records, and databases used for tracking patients with this condition. We reviewed all hospital and follow-up records to categorize them, based on accepted criteria for diagnosing Marfan syndrome, as confirmed Marfan syndrome (n = 122), marfanoid not meeting Marfan criteria (n = 23), Ehlers-Danlos syndrome (n = 5), or other non-Marfan elastic tissue disorder (n = 12). For example, Erdheim root deformity occurs in patients without marfanoid appearance but is similar to that occurring in Marfan syndrome patients. Thus, marfanoid patients were defined as having an aortic root aneurysm and musculoskeletal features in keeping with Marfan syndrome but no family history of Marfan disease or ectopia lentis. Clearly, ectopia lentis may develop later in some patients or the criteria for Marfan syndrome may develop in their family members (eg, children) and thus change the status. None of the patients underwent DNA testing at our institution for a FBN1 mutation.

Clinical and demographic data were collected for 218 variables (185 categoric, 33 continuous) and entered into a database for analyses (Tables 1 and 2). Use of existing and created databases and patient follow-up for this study were approved by the Institutional Review Board. Follow-up questionnaires were sent to patients and families, and nonresponders were interviewed by telephone. Follow-up was 98% complete, with 3 patients lost to follow-up.


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  		Table 1 Comparison of Marfan and Marfanoid Patients: Continuous Variables
 
Statistical Analyses
Group comparisons
Only Marfan syndrome and marfanoid patients were compared, because the other groups were small in number. A propensity model was developed using logistic regression, and a propensity score for Marfan syndrome was calculated for each patient [28, 29]. Adjustment of outcomes by propensity score did not change the results, however, so data are presented without this adjustment.

Multivariable analysis
For time-related outcomes (survival, reoperation), nonparametric estimates were obtained by the Kaplan-Meier method [30]. A parametric method was used to resolve the number of phases of instantaneous risk of each outcome (hazard function) and to estimate their shaping variables [31]. Thereafter, multivariable analyses were performed in the hazard function domain using the demographic, clinical, and operative variables, which are summarized in Tables 1 and 2. Risk factors were identified by bootstrap bagging [32], with automated analyses of 500 resampling data sets, using an inclusion criteria of p < 0.05. This was followed by tabulation of frequency of occurrence of both single factors and closely related clusters of factors. Variables appearing in 50% or more analyses were considered reliable risk factors.

Presentation
Proportions are presented with 68% confidence limits (CL) equivalent to one standard error.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Marfan Syndrome and Marfanoid Distinctions
The only demographic and clinical differences between characteristics of Marfan syndrome and marfanoid patients were that Marfan patients were less likely to have had either a minimally invasive J incision (4.9% versus 22%, p = 0.016), probably because of pectus deformity, or posterior-to-anterior chordal transfers during mitral valve repair (2.5% versus 13%, p = 0.05; Tables 1 and 2).

Hospital Survival
Overall hospital survival was 99.3% (144/145), with one death (1/122) in the Marfan syndrome group from pericarditis (0.8%, 68% CL, 0.1% to 2.7%) and none (0/23) in the marfanoid group (68% CL, 0% to 8.1%; p = 0.99). Other postoperative in-hospital events are listed in Table 3.


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  		Table 3 Postoperative In-Hospital Events
 
Time-Related Survival
Overall time-related survival (including the hospital death) was 98%, 96%, 92%, 89%, 85%, and 82% at 1, 2, 4, 6, 8, and 10 years, respectively, with risk of death constant at 2% per year (68% CL, 1.5% to 2.6%). Survival in the Marfan syndrome group was 98%, 96%, 92%, 88%, 85%, and 81% at 1, 2, 4, 6, 8, and 10 years, respectively, and no deaths occurred in the marfanoid group (log rank p = 0.13; Fig 1).


Figure 1
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  		Fig 1. Comparison of survival for Marfan syndrome (lower line) and marfanoid patients (upper line). Each circle represents a death and is positioned according to the Kaplan-Meier estimator. The range bars represent asymmetric 68% confidence limits equivalent to ± one standard error). Solid lines represent parametric estimates included within 68% confidence limits (dashed lines). Numbers in parentheses are patients remaining at risk.

 
Heart failure from mitral valve disease and aortic dissection were the most common modes of death in Marfan syndrome patients (5/12 with known modes; (Table 4, Table 5). Multivariable analyses (Table 2) showed that patients with aortic dissection (Fig 2) and those with mitral valve replacement had a higher risk of death. Because no deaths occurred in the marfanoid group, it was not possible to evaluate reliably the effect of Marfan versus marfanoid features on survival.


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  		Table 4 Modes of Death
 

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  		Table 5 Risk Factors for Death
 

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  		Table 2 Comparison of Marfan and Marfanoid Patients: Categoric Variables
 

Figure 2
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  		Fig 2. Survival according to aortic dissection. Each clear circle represents a death and is positioned according to the Kaplan-Meier estimator. The range bars represent asymmetric 68% confidence limits equivalent to ± one standard error. Solid lines (top, no; bottom, yes) represent parametric estimates included within 68% confidence limits (dashed line). Numbers in parentheses are patients remaining at risk.

