Clinical trial NCT03440697: Pathogenetic Basis of Aortopathy and Aortic Valve Disease
Official title: Pathogenetic Basis of Aortopathy and Aortic Valve Disease
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: 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
Vascular Ehlers-Danlos Syndrome
Shprintzen-Goldberg Syndrome
Turner Syndrome
PHACE Syndrome
Autosomal Recessive Cutis Laxa
Congenital Contractural Arachnodactyly
Arterial Tortuosity Syndrome
Bicuspid Aortic Valve-Associated Aortopathy
Bicuspid Aortic Valve
Familial Thoracic Aortic Aneurysm and Aortic Dissection
Keywords: Cardiac Disease
Cardiovascular Genetics
Lead sponsor: Indiana University
Sponsor class: OTHER
First posted: 2018-02-22
Enrollment: 3000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility 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)

Primary outcomes:
measure: Biorepository Establishment
timeFrame: 20 years
measure: Genetic Analysis
timeFrame: 20 years
Secondary outcomes:
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta
state: Georgia
city: Indianapolis
country: United States
facility: IU School of Medicine
state: Indiana
Study officials:
affiliation: IU School of Medicine
name: Benjamin Landis, MD
role: PRINCIPAL_INVESTIGATOR
References: