National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)

Objectives

The purpose of GenTAC is to enable research to improve the diagnosis and management of patients receiving treatment for thoracic aortic aneurysms and dissections, which are known or suspected to be genetically induced, through the creation of a data and specimen repository. The Registry established a biospecimen inventory and bioinformatics infrastructure to enable research to determine best medical practices to advance the clinical management of genetic thoracic aortic aneurysms and other cardiovascular complications. To achieve these, the Registry developed standard methods to collect clinical data and specimens. The data include confirmed phenotype and, if available, genotype, interpretation of images by a central imaging lab, characteristics of patients undergoing surgical repair of aneurysms and their clinical outcomes. Biospecimens include surgical tissue, DNA, plasma and immortalized lymphocytes. These resources are available through an application process to GenTAC and non-GenTAC investigators who are interested in advancing the fundamental understanding of genetic aortic aneurysms and management of afflicted patients.

Background

Thoracic aortic aneurysms and related conditions represent an important problem for patients in the United States, and are responsible for thousands of deaths, aortic valve-related heart failure, and a large burden of morbidity and costs. Increasingly, studies suggest a strong genetic basis for a number of thoracic aortic disorders. In addition, the complex interplay of genetics and environmental influences in determination of phenotype remains poorly understood. Accordingly, the National Heart, Lung and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health initiated phase I of the GenTAC Registry (GenTAC I) in 2006. The second phase of the registry (GenTAC II) began in October 2010 and expanded the cohort size and composition, adding two new contributing clinical centers, extending follow-up, evaluating imaging findings by an imaging core lab, confirming clinical phenotype and genotype by a phenotype core lab, and further validating genetic underpinnings of thoracic aortic disease.

Subjects

Except where noted in the eligibility criteria, subjects are of all ages. Both genders and all races and ethnicities are also included without restrictions. At enrollment, subjects should be willing to provide a biospecimen for DNA and be available for bi-annual follow-up. Most subjects have their disease treated and managed by one of the participating medical institutions.

Disease Classification

12 disease conditions are included in the eligibility criteria, including Marfan syndrome; Turner syndrome; Ehlers-Danlos syndrome; Loeys-Dietz syndrome; FBN1, TGFBR1, TGFBR2, ACTA2 or MYH11 genetic mutations; bicuspid aortic valve (BAV) with thoracic aortic aneurysms or dissections (TAAD); BAV with family history; BAV with coarctation; Familial TAAD; Shprintzen-Goldberg syndrome; TAAD not due to trauma in <50 years of age; and other congenital heart disease with aortic enlargement.

Design

The GenTAC Registry is a longitudinal cohort study, which is observational by design. The cohort consists of patients with conditions related to genetically-induced thoracic aortic aneurysms. There is no disease-free control or comparison group enrolled in the Registry. The study compares cross-sectional and longitudinal data on risk factors related to the diagnosis, treatment and outcomes among groups of enrolled patients. As part of the natural course of clinical care, patients and their physicians determine the approach to treatment and the study records the observed related outcomes. The study does not attempt to interfere with the outcomes through any type of planned intervention; therefore, there are no anticipated adverse events as a result of study participation.

Publications

1. Eagle, K and the GenTAC Consortium. Rationale and Design of the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Registry. Am Heart J 2009;157:319-326. PMCID: PMC2840718

2. Song HK, Bavaria JE, Kindem MW, Holmes KW, Milewicz DM, Maslen CL, Pyeritz RE, Basson CT, Eagle K, Tolunay HE, Kroner BL, Dietz H, Menashe V, Devereux RB, Desvigne-Nickens P, Ravekes W, Weinsaft JW, Brambilla D, Stylianou MP, Hendershot T, Mitchell MS, LeMaire SA; National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) Consortium. Ann Thorac Surg 2009;88(3):781-787; discussion 787-788. PMCID: PMC3042876

3. Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, Carlson OD, Griswold BF, Fu Q, De Backer J, Loeys B, Huso DL, McDonnell NB, Van Eyk JE, Dietz HC the GenTAC Consortium. Circulating Transforming Growth Factor-β in Marfan Syndrome. Circulation 2009;120:526-532. PMCID: PMC2779568

4. Holmes K, Brambilla D, Weinsaft JW, Silberbach M, Tung PP, Ravekes W, Basson CT, Maslen CL, Song HK, Pyeritz RE, Kroner B, Eagle KA, Devereux RB: Association of aortic annular dilatation with aortic regurgitation in patients with thoracic aortic aneurysms: The GenTAC Registry. Circulation 2009;120(suppl 2):s724-725.

