Defining the Basis of Fibromuscular Dysplasia (FMD) (DEFINE)

Defining the Basis of Fibromuscular Dysplasia: The Define-FMD Study

The purpose of this study has evolved and expanded since its inception. Originally the intent was to establish the functional, molecular and genetic profile of fibroblasts from Fibromuscular Dysplasia (FMD) patients as compared to carefully matched control subjects. While this remains among the objectives, the study has been expanded to undertake a fully powered cross-tissue systems genetics analysis of FMD, and now also the related arteriopathies spontaneous coronary artery dissection (SCAD) and cervical artery dissection (CvAD). The overall objective is to disclose the core biologic mechanisms of these disorders.

Study Overview

• Status: Recruiting
• Conditions: Spontaneous Coronary Artery Dissection; Fibromuscular Dysplasia; Cervical Artery Dissection

Detailed Description

Specific aims

• Specific aim 1: To establish a library of fibroblasts, DNA, plasma and serum from patients with FMD, SCAD and CvAD and unaffected healthy control subjects.
• Specific aim 2: To perform a fully powered cross-tissue systems analysis of the key regulatory gene networks and disease drivers underlying FMD, SCAD and CvAD.
• Specific aim 3: To cross-compare the molecular and genomic profiles of FMD, SCAD and CvAD to establish the degree of biologic similarity among these disorders.

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

• Study Contact: Name: Jason Kovacic, MD, PhD; Phone Number: 212-241-7014; Email: jason.kovacic@mountsinai.org
• Study Contact Backup: Name: Jeffrey Olin, DO; Email: jeffrey.olin@mountsinai.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
      • Contact: Annette King, ANP; Phone Number: 212-241-9454; Email: annette.king@mountsinai.org
      • Principal Investigator: Jason Kovacic, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Will enroll 200 FMD patients, 100 SCAD patients, and 100 CvAD patients at the Mount Sinai Hospital. 200 matched healthy controls will also be recruited to this study.

Description

Inclusion Criteria:

• Patients of any age and freely willing to participate. For patients < 18 years of age consent will be via parents.
• Fluency in either English or Spanish.
• Signed, informed consent
• For FMD, SCAD or CvAD subjects - a clinical diagnosis of FMD, SCAD or CvAD with fulfillment of standard diagnostic criteria.
• For healthy controls - no clinical features of FMD, SCAD or CvAD and absence of any major ongoing systemic disease including any condition requiring hospitalization, immune suppression, intravenous or injected medications or that result in functional impairment in the performance of activities of daily living. Healthy controls will be matched to enrolled FMD patients on the basis of gender and approximate age (within a 5 year window of another FMD subject).

Exclusion Criteria:

• Patients who have co-morbidities which reduces life expectancy to one year.
• Patients with any solid organ or hematological transplantation, or those in whom transplantation is considered.
• Active autoimmune disease.
• Illicit drug use.
• HIV positive.
• Prior malignancy.
• Any other form of vascular disease, including other arteriopathy coronary artery disease or peripheral vascular disease
• Family history of arteriopathy other than FMD, SCAD or CvAD (e.g. Ehlers-Danlos syndrome)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Healthy control subjects
FMD subjects; patients who fulfill standard diagnostic criteria for FMD
SCAD subjects; patients who fulfill standard diagnostic criteria for SCAD
CvAD subjects; patients who fulfill standard diagnostic criteria for CvAD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of regulatory gene networks	The identification of regulatory gene networks, and their key drivers, underlying FMD, SCAD and CvAD	single time point at study enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of molecular features	To cross-compare the molecular features of FMD, SCAD and CvAD	single time point at study enrollment
Identification of genomic features	To cross-compare the genomic features of FMD, SCAD and CvAD	single time point at study enrollment
RNA sequencing	To define and compare the genomic (RNA sequencing) profile of fibroblasts from FMD, SCAD and CvAD subjects versus healthy control subjects	single time point at study enrollment
Circulating cytokine	To define and compare the circulating cytokine profile of FMD versus healthy control subjects.	single time point at study enrollment

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: Jason Kovacic, MD, PhD, Icahn School of Medicine at Mount Sinai; Principal Investigator: Jeffrey Olin, DO, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Olin JW, Di Narzo AF, d'Escamard V, Kadian-Dodov D, Cheng H, Georges A, King A, Thomas A, Barwari T, Michelis KC, Bouchareb R, Bander E, Anyanwu A, Stelzer P, Filsoufi F, Florman S, Civelek M, Debette S, Jeunemaitre X, Bjorkegren JLM, Mayr M, Bouatia-Naji N, Hao K, Kovacic JC. A plasma proteogenomic signature for fibromuscular dysplasia. Cardiovasc Res. 2020 Jan 1;116(1):63-77. doi: 10.1093/cvr/cvz219.
• Kiando SR, Tucker NR, Castro-Vega LJ, Katz A, D'Escamard V, Treard C, Fraher D, Albuisson J, Kadian-Dodov D, Ye Z, Austin E, Yang ML, Hunker K, Barlassina C, Cusi D, Galan P, Empana JP, Jouven X, Gimenez-Roqueplo AP, Bruneval P, Hyun Kim ES, Olin JW, Gornik HL, Azizi M, Plouin PF, Ellinor PT, Kullo IJ, Milan DJ, Ganesh SK, Boutouyrie P, Kovacic JC, Jeunemaitre X, Bouatia-Naji N. PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance. PLoS Genet. 2016 Oct 28;12(10):e1006367. doi: 10.1371/journal.pgen.1006367. eCollection 2016 Oct.
• Georges A, Albuisson J, Berrandou T, Dupre D, Lorthioir A, D'Escamard V, Di Narzo AF, Kadian-Dodov D, Olin JW, Warchol-Celinska E, Prejbisz A, Januszewicz A, Bruneval P, Baranowska AA, Webb TR, Hamby SE, Samani NJ, Adlam D, Fendrikova-Mahlay N, Hazen S, Wang Y, Yang ML, Hunker K, Combaret N, Motreff P, Chedid A, Fiquet B, Plouin PF, Mousseaux E, Azarine A, Amar L, Azizi M, Gornik HL, Ganesh SK, Kovacic JC, Jeunemaitre X, Bouatia-Naji N. Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia. Cardiovasc Res. 2021 Mar 21;117(4):1154-1165. doi: 10.1093/cvr/cvaa161.
• Adlam D, Olson TM, Combaret N, Kovacic JC, Iismaa SE, Al-Hussaini A, O'Byrne MM, Bouajila S, Georges A, Mishra K, Braund PS, d'Escamard V, Huang S, Margaritis M, Nelson CP, de Andrade M, Kadian-Dodov D, Welch CA, Mazurkiewicz S, Jeunemaitre X; DISCO Consortium; Wong CMY, Giannoulatou E, Sweeting M, Muller D, Wood A, McGrath-Cadell L, Fatkin D, Dunwoodie SL, Harvey R, Holloway C, Empana JP, Jouven X; CARDIoGRAMPlusC4D Study Group; Olin JW, Gulati R, Tweet MS, Hayes SN, Samani NJ, Graham RM, Motreff P, Bouatia-Naji N. Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection. J Am Coll Cardiol. 2019 Jan 8;73(1):58-66. doi: 10.1016/j.jacc.2018.09.085.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2013
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: October 18, 2013
• First Submitted That Met QC Criteria: October 22, 2013
• First Posted (Estimated): October 23, 2013

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 24, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Fibroblast; Cross-sectional study; Fibromuscular dysplasia; Spontaneous Coronary Artery Dissection; Cervical Artery Dissection
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Arterial Occlusive Diseases; Fibromuscular Dysplasia; Coronary Artery Dissection, Spontaneous
• Other Study ID Numbers: GCO 13-1118

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES