The spectrum of syndromes and manifestations in individuals screened for suspected Marfan syndrome.

The diagnosis of Marfan syndrome (MFS) is based on evaluating a large number of clinical criteria. We have observed that many persons presenting in specialized centers for "Marfan-like" features do not have MFS, but exhibit a large spectrum of other syndromes. The spectrum of these syndromes and the distribution of "Marfan-like" features remain to be characterized. Thus, we prospectively evaluated 279 consecutive patients with suspected MFS (144 men and 135 women at a mean age of 34+/-13 years) for presence of 27 clinical criteria considered characteristic of MFS. The most frequent reasons to refer individuals for suspected MFS were skeletal features (31%), a family history of MFS, or aortic complications (29%), aortic dissection or aneurysm (19%), and eye manifestations (9%). Using established criteria, we confirmed MFS in 138 individuals (group 1) and diagnosed other connective tissue diseases, both with vascular involvement in 30 (group 2) and without vascular involvement in 39 (group 3), and excluded any distinct disease in 72 individuals (group 4). Clinical manifestations of MFS were present in all four patient groups and there was no single clinical criterion that exhibited positive and negative likelihood ratios that were per se sufficient to confirm or rule out MFS. We conclude that "Marfan-like" features are not exclusively indicative of MFS but also of numerous, alternative inherited diseases with many of them carrying a hitherto poorly defined cardiovascular risk. These alternative diseases require future study to characterize their responses to therapy and long-term prognosis.

FBN1 gene mutation characteristics and clinical features for the prediction of mitral valve disease progression.

BACKGROUND: Until today, FBN1 gene mutation characteristics were not compared with clinical features for the prediction of mitral valve disease progression. METHODS: Therefore, we conducted a study of 116 patients (53 men, 63 women aged 33 ± 15 years) with a causative FBN1 gene mutation and ≤ moderate mitral valve regurgitation at baseline. RESULTS: During 7.4 ± 6.8 years 30 patients developed progression of mitral valve regurgitation ≥ 1 grade (primary endpoint), and 26 patients required mitral valve surgery (secondary endpoint). Cox regression analysis identified an association of atrial fibrillation (hazard ratio (HR)=2.703; 95% confidence interval (CI) 1.013-7.211; P=.047), left ventricular ejection fraction (HR=.970; 95%CI .944-.997; P=.032), indexed end-diastolic left ventricular diameter (HR=15.165; 95%CI 4.498-51.128; P<.001), indexed left atrial diameter (HR=1.107; 95%CI 1.045-1.173; P=.001), tricuspid valve prolapse (HR=2.599; 95%CI 1.243-5.437; P=.011), posterior leaflet prolapse (HR=1.075; 95%CI 1.023-1.130; P=.009), and posterior leaflet thickening (HR=3.368; 95%CI 1.265-8.968; P=.015) with progression of mitral valve disease, whereas none of the FBN1 gene mutation characteristics were associated with progression of mitral valve disease. However, Cox regression analysis identified a marginal relationship of FBN1 gene mutations located both in a transforming-growth-factor beta-binding protein-like (TGFb-BP) domain (HR=3.453; 95%CI .982-12.143; P=.053), and in the calcium-binding epidermal growth factor-like (cbEGF) domain (HR=2.909; 95%CI .957-8.848; P=.060) with mitral valve surgery, a finding that was corroborated by Kaplan-Meier analysis (P=.014; and P=.041, respectively). CONCLUSION: Clinical features were better predictors of mitral valve disease progression than FBN1 gene mutation characteristics.

Ascending aortic aneurysm and aortic valve dysfunction in bicuspid aortic valve disease.

