Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: Do we need genetics for clinical decisions? (original) (raw)

Augmentation index and the evolution of aortic disease in marfan-like syndromes

American Journal of Hypertension, 2010

nature publishing group original contributions Applanation tonometry (APT) is a noninvasive, highly reproducible, cost-efficient, and easy-to-use bedside test for assessing important parameters of arterial stiffness and pulse wave reflection including central pulse pressure (CPP), central systolic blood pressure, augmentation index (AIx), and carotid-femoral pulse wave velocity. 1,2 We have shown recently that an increased AIx and increased CPPs are related to aortic disease progression in Marfan syndrome (MFS). 2-6 MFS is caused by mutations in the gene coding for fibrillin-1, FBN1, resulting in aortic aneurysm, ectopia lentis, pneumothorax, and skeletal manifestations. 7 However, about one quarter of individuals with Marfan-like features display a wide spectrum of other syndromes. 8 Many of these syndromes carry a risk for aortic disease including Loeys-Dietz syndrome (LDS), 9 familial thoracic aortic aneurysm or dissection (TAAD), 10 vascular type of Ehlers-Danlos syndrome (EDS), 11 and nonsyndromic bicuspid aortic valves (BAVs), 7 whereas aortic disease is not described in familial ectopia lentis, 12 or familial Marfan-like habitus (MFS-like). 13 Other individuals with Marfan-like features cannot be diagnosed with any specific syndrome, although hereditary aortic disease may be present. 12,14 In clinical practice, it thus remains difficult to identify an increased aortic risk in individuals with Marfan-like features, especially when these do not have classic MFS. In this observational study, we performed APT in 78 consecutive adults with Marfan-like features in whom classic MFS had been excluded. We assessed the evolution of aortic disease during 20 ± 18 months of clinical follow-up in all individuals including echocardiography The first two authors contributed equally to this work.

Critical analysis of aortic dysmorphism in Marfan Syndrome

Journal of Morphological Sciences, 2017

Introduction: Marfan syndrome (OMIM #154700) was described for the first time in 1896 by Antoine Bernard-Jean Marfan. It is characterized by its autosomal dominant inheritance pattern, affects 1:5000 of those born alive, and involves the gene that codifies the structural protein fribrillin-1. Fibrillin-1 is critical for the formation of the elastic system backbone and for the negative regulation of the cytokine transforming growth factor beta 1 (TGF-β1). In the syndrome this fibrillar component causes the degeneration of the fibers of the elastic system, which no longer sequesters matrix TGF-β, causing disorganization of the collagen fibers and vascular smooth muscles. The disease affects mainly the cardiovascular system, cardiovascular problems being the main cause of death. This is because arteries have large amounts of elastic fibers that rupture in an adverse process, causing mainly dissections and aneurisms, which have been better clariied in experimental studies with mice. Obj...

Medical Treatment of Aortic Aneurysms in Marfan Syndrome and other Heritable Conditions

Thoracic aortic aneurysms can be triggered by genetic disorders such as Marfan syndrome (MFS) and related aortic diseases as well as by inflammatory disorders such as giant cell arteritis or atherosclerosis. In all these conditions, cardiovascular risk factors, such as systemic arterial hypertension, may contribute to faster rate of aneurysm progression. Optimal medical management to prevent progressive aortic dilatation and aortic dissection is unknown. β-blockers have been the mainstay of medical treatment for many years despite limited evidence of beneficial effects. Recently, losartan, an angiotensin II type I receptor antagonist (ARB), has shown promising results in a mouse model of MFS and subsequently in humans with MFS and hence is increasingly used. Several ongoing trials comparing losartan to β -blockers and/or placebo will better define the role of ARBs in the near future. In addition, other medications, such as statins and tetracyclines have demonstrated potential benefit in experimental aortic aneurysm studies. Given the advances in our understanding of molecular mechanisms triggering aortic dilatation and dissection, individualized management tailored to the underlying genetic defect may be on the horizon of individualized medicine. We anticipate that ongoing research will address the question whether such genotype/pathogenesis-driven treatments can replace current phenotype/syndromedriven strategies and whether other forms of aortopathies should be treated similarly. In this work, we review currently used and promising medical treatment options for patients with heritable aortic aneurysmal disorders.

Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome

International Journal of Cardiology, 2015

Background: Patients with Marfan syndrome (MFS) have a highly variable occurrence of aortic complications. Aortic tortuosity is often present in MFS and may help to identify patients at risk for aortic complications. Methods: 3D-visualization of the total aorta by MR imaging was performed in 211 adult MFS patients (28% with prior aortic root replacement) and 20 controls. A method to assess aortic tortuosity (aortic tortuosity index: ATI) was developed and reproducibility was tested. The relation between ATI and age, body size and aortic dimensions at baseline was investigated. Relations between ATI at baseline and the occurrence of a clinical endpoint (aortic dissection, and/or aortic surgery) and aortic dilation rate during 3 years of follow-up were investigated. Results: ATI intra-and interobserver agreement were excellent (ICC: 0.968 and 0.955, respectively). Mean ATI was higher in 28 age-matched MFS patients than in the controls (1.92±0.2 versus 1.82±0.1, p=0.048). In the total MFS cohort, mean ATI was 1.87±0.20, and correlated with age (r=0.281, p<0.001), aortic root diameter (r=0.223, p=0.006), and aortic volume expansion rate (r=0.177, p=0.026). After 49.3±8.8 months follow-up, 33 patients met the combined clinical endpoint (7 dissections) with a significantly higher ATI at baseline than patients without endpoint (1.98±0.2 versus1.86±0.2, p=0.002). Patients with an ATI>1.95 had a 12.8 times higher probability of meeting the combined endpoint (log rank-test, p<0.001) and a 12.1 times higher probability of developing an aortic dissection (log rank-test, p=0.003) compared to patients with an ATI<1.95. Conclusions: Increased ATI is associated with a more severe aortic phenotype in MFS patients.

Medical management of aortic disease in Marfan syndrome

Annals of cardiothoracic surgery, 2017

Marfan syndrome (MFS) is a hereditary disorder with numerous pathophysiological effects, some specifically creating elastic dysfunction in cardiovascular organs. Aortic dilatation, dissection and rupture are major concerns in the management of MFS patients. Predilection to form aneurysms is an indication for prophylactic medical management of thoracic aortic aneurysm disease in these patients. The current guidelines describe β-blockers as the standard of care with angiotensin receptor blockers (ARBs) emerging as an equal, if not better alternative. We elaborate current evidence for and against different medical regimens used for the medical management of MFS patients.

Possible extracardiac predictors of aortic dissection in Marfan syndrome

BMC Cardiovascular Disorders, 2014

Background: According to previous studies, aortic diameter alone seems to be insufficient to predict the event of aortic dissection in Marfan syndrome (MFS). Determining the optimal schedule for preventive aortic root replacement (ARR) aortic growth rate is of importance, as well as family history, however, none of them appear to be decisive. Thus, the aim of this study was to search for potential predictors of aortic dissection in MFS. Methods: A Marfan Biobank consisting of 79 MFS patients was established. Thirty-nine MFS patients who underwent ARR were assigned into three groups based on the indication for surgery (dissection, annuloaortic ectasia and prophylactic surgery). The prophylactic surgery group was excluded from the study. Transforming growth factor-β (TGF-β) serum levels were measured by ELISA, relative expression of c-Fos, matrix metalloproteinase 3 and 9 (MMP-3 and −9) were assessed by RT-PCR. Clinical parameters, including anthropometric variables-based on the original Ghent criteria were also analyzed. Results: Among patients with aortic dissection, TGF-β serum level was elevated (43.78 ± 6.51 vs. 31.64 ± 4.99 ng/l, p < 0.0001), MMP-3 was up-regulated (Ln2 α = 1.87, p = 0.062) and striae atrophicae were more common (92% vs. 41% p = 0.027) compared to the annuloaortic ectasia group. Conclusions: We found three easily measurable parameters (striae atrophicae, TGF-β serum level, MMP-3) that may help to predict the risk of aortic dissection in MFS. Based on these findings a new classification of MFS, that is benign or malignant is also proposed, which could be taken into consideration in determining the timing of prophylactic ARR.

Spectrum of Aortic Operations in 300 Patients With Confirmed or Suspected Marfan Syndrome

The Annals of Thoracic Surgery, 2006

Background. Cardiovascular disease is the main cause of morbidity and mortality in patients with Marfan syndrome. Many patients with presumed Marfan syndrome do not meet current diagnostic criteria. This study reviews the surgical aspects of aortic disease in 300 patients referred with the diagnosis of Marfan syndrome.

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