5. Weinsaft JW, Daoko J, Fong J, Sethi S, Mendoza D, Devereux RB, Basson CT, Holmes KW, Tung PP, Milewicz DM, Pyeritz RE, Maslen C, Brambilla D, Kroner B, Tolunay E, Eagle KA: Impact of imaging methodology on measurements of aortic size in patients with thoracic aortic aneurysms – Results from the GenTAC imaging database. J Am Coll Cardiol 2010;55:A162. [Epub on DVD].

6. Kuang S-Q, Guo D-C, Prakash SK, Johnson RJ, Wang M, Regalado E, Russell L, Cao J, Kwartler CS, Fraivillig K, Coselli JS, Safi H, Estrera A, Leal SM, LeMaire SA, Belmont J, Milewicz DM, GenTAC Investigators: Recurrent chromosomes 16p13.1 duplications are a risk factor for aortic dissection. PLoS Genet 2011;7(6):e1002118. PMCID: PMC3116911

7. Mendoza DD, Kochar M, Devereux RB, Basson CT, Min JK, Holmes K, Dietz HC, Milewicz DM, Lemaire SA, Pyeritz RE, Bavaria JE, Maslen CL, Song H, Kroner BL, Eagle KA, Weinsaft JW, GenTAC Study Investigators: Impact of image analysis methodology on diagnostic and surgical classification of patients with thoracic aortic aneurysms. Ann Thorac Surg 2011;92:904-912.

8. LeMaire SA, McDonald M-LN, Guo D-C, Russell L, Miller CC III, Johnson RJ, Bekheirnia MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C, Holmes KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M, Coselli JS, Estrera AL, Safi HJ, Belmont JW, Leal SM, Milewicz DM: Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat Genet 2011;43(10):996-1000. PMCID: PMC3244938

9. Kroner BL, Tolunay HE, Basson CT, Pyeritz RE, Holmes KW, Maslen CL, Milewicz DM, Lemaire SA, Hendershot T, Desvigne-Nickens P, Devereux RB, Dietz HC, Song HK, Ringer D, Mitchell M, Weinsaft JW, Ravekes W, Menashe V, Eagle KA: The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): Results from phase I and scientific opportunities in phase II. Am Heart J 2011;162(4):627-632. PMCID: PMC3190125

10. Song HK, Kindem M, Bavaria JE, Dietz HC, Milewicz DM, Devereux RB, Eagle KA, Maslen CL, Kroner BL, Pyeritz RE, Holmes KW, Weinsaft JW, Menashe V, Ravekes W, Lemaire SA. Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium. Long-term implications of emergency versus elective proximal aortic surgery in patients with Marfan syndrome in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium Registry. J Thorac Cardiovasc Surg 2012;143(2):282-286. PMCID: PMC3260411

11. LeMaire SA, McDonald M-LN, Guo D-C, Russell L, Miller CC III, Johnson RJ, Bekheirnia MR, Franco LM, Nguyen M, Pyeritz RE, Bavaria JE, Devereux R, Maslen C, Holmes KW, Eagle K, Body SC, Seidman C, Seidman JG, Isselbacher EM, Bray M, Coselli JS, Estrera AL, Safi HJ, Belmont JW, Leal SM, Milewicz DM: Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat Genet. 2011 Sep 11;43(10): 996-1000. PMCID: PMC3244938

12. Kroner BL, Tolunay HE, Basson CT, Pyeritz RE, Holmes KW, Maslen CL, Milewicz DM, Lemaire SA, Hendershot T, Desvigne-Nickens P, Devereux RB, Dietz HC, Song HK, Ringer D, Mitchell M, Weinsaft JW, Ravekes W, Menashe V, Eagle KA: The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): Results from phase I and scientific opportunities in phase II. Am Heart J. 2011 Oct;162(4):627-632.e1. PMCID: PMC3190125

13. Song HK, Kindem M, Bavaria JE, Dietz HC, Milewicz DM, Devereux RB, Eagle KA, Maslen CL, Kroner BL, Pyeritz RE, Holmes KW, Weinsaft JW, Menashe V, Ravekes W, Lemaire SA. Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium. Long-term implications of emergency versus elective proximal aortic surgery in patients with Marfan syndrome in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium Registry. J Thorac Cardiovasc Surg. 2012, 143(2):282-6. PMCID: PMC3260411