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Report of the National Heart, Lung, and Blood Institute and National Marfan Foundation Working Group on Research in Marfan Syndrome and Related Disorders

Year: 2008

Type: article

Abstract: A ortic aneurysm and dissection is a common phenotype, accounting for 1% to 2% of all deaths in industrialized countries and Ϸ50 000 deaths annually in the United States. 1 In contrast to abdominal aortic aneurysm, thoracic aortic aneurysm, particularly in the ascending segment, commonly occurs in young individuals in the absence of identifiable environmental risk factors.Marfan syndrome (MFS) is the most common syndromic presentation of ascending aortic aneurysm, but other syndromes such as vascular Ehlers-Danlos syndrome and Loeys-Dietz syndrome (LDS) also have ascending aortic aneurysms and the associated cardiovascular risk of aortic dissection and rupture.Familial segregation of the risk for ascending aortic aneurysm can also occur in the absence of associated systemic findings of a connective tissue abnormality in patients with familial thoracic aortic aneurysm and dissection (FTAAD) or bicuspid aortic valve with ascending aortic aneurysm (BAV/AscAA).The knowledge gained through basic and clinical research focused on MFS has improved and will continue to improve the care of patients with these related conditions.Recent paradigm-shifting discoveries about the molecular pathogenesis of MFS have highlighted the need for a focused research agenda to solidify the gains of the past 30 years and set the stage for future advances in MFS and related conditions.In April 2007, the National Heart, Lung, and Blood Institute (NHLBI) and the National Marfan Foundation convened a working group on research in MFS and related disorders to foster a multidisciplinary discussion.The working group, which included experts in cardiovascular disease, developmental biology, genetics and genomics, and proteomics, was charged with identifying opportunities and barriers to advancing the research agenda and developing recommenda-tions to the NHLBI in the context of the Institute's strategic plan (http://apps.nhlbi.nih.gov/strategicplan/). Marfan SyndromeMFS is a systemic disorder of connective tissue caused by heterozygous mutations in the gene (FBN1) that encodes the extracellular matrix protein fibrillin-1. 2The estimated prevalence of MFS ranges between 1 in 5000 and 1 in 10 000, without any ethnic or gender bias.Manifestations occur in many body systems, including the eye, skeleton, skin and integument, lung, and most importantly, the heart and blood vessels. 3The primary cause of death is cardiovascular collapse due to aortic dissection, rupture, and pericardial tamponade.The prognosis and clinical outcome for people with MFS have improved steadily over the last 3 decades, largely owing to medical and surgical advances.In 1972, the average age at death and the median cumulative probability of survival for an individual with MFS were 32 and 48 years, respectively, but these had increased to 41 and 72 years, respectively, when reassessed in 1995. 4,5Many of the current medical and surgical practices for the care of individuals with aortic aneurysm have either been developed or refined in MFS, in part because validated animal models have been developed.In addition, a highly motivated patient population has facilitated clinical research.Current therapy for the cardiovascular complications of MFS consists of medical management, with the goal of slowing the rate of aortic root dilation, and surgery to prevent dissection when the aortic root reaches a diameter of Ϸ5 cm or is growing at a rate of more than 1 cm a year. 3Medical therapy is usually with ␤-blockers, but ACE inhibitors and calcium channel blockers have also been used (reviewed in Keane and Pyeritz 6 ).Although multiple small, largely retro-

Source: Circulation

DOI: 10.1161/circulationaha.108.783753