Pathogenetic Basis of Aortopathy and Aortic Valve Disease (TAA)

• ClinicalTrials.gov Identifier: NCT03440697
• Recruitment Status: Recruiting
• First Posted: February 22, 2018
• Last Update Posted: February 22, 2023
• Sponsor: Indiana University
• Information provided by (Responsible Party): Benjamin Landis, Indiana University

Study Description

Brief Summary:

The main purpose of this study is to define the complex genetic and pathogenic basis of thoracic aortic aneurysm (TAA) and other forms of aortopathy and/or aortic valve disease by identifying novel disease-causing genes and by identifying important genetic modifiers for aortic and aortic valve disease severity.

Condition or disease

Aortopathies; Thoracic Aortic Aneurysm; Aortic Valve Disease; Thoracic Aortic Disease; Thoracic Aortic Dissection; Thoracic Aortic Rupture; Ascending Aortic Disease; Descending Aortic Disease; Ascending Aortic Aneurysm; Descending Aortic Aneurysm; Marfan Syndrome; Loeys-Dietz Syndrome; Ehlers-Danlos Syndrome; Shprintzen-Goldberg Syndrome; Turner Syndrome; PHACE Syndrome; Autosomal Recessive Cutis Laxa; Congenital Contractural Arachnodactyly; Arterial Tortuosity Syndrome

Detailed Description:

Thoracic aortic aneurysm (TAA) is a type of aortopathy describing dilation of the proximal aortic dimensions including the aortic root, which is a risk factor for aortic dissection and sudden cardiac death. TAA and other forms of aortopathy (e.g. aortic tortuosity or aortic hypoplasia/stenosis) develop in the presence or absence of additional cardiovascular malformations including bicuspid aortic valve. TAA is associated with connective tissue disorders (e.g. Marfan syndrome), and familial clustering has been identified in a significant proportion of nonsyndromic cases, establishing high heritability. Pedigree analysis of TAA kindreds clearly identifies complex inheritance; however, progress towards understanding the genetic basis of TAA and other forms of aortopathy and, ultimately, the susceptibility to aortic dissection remains incomplete. There is a clinical need to develop novel methods for predicting disease risk based on genotype and phenotype, to further elucidate the genetic and pathogenic mechanisms of aortopathy, and to improve medical and surgical therapies. The overarching hypothesis of this study is that individual genetic variation modulates susceptibility to disease severity and progression. The goals of this study are 1) to ascertain a cohort of subjects who have aortopathy and/or aortic valve disease including TAA or who have genetic risk for the development of aortopathy and/or aortic valve disease, 2) to collect paired blood and tissue samples from well-characterized subjects, family members of subjects, and controls to perform genome-wide DNA sequence, histopathologic, transcriptional, and proteomic analyses, and 3) to establish a tissue biorepository with detailed phenotype information to facilitate a broad spectrum of current and future studies.

Study Design

• Study Type: Observational
• Estimated Enrollment: 3000 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Pathogenetic Basis of Aortopathy and Aortic Valve Disease
• Study Start Date: December 2015
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: December 2028

Groups and Cohorts

Group/Cohort
Aortopathy- Closed to external enrollment; Subjects with aortic disease including TAA or dissection, aortic tortuosity, or aortic hypoplasia/stenosis (based on any cardiac imaging modality including echocardiography, CT, MRI, or angiography)
Syndromic- Open to external enrollment; Subjects with a genetic diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS), Vascular Ehlers-Danlos Syndrome (EDS) •positive genetic testing and/or a previous cardiac study required to be eligible
Aortopathy with Positive Genetic Results- Open to Enrollment; Subjects with aortic disease including TAA or dissection, aortic tortuosity, or aortic hypoplasia/stenosis (based on any cardiac imaging modality including echocardiography, CT, MRI, or angiography) who also have positive genetic testing results related to aortopathy.
Aortic Valve Disease- Closed to enrollment; Subjects with aortic valve disease (bicuspid, unicuspid, or tricuspid disease)
Family Members- Open to external enrollment; Family members of eligible subjects •Only family members of subjects with syndromic diagnoses are eligible for external enrollment at this time
Controls- Closed to external enrollment; Control subjects having tissue removed during a surgical procedure (e.g. coronary artery bypass graft surgery (CABG), cardiac transplant, etc.)

Outcome Measures

Primary Outcome Measures :

1. Biorepository Establishment [ Time Frame: 10 years ]
   Establish a biorepository with detailed phenotype information to facilitate a broad spectrum of current and future studies
2. DNA Sequence Analysis [ Time Frame: 10 years ]
   The mechanisms of TAA pathogenesis will be determined by studying explanted aortic tissue and cells derived from patients with TAA for gene expression, protein expression, and other functional assays.

Biospecimen Retention:   Samples With DNA

Whole Blood, Tissue, Saliva

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Families affected by aortopathy, aortic valve disease, or syndromic or genetic diagnosis that poses risk for the development of aortic disease who have not yet developed disease.

Criteria

Inclusion Criteria:

• Open to external enrollment:

  • Subjects with a genetic diagnosis of Marfan Syndrome (MDS), Loeys-Dietz Syndrome (LDS), or Vascular Ehlers-Danlos Syndrome (EDS); (Positive genetic testing or a previous cardiac study required to be eligible)
  • Family members of eligible subjects (Only family members of subjects with syndromic diagnoses are eligible for external enrollment at this time)

• Closed to external enrollment:

  • Subjects with aortic disease including TAA* or dissection, aortic tortuosity, or aortic hypoplasia/stenosis (based on any cardiac imaging modality including echocardiography, CT, MRI, or angiography)
  • Subjects with aortic valve disease (bicuspid, unicuspid, or tricuspid disease)
  • Control subjects having tissue removed during a surgical procedure (e.g. coronary artery bypass graft surgery (CABG), cardiac transplant, etc.)

Exclusion Criteria:

• Inability or unwillingness to provide consent (assent when indicated)

Contacts and Locations

Contacts

Contact: Lindsey Elmore, BS, BA; 317-278-3020; lhelvaty@iupui.edu

Contact: Benjamin Landis, MD; 317-278-2808; benjland@iu.edu

Locations

United States, Indiana

IU School of Medicine; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Lindsey Elmore, BA, BS 317-278-3020 lhelvaty@iupui.edu

Contact: Benjamin Landis, MD 317-278-2808 benjland@iu.edu

Sponsors and Collaborators

Indiana University

Investigators

• Principal Investigator: Benjamin Landis, MD; IU School of Medicine

More Information

• Responsible Party: Benjamin Landis, Assistant Professor of Pediatrics and Medical and Molecular Genetics, Indiana University
• ClinicalTrials.gov Identifier: NCT03440697
• Other Study ID Numbers: 1509977311
• First Posted: February 22, 2018
• Last Update Posted: February 22, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Benjamin Landis, Indiana University:

Cardiovascular Disease

Additional relevant MeSH terms:

Marfan Syndrome; Arachnodactyly; Loeys-Dietz Syndrome; Turner Syndrome; Aneurysm, Dissecting; Aneurysm; Aortic Aneurysm; Aortic Valve Disease; Heart Defects, Congenital; Heart Valve Diseases; Ehlers-Danlos Syndrome; Aortic Aneurysm, Thoracic; Aortic Diseases; Aortic Rupture; Cutis Laxa; Syndrome; Rupture; Disease; Pathologic Processes; Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries; Gonadal Dysgenesis; Disorders of Sex Development; Urogenital Abnormalities; Sex Chromosome Disorders of Sex Development; Cardiovascular Abnormalities; Heart Diseases; Congenital Abnormalities; Sex Chromosome Disorders