 
Reoperation
Overall freedom from reoperation was 89%, 87%, 84%, 80%, 75%, and 70% at 1, 2, 4, 6, 8, and 10 years, respectively. Risk of reoperation was highest immediately after surgery and fell to a low level at about a 1.5 years. However, early risk of reoperation was entirely confined to the Marfan group. Freedom from reoperation was 86%, 83%, 79%, 76%, 72%, and 66% at 1, 2, 4, 6, 8, and 10 years, respectively, for the Marfan group, compared with 100%, 99%, 97%, 93%, 87%, and 81% for the marfanoid group (log-rank p = 0.009; Fig 3).


Figure 3
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  		Fig 3. Freedom from reoperation according to Marfan syndrome (lower solid line) or marfanoid diagnosis (upper solid line). Each circle represents a death and is positioned according to the Kaplan-Meier estimator. The range bars represent asymmetric 68% confidence limits equivalent to ± one standard error. Solid lines represent parametric estimates included within 68% confidence limits (dashed lines). Numbers in parentheses are patients remaining at risk.

 
The most common indication for aortic valve reoperation was a failed aortic procedure; for mitral valve reoperation, progression of disease; and for aortic procedures, new site of aneurysm or dissection (Table 6). By multivariable analyses, Marfan patients (Fig 3) and those with preoperative atrial fibrillation or a separate valve and ascending aorta graft had the highest risk of early reoperation, and taller patients had a higher risk of late reoperation (Table 7). Mean height was 186 ± 12 cm for Marfan patients and 184 ± 9.6 cm for marfanoid patients.


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  		Table 6 Indications for Reoperation
 

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  		Table 7 Risk Factors for Reoperation
 
There was no obvious reason why preoperative atrial fibrillation was a risk factor, other than that 3 of the 5 patients with atrial fibrillation also had mitral valve disease. Both patients requiring reoperation after root-sparing procedures had undergone previous root remodeling. None of the 24 Marfan patients with a modified David reimplantation has required reoperation.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Marfan Syndrome and Marfanoid Distinctions
We found no demographic or clinical differences between Marfan syndrome and marfanoid patients. Our study, however, showed that when patients are properly categorized as having either Marfan syndrome or marfanoid appearance, according to accepted criteria and more recent modification thereof [3], this distinction is associated with risk of reoperation. Furthermore, patient height, not included as a specific criterion for Marfan syndrome but recognized as an important indicator, was found to influence risk of reoperation. Most patients with Marfan syndrome are taller than 187 cm (6 feet, 2 inches); however, this must be viewed in the clinical context of kyphoscoliosis resulting in patients inaccurately appearing to be shorter and women also being shorter on average. Nevertheless, the mean height of our Marfan patients was 186 cm, and of marfanoid patients, 183 cm. It may be that patients taller than about 190 cm display a more severe form of connective tissue disorder that makes them more prone to tissue failure and reoperation (Fig 4).


Figure 4
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  		Fig 4. Freedom from reoperation according to patient height. This is a nomogram based on the multivariable analysis presented in Table 2 with both preoperative atrial fibrillation and separate aortic valve surgery and ascending aorta graft set to "no." Solid line represents a parametric estimate included within 68% confidence limits (dashed lines).

 
In contrast, the distinction of Marfan syndrome or marfanoid was not associated with difference in long-term survival, perhaps because the study had insufficient statistical power for long-term follow-up comparison. Although survival was 100% in marfanoid patients, follow-up is still needed because of reoperations, the possibility that statistical power was inadequate, or a positive diagnosis of Marfan syndrome developing later.

Clinical categorization of patients as having either Marfan syndrome or a marfanoid appearance raises the complex issue of how to best manage each group. Ideally, a single blood test and polymerase chain reaction analysis of genes or fibrillin-1 fragment would have defined which patients had Marfan syndrome. Genetic research, however, has found at least 400 different associated gene mutations on chromosome 15 and some on chromosome 5, and most of these are unique to each family pedigree. Thus, to identify who has Marfan syndrome within a family pedigree—if the gene mutation can be found—the entire family must be analyzed, at considerable cost.

This research has also shown that there is a wide spectrum of severity and penetration of these mutations within families. There is a wide range of elastic tissue abnormalities. Furthermore, some pedigrees have more severe forms than others. Complicating genetic analysis of clinical disorders affecting the aorta, including Marfan syndrome, are several other disorders that affect elastic tissue in the aorta, such as Williams syndrome, polycystic kidney disease, and bicuspid aortic valves. Obtaining complete family histories or blood samples from other family members may also be impossible because of index patients being adopted or parents dying at a young age without adequate documentation of Marfan syndrome.

Marfanoid Patients
Although the prognosis of patients with Marfan syndrome has been studied extensively through long-term follow-up, our data suggest that marfanoid patients, particularly those with aortic dissection, important mitral valve disease, atrial fibrillation, or tall stature, should also be monitored carefully long-term. Many may be recategorized over time as having Marfan syndrome. For example, a patient may be initially categorized as marfanoid, but eye problems may develop later or the patient may have marfanoid-appearing children or a child with aortic complications. These may allow a sufficient number of criteria to be met to reclassify the patient as Marfan.

Cardiac Surgery
This study covers a period of considerable evolution in the medical and operative management of Marfan syndrome [2, 4–11, 13–17, 20, 22, 33–41]. Thus, earlier surgery for mitral valve regurgitation is now associated with both a higher frequency and likelihood of success of mitral valve repair [6]. A Maze procedure can also be added for atrial fibrillation. The importance of this is that survival may be improved and morbidity and risk of reoperation reduced by modern procedures.

Aortic Surgery
For combined aortic valve, aortic root, and ascending aorta pathology, separate aortic valve and ascending graft procedures have been abandoned in favor of composite mechanical valves and ascending grafts (Bentall procedure). However, the classic Bentall method, in which coronary artery buttons are attached directly to the graft, is associated with false aneurysm development in Marfan patients [5, 15]. Although composite valve grafts with free coronary buttons have thus proven durable, the need for anticoagulation and risk of bleeding are drawbacks. The risk of endocarditis or graft infection is also higher than for isolated aortic valve replacement [5, 15].

Modified David Reimplantation
At The Cleveland Clinic, we have therefore switched to performing aortic valve and aortic root-sparing procedures rather than inserting composite grafts [6, 38, 41]. Aortic root-sparing procedures, also sometimes called root-preserving procedures, are mostly categorized as either root remodeling or David reimplantation operations. For remodeling operations, cuts are made in a tube graft to accommodate the commissures as the graft is sewed to the anulus. For David reimplantation, or modifications thereof, the entire aortic valve is mobilized and then reimplanted within the tube graft [17, 38, 39, 41].

In our recently updated series of 388 such root-sparing repairs, including 39 patients with Marfan syndrome, no Marfan syndrome patient who had a modified David-type aortic valve reimplantation (n = 24) has required reoperation to date. The Toronto group [41] similarly reported that in a series of 39 reimplantation and root-sparing procedures, freedom from reoperation was 100% at 10 years for valve-sparing procedures versus 75% for valve replacement. Freedom from embolization was 100% for root sparing versus 65% for replacements, and survival was 90% versus 87%. By echocardiography, valve reimplantation was also associated with a better outcome compared with root remodeling, probably by preventing root dilatation. Thus, this approach has been adopted and used by others [16, 17, 39].

Timing of Surgery
Timing of cardiac surgery for patients with Marfan syndrome has also changed. Patients who meet the usual criteria for surgery—heart failure symptoms or ventricular dysfunction related to mitral or aortic valve regurgitation—should undergo surgery. Surgery is being increasingly recommended for patients with aortic root dilatation at a smaller aortic diameter than previously. Based on a study of the risk of aortic dissection in 103 patients with Marfan syndrome, we have recommended that surgery is indicated when the ratio of a patient’s aortic cross-sectional area (cm2) divided by the patient’s height (m) exceeds 10 [7]. The same holds true for patients with bicuspid aortic valves and dilated aortas [36]. Echocardiographic studies by the Framingham group showed that height correlates better with aortic root diameter than does body surface area [34, 35]. Older recommendations based on aortic ratios, absolute size, or body surface area had drawbacks. For example, 15% of patients dissect at an aortic size of less than 5 cm [7, 10], and patients with Marfan syndrome may have an increased body mass index, as in this study.

Further reasons for use of this recent criterion are as follows:

• There is an exponential risk of dissection according to aortic diameter [7, 36].
• Use of this ratio for timing surgery takes into account the greater risk of dissection in shorter patients with a given aortic cross-sectional area.
• If the patient survives the initial dissection (immediate risk of death is 40% and 3% per hour thereafter), surgery carries an operative mortality of 10% to 20%, and long-term survival is severely curtailed, with a 5-year survival of only 50% [8, 10, 15].
• Surgery in this population before acute dissection is safe; overall hospital survival in this study was 99.3% (hospital survival was 99.5% for our total series of 221 Marfan syndrome patients).
• Long-term survival is improved with earlier surgery [1, 4–17, 38, 39, 41].
• Better operations are now available; in particular, preservation of the aortic valve can be accomplished in 90% of patients undergoing early surgery, and mitral valve repair results have also improved.

Strengths and Limitations
A limitation of this study is that it is a clinical cohort study covering a long period. Nevertheless, it documents the difference between Marfan syndrome and marfanoid patients, benefits of newer operative approaches, and importance of long-term, diligent follow-up, particularly of patients with mitral valve replacement, atrial fibrillation, aortic dissection, and tall stature.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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