Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy (original) (raw)
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Determinants of rapid progression of aortic root dilatation and complications in Marfan syndrome
International Journal of Cardiology, 2006
Background: Progressive aortic dilatation has prognostic significance in the Marfan syndrome. Methods: To identify which patients were at high risk of rapid progression, we echocardiographically studied 43 patients (age 22 F 14 years) with the mean follow-up period of 5.2 F 3.2 years. Aortic diameters, left ventricular (LV) size, fractional shortening, and the severity of aortic and mitral regurgitation were assessed. Transmitral peak early and atrial flow velocities, their ratio and the deceleration time of peak early velocity were also obtained. Results: Mean annual increases of aortic diameters were 0.4 F 0.3 mm at the annulus, 1.5 F 1.3 mm at the sinuses of Valsalva, 0.7 F 0.6 mm at the supraaortic ridge and 0.4 F 0.4 mm at the proximal ascending aorta. Patients were divided into 2 groups according to the aortic growth rate at the sinuses of Valsalva level: rapid (R, N 3% per year, 15 patients) or slow (S, V3% per year, 28 patients) progression groups. Measured variables did not show significant differences between the 2 groups except older age, higher blood pressure and more severe aortic regurgitation in group R. Multiple regression analysis identified prolonged deceleration time as the most important variable predicting aortic complications. Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, Pb0.001). Conclusions: Marfan patients at older age, with higher blood pressure, and with significant aortic regurgitation were at high risk of progression of aortic dilatation, with the most remarkable increase at the sinuses of Valsalva. Prolonged deceleration time may relate to an increased risk for aortic complications. D
2009
Background The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-b (TGF-b), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-b blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-b effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. b-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation b-adrenergic blocker nebivolol retains the b-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS. Methods The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score >-2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-b, quantitative assessment of the expression of the mutated gene (FBN1, both 5 0 and 3 0), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48. Conclusion The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding b-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability. J Cardiovasc Med 10:354-362 Q 2009 Italian Federation of Cardiology.
Marfan Syndrome—Diagnosis and Management
Current Problems in Cardiology, 2008
Marfan syndrome (MFS) is the most common inherited disorder of connective tissue that affects multiple organ systems. This autosomal-dominant condition has an incidence of 2-3 per 10,000 individuals. Although genetic testing is available, the diagnosis is still primarily made using the Ghent criteria. Early identification and appropriate management is critical for patients with MFS who are prone to the lifethreatening cardiovascular complications of aortic dissection and rupture. Advances in the understanding of the cause of MFS, early recognition of the disorder, and subsequent institution of medical and surgical therapy has resulted in dramatic improvement in the prognosis of this patient population over the past few decades. Beta-blockers have been demonstrated to slow aortic growth and thus delay the time to aortic surgery. Operative intervention has markedly changed the prognosis of patients with MFS and can be safely performed on an elective basis. Identification of presymptomatic patients is critical to reduce the frequency of catastrophic aortic events. (Curr Probl Cardiol 2008;33:7-39.)
Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome
Journal of the American College of Cardiology, 1993
was localized in 2S% and generalized in 51%. Aortic compika. tions occurred during follow-up in none of 23 patients with normal initial aortic size, in 2 (656) of 32 patients with initially localized dilation end in 19 (33%) of 58 patients with generated dilation (p < 0.0005), Complications were associated with larger initial aortic sine (p < 0 .00005), higher systolic blood pressure (p < 0.005), height (p < 0 .05), aortic growth rate (p c 0.05) and older age (p < 0.01). The Only independent predictor of Sortie complications was initial aortic root sine (p < 0.006). However, when aortic size, one of the indications for surgical referral, was excluded from analyses, the only independent predictor of aortic complications was generalized aortic dilation (p < 0 .005). Couciustorts. The present study indicates that generalized ortic root dila ion is a potent marker of m Increased risk for subsequent aortic complications in Marfm syndrome. (J Am Cog CardoI 1993;22:1470-6) phy and dysfunction in those patients with generalized aortic dilation (extending from the sinuses of Valsalva into the supraaortic ridge and proximal ascending aorta) than in those with localized dilation (confined to the sinuses of Valsalva) (11). Preliminary observations in 51 adult patients with the Marfan syndrome indicated that localized dilation may be associated with a more benign prognosis (12). This report extends these observations to a larger series of patients with a longer duration of follow-up. Methods Study group. The study group comprised 113 consecutive patients with the Marian syt :drums who were evaluated at the New York Hospital-Cornell Medical Center and followed-up for an average of 49 } 24 months. Patients were studied under a protocol approved by the Committee on Human Rights in Research in 1979 and at regular intervals thereafter. The diagnosis of the Marfan syndrome was established in all patients adhering to established diagnostic criteria (13). Patients who had undergone proximal aortic surgery before the initial evaluation or who had no follow-up information available were excluded from analysis. There were 84 adults and 29 children and adolescents (age <16 years in girls and < 18 years in boys), with an average age at 0733-1077.9315bAD brought to you by CORE View metadata, citation and similar papers at core.ac.uk
The Marfan syndrome and the cardiovascular surgeon
European Journal of Cardio-Thoracic Surgery, 1996
The authors present the current status of surgery for the cardiovascular manifestations of the Marfan syndrome. In addition, a brief review of current Marfan genetic research is presented. Data on all Marfan patients undergoing aortic root replacement at the Johns Hopkins Hospital (September 1976-June 1995) were analyzed. Survival and event-free curves were calculated and risk factors for early and late death were determined by univariate and multivariate analysis. Two hundred twelve Marfan patients underwent aortic root replacement using composite graft (202), homograft (8) or valve-sparing procedures (2). One hundred eighty-five patients underwent elective repair with no 30-day mortality. Twenty-seven patients underwent urgent surgery, primarily for acute dissection; two patients with aortic rupture died in the operating room. Actuarial survival of the 212 patients was 88% at 5 years, 78% at 10 years and 71% at 14 years. By multivariate analysis, only poor NYHA class, male gender and urgent surgery emerged as significant independent predictors of early or late mortality. Histologic examination of excised Marfan aortic leaflets by immunofluorescent staining for fibrillin showed fragmentation of elastin-associated microfibrils. These studies suggest cautious use of valve-sparing procedures in Marfan patients. Over the last 5 years significant progress has been made in identifying mutant genes that code for defective fibrillin microfibrils in Marfan patients. Attempts are underway to develop animal models of Marfan disease for study of possible gene therapy. Aortic root replacement can be performed in Marfan patients with operative risk under 5%. Long-term results are gratifying. At present, valve-sparing procedures should be used cautiously in Marfan patients because of fibrillin abnormalities in the preserved aortic valve leaflets.
Diagnosis and management of Marfan syndrome
Future Cardiology, 2008
Marfan syndrome is a disorder of the connective tissue that is inherited in an autosomal-dominant fashion and is caused by mutations in the gene coding for fibrillin-1, FBN1. Although complications of the syndrome may involve the eye, the lung and the skeleton, the high mortality of untreated cases results almost exclusively from cardiovascular complications, including aortic dissection and rupture. Recently, a series of experiments has begun to elucidate the complex molecular etiology of Marfan syndrome, and a number of new heritable syndromes with an associated risk for aortic complications, such as Loeys–Dietz syndrome types I and II, have been described. The multiorgan involvement of many of these syndromes requires multidisciplinary expert centers that can increase the average life expectancy of affected patients from only 32 years to over 60 years. The present article both reviews classical standards of managing cardiovascular manifestations and outlines significant advances i...