BACKGROUND: The relationship of aortic valve dysfunction and ascending aortic aneurysm is unclear in adults with bicuspid aortic valve disease. METHODS: We retrospectively studied 134 consecutive out-patients (98 men, 36 women aged 43 ± 18 years) with bicuspid aortic valve disease. To investigate the relationship of ascending aortic aneurysm and aortic valve dysfunction we exclusively considered severe pathologies that required treatment by surgical or percutaneous intervention. RESULTS: Of 134 patients, 39 had aortic valve dysfunction without concomitant ascending aortic aneurysm which had been treated previously with isolated valve surgery or percutaneous valvuloplasty comprising 25 patients with aortic stenosis (19%) and 14 patients with aortic regurgitation (10%). Conversely, 26 patients had ascending aortic aneurysm which had been treated previously with aortic surgery (19%). Of these, ascending aortic aneurysm was associated with severe aortic stenosis in 13 patients and with severe aortic regurgitation in 7 patients, whereas aneurysm was unrelated to severe aortic valve dysfunction in the remaining 6 patients including 2 without any degree of aortic valve dysfunction. The maximal aortic diameters were similar at the time of aortic surgery irrespective of presence of severe aortic valve dysfunction (P=.527). Other characteristics of patients with ascending aortic aneurysm were also similar irrespective of presence or type of aortic valve dysfunction. CONCLUSION: The majority of patients with bicuspid aortic valve disease exhibit ascending aortic aneurysm in conjunction with severe aortic valve dysfunction. However, in our study 6 of 134 (5%) of persons with bicuspid aortic valve disease developed ascending aortic aneurysm without aortic valve dysfunction.

Comparison of aortic root replacement in patients with Marfan syndrome.

OBJECTIVES: Although the aortic-valve-sparing (AVS) reimplantation technique according to David has shown favorable durability results in mid-term and long-term studies, composite valve grafting (CVG) according to Bentall is still considered the standard procedure. METHODS: Retrospectively, we evaluated the results of aortic root replacement of patients with Marfan syndrome (MFS) who underwent surgery between January 1995 and January 2010. MFS was diagnosed using the Ghent criteria. AVS was used in 58 patients and CVG in 30 patients with MFS. AVS was done for aortic-root aneurysm (n=48) or aortic dissection type A (n=10). CVG was used for aortic-root aneurysm in 14 patients or aortic dissection type A in 16 patients. The mean follow-up was 3.2 (95% CI: 2.4-4.2) years. RESULTS: In both groups, 30-day mortality was 0%. Three patients (10.0%) in the CVG group required resternotomy for postoperative bleeding versus two patients (3.4%) in the AVS group (p=0.3). At follow-up, mortality was 10% in the CVG group versus 3.4% in the AVS group (p=0.3). Re-operation was required in two patients (3.4%) after AVS and in three patients after CVG (10%) (p=0.3). Three patients (10.0%) who underwent CVG had endocarditis and two patients (6.7%) had a stroke during follow-up, whereas no endocarditis and stroke occurred after AVS. After 14 years, stratified event-free survival was better in the AVS group (event-free survival was 82.3% vs 58.6%, log-rank test p=0.086), especially after aneurysm (p=0.057). After 10 years, freedom from aortic regurgitation ≥II° in the AVS group was 80% for aneurysm and 50% after dissection (p=0.524). CONCLUSION: The reimplantation technique according to David was associated with excellent survival, good valve function and a low rate of re-operation, endocarditis, and stroke. There was a trend to better event-free survival for AVS patients making it the procedure of choice in MFS patients.

Predictors of outcome of mitral valve prolapse in patients with the Marfan syndrome.

Mitral valve prolapse has a prevalence of 2% to 3% in the general population, with adverse outcomes such as mitral valve regurgitation (MVR), heart failure, and endocarditis. Predictors of outcomes are used in idiopathic mitral valve prolapse for the timing of surgery, but such predictors are unknown in Marfan syndrome. Therefore, a population-based cohort study of 112 patients (49 male, 63 female; mean age 34 ± 15 years) with classic Marfan syndrome and mitral valve prolapse with moderate or less MVR at baseline was conducted. During 4.6 ± 3.6 years of follow-up, progression of MVR was observed in 41 patients and valve-related events, which comprised mitral valve endocarditis (7 events), heart failure (5 events), and mitral valve surgery (25 events), were observed in 31 patients. Multivariate Cox proportional-hazards regression analysis identified a flail mitral leaflet (hazard ratio [HR] 3.262, 95% confidence interval [CI] 1.406 to 7.566, p = 0.006) and increased indexed end-systolic left ventricular diameters (HR 1.113, 95% CI 1.043 to 1.188, p = 0.001) as independent predictors of progression of MVR. Similarly, mitral valve-related events were independently predicted by a flail mitral leaflet (HR 5.343, 95% CI 2.229 to 12.808, p <0.001), and mild (HR 14.336, 95% CI 1.873 to 109.755, p = 0.01) or moderate (HR 16.849, 95% CI 2.205 to 128.76, p = 0.006) degree of MVR. Conversely, aortic dilatation, dural ectasia, and sporadic mode of inheritance were not associated with outcome. In conclusion, the same clinical determinants that predict outcomes in idiopathic mitral valve prolapse also predict outcomes in mitral valve prolapse associated with Marfan syndrome.

[Analysis of costs and profits of ambulatory care of Marfan patients after initiation of a novel German legal directive (116 b SGB V)]. / Analyse der Erlössituation bei der ambulanten Behandlung nach 116 b SGB V am Beispiel des Marfan-Syndroms.

BACKGROUND: The Marfan syndrome is a typical rare disease with multiorgan involvement and the need for specialized interdisciplinary medical care. A novel German legal directive according to section sign 116 b of the Social Statutes Book V (116 b SGB V) improves options for reimbursement and thus encourages specialized hospitals to provide ambulatory care for rare diseases such as Marfan syndrome. The authors provide the first economic analysis of section sign 116 b in a German Marfan center. METHODS: The costs were assessed in 184 cases with Marfan syndrome receiving medical care in the Hamburg Marfan Clinic. The authors assessed the financial profit both according to payments received from invoices established according to the 116 b directive [reimbursement (116b)] and from calculations according to section sign 117 SGB V [reimbursement (117)]. RESULTS: A total of 117 patients traveled to the Marfan clinic (64%) < 50 km, 27 patients (15%) between >or= 50 and 100 km. The total costs for ambulatory care were 71,606.28 Euro. The reimbursement (116b) was 55,549.87 Euro and the reimbursement (117) was 11,776.00 Euro. CONCLUSION: Many patients accept long distances of traveling to receive specialized ambulatory medical care. However, for optimal patient management specialized centers need to cooperate intensively with local health care providers. The novel legal directive according to section sign 116 b has significantly improved reimbursement for Marfan centers and allows for improving the quality of medical care.

Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome.

Mitral valve (MV) prolapse (MVP) has a high prevalence of 2% to 3% in the general population and thus constitutes the most common cause of severe nonischemic MV regurgitation (MVR). MVP is also common in persons with the Marfan syndrome. However, to date, a large-scale population-based cohort study using modern echocardiographic techniques has not been performed, and the frequency of MVP and the relation of MV dysfunction and age have not been investigated. Therefore, we conducted a population-based cohort study of 204 patients (108 males and 96 females, aged 31.2 ± 16.4 years) with classic Marfan syndrome. We performed echocardiographic follow-up of 174 patients for a mean of 4.4 ± 4.3 years. On the initial or subsequent echocardiographic scan, MVP was present in 82 patients (40%), severe MVR in 25 (12%), and MV endocarditis in 5 patients (2.5%). At 30 years of age, the Weibull cumulative distribution was 42.6% (95% confidence interval [CI] 36% to 50%) for MVP, 56.5% (95% CI 49.3% to 64%) for MVR of any degree, 6.7% (95% CI 3.9% to 11.3%) for severe MVR, and 0.92% (95% CI 0.21% to 3.91%) for MV endocarditis. The cumulative hazard for severe MVR and MV endocarditis was estimated to increase with age. MVP was associated with dural ectasia (p = 0.01), ectopia lentis (p = 0.02), and skeletal involvement (p <0.001). Severe MVR was related to tricuspid valve prolapse (p = 0.002) and to the sporadic form of the Marfan syndrome (p = 0.006). In conclusion, MVP was comparatively frequent in patients with the Marfan syndrome and carries an increased risk of progression to severe MVR and endocarditis, especially in older adults.

Frequency of sleep apnea in adults with the Marfan syndrome.

Obstructive and central sleep apneas are treatable disorders, which contribute to cardiovascular morbidity in older adults. Younger adults with Marfan syndrome may also be at risk for sleep apnea, but the relation between cardiovascular complications and sleep apnea is unknown. We used MiniScreen8 portable monitoring devices for polygraphy in 68 consecutive adults with Marfan syndrome (33 men, 35 women, 41 +/- 14 years old) to investigate frequency of sleep apnea and its relation to cardiovascular morbidity. The apnea-hypopnea index (AHI) was 6 to 15/hour in 14 subjects (mild sleep apnea, 21%), and AHI was >15/hour in 7 subjects (moderate or severe sleep apnea, 10%). Among established risk factors for sleep apnea, only older age (Spearman rho = 0.35, p = 0.004) and body mass index (rho = 0.26, p = 0.03) were associated with increased AHI. Of all cases of apnea, 12 +/- 27 were obstructive, 11 +/- 25 central, and 3 +/- 9 mixed. AHI was associated with decreased left ventricular ejection fraction (rho = -0.33, p = 0.01), increased N-terminal pro-brain natriuretic peptide levels (rho = 0.35, p = 0.004), enlarged descending aortic diameters (rho = 0.44, p = 0.001), atrial fibrillation (phi = 0.43, p = 0.002), and mitral valve surgery (phi = 0.34, p = 0.02). Of these, left ventricular ejection fraction, N-terminal pro-brain natriuretic peptide levels, atrial fibrillation, and mitral valve surgery were associated with AHI independently of age and body mass index. We found similar associations with oxygen desaturation index. In conclusion, sleep apnea exhibits increased frequency in Marfan syndrome and is not predicted by classic risk factors. Obstructive and central sleep apneas may relate to cardiovascular disease variables.

Augmentation index relates to progression of aortic disease in adults with Marfan syndrome.

BACKGROUND: Noninvasive applanation tonometry (APT) is useful to assess aortic stiffness and pulse wave reflection. Moreover, APT can predict outcome in many conditions such as arterial hypertension. In this study, we test whether APT measurements relate to progression of aortic disease in Marfan syndrome (MFS). METHODS: We performed APT in 50 consecutive, medically treated adults with MFS (19 men and 31 women aged 32 +/- 13 years), who had not undergone previous cardiovascular surgery. During 22 +/- 16 months of follow-up, 26 of these patients developed progression of aortic disease, which we defined as progression of aortic root diameters >or=5 mm/annum (18 individuals), aortic surgery >or=3 months after APT (seven individuals), or onset of acute aortic dissection any time after APT (one individual). RESULTS: Univariate Cox regression analysis suggested an association of aortic disease progression with age (P = 0.001), total cholesterol levels (P = 0.04), aortic root diameter (P = 0.007), descending aorta diameter (P = 0.01), aortic root ratio (P = 0.02), and augmentation index (AIx@HR75; P < 0.006). Multivariate Cox regression analysis confirmed an independent impact on aortic disease progression exclusively for baseline aortic root diameters (hazard ratio = 1.347; 95% confidence interval (CI) 1.104-1.643; P = 0.003) and AIx@HR75 (hazard ratio = 1.246; 95% CI 1.029-1.508; P = 0.02). In addition, Kaplan-Meier survival curve analysis illustrated significantly lower rates of aortic root disease progression both with lower AIx@HR75 (P = 0.025) and with lower pulse wave velocity (PWV) values (P = 0.027). CONCLUSIONS: We provide evidence that APT parameters relate to aortic disease progression in medically treated patients with MFS. We believe that APT has a potential to improve risk stratification in the clinical management of MFS patients.