NHLBI Working Group
Research in Marfan Syndrome and Related Disorders

Executive Summary

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) of investigators on April 30, 2007, in New York City to advise the NHLBI on new research directions needed to improve the care of people with Marfan syndrome and related aneurysm syndromes.

Discussion:

The Working Group met in New York City in conjunction with a meeting of the National Marfan Foundation to discuss the current state of knowledge about Marfan Syndrome and related conditions (e.g., familial thoracic aortic aneurysms and dissections, Ehlers-Danlos Syndrome, Loeys-Dietz Syndrome), identify opportunities and barriers to advancing the research agenda, and make recommendations to NHLBI about areas in which NHLBI leadership is required.

What these conditions have in common is thoracic aortic aneurysm, primarily in the ascending segment, which occurs in relatively young individuals who are genetically predisposed. This is in contrast to abdominal aortic aneurysm, which is related to well-defined environmental risk factors and less well-defined genetic predispositions, and occurs primarily in older individuals. Marfan syndrome (MFS) is the most common presentation of ascending aortic aneurysm in the young. Other conditions with aortic root aneurysm in the young include Loeys-Dietz syndrome, Ehlers-Danlos syndrome, and several other rare familial syndromes. These conditions also share is a common cardiovascular risk: potential aortic dissection and rupture.

The prognosis and clinical outcome for people with MFS has improved steadily over the last three decades, but continued progress will depend on accurate prospective data that permits correlation of multiple complex determinants of outcomes. This need is magnified for conditions that have been recognized only recently (e.g., Loeys-Dietz syndrome), that have few discriminating manifestations (e.g., Familial Thoracic Aortic Aneurysm and Dissection), or that are extremely rare (e.g., Arterial Tortuosity Syndrome). Registries that capture clinical information relevant to this broad patient population include the International Registry of Acute Aortic Dissection (IRAD), the NHLBI-funded Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) registry, and the Aortic Valve Operative Outcomes in Marfan Patients registry. These efforts, although valuable, could have considerable value added by collecting detailed longitudinal phenotypic and imaging data. Rather than being strictly observational, such dedicated examinations and specialized imaging could be used to address specific clinical questions or hypotheses focused on a specific phenotype. Including a sufficient number of children will ensure adequate pediatric data to support management guidelines. In addition, a common nomenclature for data elements across registries will permit the robust aggregation of data from multiple sources.

There is a particular need to obtain biological specimens that are temporally associated with clinical events such as the initiation of medical therapies, the perceived need for prophylactic aortic surgery, aneurysm progression, and vascular dissection or rupture in order to identify diagnostic, prognostic and therapeutic markers. This is not currently done systematically, and is costly. However, gene discovery and other translational research would be greatly facilitated by incorporating biological specimen collection in every clinical research program.

The number of emerging therapeutic strategies for aortic aneurysm conditions parallels a refined understanding of their etiology and pathogenesis. The NHLBI’s Pediatric Heart Network has launched a clinical trial comparing beta-blocker therapy (Atenolol) to angiotensin II receptor blocker therapy (Losartan) in individuals with MFS. This study will enroll individuals with MFS between 6 months and 25 years of age who have not had prior aortic surgery or dissection. However, additional studies are needed to address other clinical questions in MFS, as well as other patient populations. NHLBI’s network model provides an ideal structure to test new medical or surgical therapies in uncommon conditions, such as genetically-induced aortic aneurysm conditions.

The paradigm in MFS research has been one of successful bidirectional translation between bench and bedside, in part because valid animal models have been developed. Animal models are not available for related conditions, which limits the ability to identify modifiers of genetic predisposition and potential therapeutic targets, to test therapies, and to understand contributing developmental perturbations. Developmental perturbations are of interest because they may establish functional programs or structural milieus that underlie later-onset complications. Understanding in detail the developmental sequelae of genetic mutations may shed light on disease pathogenesis and help to refine optimal therapeutic strategies.

Recommendations:

Scientific opportunities to advance this field are conferred by technological advances in gene discovery, the ability to dissect cellular processes at the molecular level and imaging, and the establishment of multi-disciplinary teams. The barriers to progress are addressed through the following recommendations, which are also consistent with Goals and Challenges in the NHLBI Strategic Plan.

Existing registries should be expanded or new registries developed to define the presentation, natural history, and clinical history of aneurysm syndromes. (NHLBI Strategic Plan Goal 2, Challenge 2.2)

Biological and aortic tissue sample collection should be incorporated into every clinical research program on MFS and related disorders and funds should be provided to ensure that this occurs. Such resources, once established, should be widely shared among investigators. (NHLBI Strategic Plan Goal 2, Challenges 2.1 – 2.3)

An Aortic Aneurysm Clinical Trials Network (ACTnet) should be developed to test both surgical and medical therapies in patients with thoracic aortic aneurysms. Partnership in this effort should be sought with industry, academic organizations, foundations, and other governmental entities. (NHLBI Strategic Plan Goal 2, Challenge 2.4)

The identification of novel therapeutic targets and biomarkers should be facilitated by the development of genetically-defined animal models and the expanded use of genomic, proteomic and functional analyses. There is a specific need to understand cellular pathways that are altered leading to aneurysms and dissections, and to develop robust in vivo reporter assays to monitor TGFb and other cellular signaling cascades. (NHLBI Strategic Plan Goal 1, Challenge 1.2)

The developmental underpinnings of apparently acquired phenotypes should be explored. This effort will be facilitated by the dedicated analysis of both prenatal and early postnatal tissues in genetically-defined animal models and through the expanded availability to researchers of surgical specimens from affected children and young adults. (NHLBI Strategic Plan Goal 1, Challenge 1.1)

Publication Plans:

The Working Group is planning to publish a formal report, which will include an overview of the field and review of the literature, as well as an expanded rationale for these recommendations. The report will be posted on the NHLBI public web site with a link to any peer-reviewed journal of journals where the report is published. The anticipated publication date is early 2008.

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