Dilated Cardiomyopathy-Cardiac Magnetic Resonance (DCM-CMR) Ancillary Study

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Brief Title

Dilated Cardiomyopathy-Cardiac Magnetic Resonance (DCM-CMR) Ancillary Study

Official Title

Precision Medicine for Dilated Cardiomyopathy-Cardiac Magnetic Resonance to Identify Early Family Phenotypes

Brief Summary

      The Dilated Cardiomyopathy-Cardiac Magnetic Resonance (DCM-CMR) Study is an ancillary study
      from the parent study, DCM Precision Medicine Study. The rationale for the DCM-CMR study is
      to leverage cardiac magnetic resonance (CMR) imaging to detect earliest findings of DCM in
      the at-risk family members enrolled into the parent study.
    

Detailed Description

      Dilated cardiomyopathy of unknown cause (DCM) is a major public health problem affecting more
      than a million people in the U.S. Most DCM is now known to have an underlying genetic basis.
      First-degree relatives (FDRs) of an individual with DCM are considered to be genetically at
      risk, particularly if they carry variants classified as pathogenic (P), likely pathogenic
      (LP) or uncertain significance (VUS) in DCM genes. Practice guidelines recommend that these
      FDRs undergo serial imaging because prompt intervention may avert advanced disease. While
      tissue damage is already well underway when DCM is manifest, myocardial tissue changes,
      termed "pre-DCM" herein, are known to precede adverse changes in myocardial structure and
      function. The investigators central hypothesis states that cardiac magnetic resonance (CMR)
      imaging may detect pre-DCM in individuals with increased genetic risk by identifying
      myocardial tissue changes prior to myocardial structural and functional changes. CMR measures
      of myocardial tissue characteristics, including late gadolinium enhancement and myocardial T1
      mapping, have been histopathologically validated and have established diagnostic and
      prognostic value in DCM. Thus, the investigators specific hypotheses state that adverse
      CMR-based myocardial tissue characteristics will be associated with (1) A higher burden
      (number) of relevant variants (P, LP, VUS) in established DCM genes; and (2) Subsequent
      adverse changes in measures of cardiac structure and function. The investigators propose to
      leverage the DCM Precision Medicine Study, a multisite DCM Consortium study now with 1230 DCM
      patients (probands), balanced for race and sex, and their FDRs, most with no history of DCM.
      FDRs are cascade tested for relevant variants (P, LP, VUS) in DCM genes identified in
      probands. The investigators aim to (1) Estimate the associations between CMR-based myocardial
      tissue characteristics and the number (burden) of the proband's variants in DCM genes in
      at-risk FDRs. In 650 FDRs of probands with LP/P variants and/or VUSs, CMR scans will be
      completed at 9 participating DCM Consortium sites. The association between CMR-based
      myocardial tissue characteristics and the number of the proband's variants of each class
      (LP/P, VUS) carried by an at-risk FDR in a particular age group will be evaluated, adjusting
      for biologically relevant covariates. The investigators will also (2) Estimate the
      association between CMR-based myocardial tissue characteristics and subsequent changes in
      measures of cardiac structure and function in FDRs with normal baseline left-ventricular size
      and function. FDRs examined in Aim 1 will receive a second CMR exam 2.5 years after their
      baseline exam. The investigators will estimate the covariate-adjusted associations between
      baseline myocardial tissue characteristics and subsequent changes in CMR-derived measures of
      cardiac structure and function in groups defined by the most deleterious of the proband's
      variants carried (none, VUS, or LP/P). This study will validate a CMR-derived "pre-DCM"
      phenotype for FDRs who carry P or LP variants (established risk), and also provide
      preliminary evidence that some VUSs are biologically relevant.
    


Study Type

Observational


Primary Outcome

The association between CMR-derived tissue characteristics and the number (burden) of the proband's variants in DCM genes in at-risk first-degree relatives


Condition

Dilated Cardiomyopathy



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

650

Start Date

October 20, 2020

Completion Date

March 31, 2025

Primary Completion Date

October 31, 2023

Eligibility Criteria

        Inclusion Criteria:

          1. The FDR's proband was enrolled in the DCM Precision Medicine Study at 1 of 9
             participating sites, or exceptions granted by study PI.

          2. The FDR's proband has had one or more variants identified, including P, LP and VUS.

          3. The FDR is able report to one of the participating sites for study enrollment.

          4. The FDR has no current contraindication for CMR (glomerular filtration rate (GFR) <30
             mL/min/1.73 m2, non-compatible device implant, or allergy to gadolinium contrast).

          5. The FDR has had no prior heart transplant.

          6. The FDR is ≥18 years of age.

          7. All races/ethnicity

          8. Ability to give informed consent.

          9. Ability to communicate in English.

         10. Subject is not pregnant (CMR may be conducted 3-6 months post delivery)

         11. Willingness to participate in a family-based study (subject willing to interact with
             OSU).

        Exclusion Criteria:

          1. Coronary artery disease (CAD) causing ischemic cardiomyopathy (> 50% narrowing, any
             major epicardial coronary artery).

          2. Primary valvular disease.

          3. Adriamycin or other cardiotoxic drug exposure.

          4. Other forms of cardiomyopathy: Hypertrophic, Restrictive, or Arrhythmogenic Right
             Ventricular Dysplasia/Cardiomyopathy.

          5. Congenital heart disease.

          6. Other detectable causes of dilated cardiomyopathy, including sarcoid and
             hemochromatosis.

          7. Other active multisystem disease, even if very rare, that may plausibly cause DCM
             (e.g., hypereosinophilic syndrome, cardiac involvement with connective tissue disease,
             Loeffler's endocarditis, endomyocardial fibrosis, etc) are excluded. Please call the
             PI to discuss if uncertain or not clear.

          8. Severe and untreated or untreatable hypertension (systolic blood pressures routinely
             greater than 180 mm Hg and/or diastolic blood pressures greater than 120 mm Hg, and if
             resistant to multidrug treatment). This includes profound hypertension associated with
             other multisystem disease (e.g., scleroderma, other vasculitides, etc).
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Ray Hershberger, MD, 1-614-688-1388, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04638621

Organization ID

831408

Secondary IDs

R01HL148581-01A1

Responsible Party

Principal Investigator

Study Sponsor

Ohio State University

Collaborators

 National Heart, Lung, and Blood Institute (NHLBI)

Study Sponsor

Ray Hershberger, MD, Principal Investigator, Ohio State University


Verification Date

November 2020