Bearing in mind the current state of the science, the Working Group discussed scientific opportunities and barriers to progress. The scientific opportunities to advance this field are conferred by technological advances in gene discovery, the ability to dissect cellular processes at the molecular level, imaging, and the establishment of multidisciplinary research teams. The barriers to progress are addressed through the following 5 key recommendations. All of these recommendations are based on and consistent with the goals and challenges in the NHLBI’s Strategic Plan (http://apps.nhlbi.nih.gov/strategicplan/
- Existing registries should be expanded or new registries developed to define the presentation and course of aneurysm syndromes. (NHLBI Strategic Plan Goal 2, Challenge 2.2.)
The prognosis and clinical outcome for people with MFS has improved steadily over the last 3 decades, both because of the ability to anticipate medical problems and the ability to apply medical and surgical protocols that have been developed and refined to meet the needs of this discrete patient population. Likewise, the basic science discoveries that have the potential to further revolutionize care for MFS would not have been possible before disease gene discovery, an event that also required the ability to discriminate MFS from overlapping phenotypes. Even if losartan or other therapies fulfill their promise, the new reality will undoubtedly be the need to define the new emerging clinical history of MFS that will only become evident once genetically imposed predispositions integrate with those imposed by aging and prolonged environmental influence.
The need for accurate prospective data that permit correlation of multiple complex determinants of outcomes is magnified for conditions that have been recognized only recently (eg, LDS), that have few discriminating manifestations (eg, FTAAD), or that are extremely rare (eg, arterial tortuosity syndrome). Examples of highly relevant questions include the following: How well do follow-up and treatment guidelines developed for MFS generalize to other genetically induced forms of thoracic aortic aneurysm? Are there clinical or imaging parameters that can inform patient counseling and management? Should guidelines developed for the broader cardiovascular community (eg, recent modification of American Heart Association guidelines to exclude mitral and/or aortic valve regurgitation as an indication for bacterial endocarditis prophylaxis70
) apply to individuals with systemic connective tissue disorders?
National or international registries that capture clinical information relevant to this broad patient population include the International Registry of Acute Aortic Dissection, the NHLBI-funded Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions registry (https://gentac.rti.org/), and the Aortic Valve Operative Outcomes in Marfan Patients registry. These efforts, although valuable, could have considerable value added by the collection of detailed longitudinal phenotypic and imaging data. Rather than being strictly observational, dedicated examinations and specialized imaging could be used to address specific clinical questions or hypotheses focused on a specific phenotype. The inclusion of 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.
- Biological 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 to 2.3.)
A central repository for standardized clinical sample collection, processing, and distribution should be formed. Whenever feasible, every sponsored initiative dedicated to the collection of phenotypic information relevant to aortic aneurysm conditions should collect and submit clinical specimens. This resource would greatly facilitate gene discovery efforts and other fundamental studies. There is a particular need to obtain specimens that are temporally associated with clinical events, such as the initiation of medical therapies, surgery, aneurysm progression, and vascular dissection or rupture, to identify diagnostic, prognostic, and therapeutic markers.
- An Aortic Aneurysm Clinical Trials Network (ACTnet) should be developed. 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 number of emerging therapeutic strategies for aortic aneurysm conditions parallels a refined understanding of their causes and pathogenesis. The Pediatric Heart Network trial of losartan versus atenolol has the true potential to inform the care of people with MFS in a comprehensive and rigorous manner; however, additional studies are needed to address other clinical questions in MFS, as well as other patient populations. The NHLBI network model provides an ideal structure to test new medical or surgical therapies in rare conditions, such as genetically induced aortic aneurysm. Additional TGF-β antagonists, such as neutralizing antibodies or Smad kinase inhibitors, may prove useful in isolation or in combination with angiotensin II type 1 receptor blockers. Agents with other or overlapping mechanisms of action with demonstrated or theoretical promise include matrix metalloproteinase and ACE inhibitors and angiotensin II type 2 receptor agonists, alone or in combination. An immediate hypothesis to be tested is that TGF-β antagonists will prove relevant to conditions other than MFS.
Given the relative rarity of genetically induced aortic aneurysm conditions, a network of centers will be needed to adequately test new medical or surgical therapies. As with the Pediatric Heart Network, such an effort would be greatly facilitated by centralized infrastructure and the availability of flexible funding strategies to permit rapid response to novel opportunities. Such collaboration may also be able to take advantage of new infrastructure resources becoming available through the National Center for Research Resources’ Clinical and Translational Science Awards Program or the National Institute of Health’s Office of Rare Diseases.
- The identification of novel therapeutic targets should be facilitated by the development of genetically defined animal models and the expanded use of genomic, proteomic, and functional analyses. (NHLBI Strategic Plan Goal 1, Challenge 1.2.)
It is likely that elucidation of events that occur upstream (eg, mediators of TGF-β activation) and downstream (eg, transcriptional responses) of increased TGF-β signaling in MFS will result in the identification of novel therapeutic targets for this disorder. Parallel approaches should be directed at the identification of genetic modifiers of MFS. The paradigm established for MFS that a deficiency of a structural matrix element can initiate pathogenic perturbations of cell signaling should be explored for other connective tissue disorders, such as vascular Ehlers-Danlos syndrome. Such efforts will 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 develop robust in vivo reporter assays for the monitoring of the TGF-β (and other cellular) signaling cascades.
- 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. (NHLBI Strategic Plan Goal 1, Challenge 1.1.)
The recent finding that TGF-β–induced developmental perturbations may lead to abnormal lung development and establish the structural predisposition for later-onset emphysema may prove relevant to other aspects of the Marfan phenotype and to genetically induced forms of myxomatous valve disease and/or aortic aneurysm in general. Elucidation of the developmental sequelae of relative fibrillin-1 deficiency and excess TGF-β signaling may explain known predispositions (eg, for dilation of vascular segments enriched for neural crest-derived vascular smooth muscle cells), reveal unanticipated predispositions or limitations of postnatal interventions, or indicate novel therapeutic strategies. This will require a more refined understanding of late (including postnatal) developmental events that contribute to tissue morphogenesis and homeostasis.