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Pathogenetic Basis of Aortopathy and Aortic Valve Disease (TAA)

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ClinicalTrials.gov Identifier: NCT03440697
Recruitment Status : Recruiting
First Posted : February 21, 2018
Last Update Posted : August 8, 2018
Sponsor:
Information provided by (Responsible Party):
Benjamin Landis, Indiana University

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 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


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.)



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


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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)


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03440697


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

Responsible Party: Benjamin Landis, Assistant Professor of Pediatrics and Medical and Molecular Genetics, Indiana University
ClinicalTrials.gov Identifier: NCT03440697     History of Changes
Other Study ID Numbers: 1509977311
First Posted: February 21, 2018    Key Record Dates
Last Update Posted: August 8, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Benjamin Landis, Indiana University:
Cardiovascular Disease

Additional relevant MeSH terms:
Syndrome
Aneurysm
Aortic Aneurysm
Rupture
Turner Syndrome
Gonadal Dysgenesis
Primary Ovarian Insufficiency
Heart Defects, Congenital
Heart Valve Diseases
Marfan Syndrome
Arachnodactyly
Aortic Aneurysm, Thoracic
Ehlers-Danlos Syndrome
Aortic Diseases
Aortic Rupture
Loeys-Dietz Syndrome
Cutis Laxa
Craniosynostoses
Contracture
Joint Instability
Skin Diseases, Genetic
Vascular Malformations
Disease
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Wounds and Injuries
Disorders of Sex Development
Urogenital Abnormalities
Sex Chromosome Disorders of Sex Development