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Cell Free DNA in Cardiac Sarcoidosis (cfDNA in CS)

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ClinicalTrials.gov Identifier: NCT03858777
Recruitment Status : Recruiting
First Posted : March 1, 2019
Last Update Posted : August 27, 2019
Sponsor:
Information provided by (Responsible Party):
Nabeel Hamzeh, University of Iowa

Brief Summary:

Sarcoidosis is a multisystem granulomatous disease of unknown cause that can affect any organ in the body, including the heart. Granulomatous myocarditis can lead to ventricular dysfunction and ventricular arrhythmias causing significant morbidity and mortality. Immunosuppressive therapy (IST) has been shown to reverse active myocarditis and preserve left ventricular (LV) function and in some cases improve LV function. In addition, IST can suppress arrhythmias that develop due to active myocarditis and prevent the formation of scar.

The potential role of cardiac biomarkers, including brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and cardiac troponins, in detecting active myocarditis is limited and studies have been disappointing. At present, there are no biomarkers to detect active myocarditis and the use of advanced imaging modalities (FDG-PET) for assessing and monitoring active myocarditis is not feasible or practical and is associate with high radiation exposure. As such, a biomarker that is reflective of active myocarditis and that is cardiac specific will assist physicians in assessing the presence of active myocarditis to guide therapeutic decisions and to assess response to therapy which can limit further cardiac damage.

Cell free DNA (cfDNA) are fragments of genomic DNA that are released into the circulation from dying or damaged cells. It is a powerful diagnostic tool in cancer, transplant rejection and fetal medicine especially when the genomic source differs from the host. A novel technique that relies on tissue unique CpG methylation patterns can identify the tissue source of cell free DNA in an individual reflecting potential tissue injury. We will be conducting a pilot study to explore the utility of this diagnostic tool to identify granulomatous myocarditis in patients with sarcoidosis.


Condition or disease Intervention/treatment Phase
Sarcoidosis With Myocarditis Sarcoidosis Healthy ST Elevation Myocardial Infarction Diagnostic Test: cell free DNA Not Applicable

Detailed Description:

Sarcoidosis is a multisystem granulomatous disease of unknown cause that can affect any organ in the body, including the heart. Sarcoidosis results from an immune reaction to an environmental exposure to yet unknown antigen(s) in a genetically predisposed individual. Autopsy studies have suggested that cardiac involvement with sarcoidosis occurs in up to 25% of cases, although more than half of these cases are sub-clinical. Cardiac sarcoidosis (CS) CS can lead to life-threatening heart failure, heart block, or rhythm disturbance and accounts for 13-25% of all sarcoidosis deaths in the USA. Therefore, although respiratory failure from lung sarcoidosis is the most common cause of sarcoidosis-related death in the USA, sudden death from cardiac sarcoidosis is a major concern owing to its acute nature. CS can present in a multitude of ways. It can be the initial manifestation of sarcoidosis in an individual not known to have sarcoidosis (a cohort beyond the aims of this proposal), patients can present with cardiac symptoms which can include palpitations, near-syncope or syncopal episodes which require a complete workup for potential CS and patients can be asymptomatic which is a sizable cohort considering the discrepancy between the expected prevalence of CS (25-40%) and CS that is detected clinically (5%).

Granulomatous myocarditis can lead to ventricular dysfunction and ventricular arrhythmias causing significant morbidity and mortality. Immunosuppressive therapy (IST) has been shown to reverse active myocarditis and preserve left ventricular (LV) function and in some cases improve LV function. In addition, IST can suppress arrhythmias that develop due to active myocarditis and prevent the formation of scar. Cardiac MRI (cMRI) and cardiac PET scans are currently used as complementary diagnostic tests for cardiac sarcoidosis, although with some limitations. Cardiac MRI with gadolinium has a sensitivity of 76-100% and specificity of 78-92% for the diagnosis of cardiac sarcoidosis, but its use is limited in patients with implantable cardiac devices. The presence of delayed enhancement on gadolinium-enhanced MRI is suggestive of scar tissue formation. 18FDG PET uses radioactive glucose to detect areas of active inflammation. The use of 18FDG PET as a marker of active granulomatous myocarditis should be interpreted carefully as several studies have shown the limitations of such protocols that force the myocardium to generate energy using free fatty acid metabolism exclusively. In addition, studies have also shown that the presumed pathological patterns, focal and focal on diffuse uptake, are also seen in healthy controls and patients with ischemic congestive heart failure who have undergone 18-FDG-PET12 and that a blood glucose level of >7.5mmol/L (>137mg/dl) at the time of the study results in absent or minimal myocardial FDG activity.

The potential role of cardiac biomarkers, including brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and cardiac troponins, in detecting active myocarditis is limited and studies have been disappointing. At present, there are no biomarkers to detect active myocarditis and the use of advanced imaging modalities (FDG-PET) for assessing and monitoring active myocarditis is not feasible or practical and is associate with high radiation exposure. As such, a biomarker that is reflective of active myocarditis and that is cardiac specific will assist physicians in assessing the presence of active myocarditis to guide therapeutic decisions and to assess response to therapy which can limit further cardiac damage.

Cell free DNA (cfDNA) are fragments of genomic DNA that are released into the circulation from dying or damaged cells. It is a powerful diagnostic tool in cancer, transplant rejection and fetal medicine especially when the genomic source differs from the host. A novel technique that relies on tissue unique CpG methylation patterns can identify the tissue source of cell free DNA in an individual reflecting potential tissue injury. A recent paper utilized this technique to identify cardiac specific cfDNA in the bloodstream of patients with acute myocardial injury and sepsis reflecting cardiomyocyte injury/death. We will be conducting a pilot study to explore the utility of this diagnostic tool to identify granulomatous myocarditis in patients with sarcoidosis.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Cardiomyocyte Specific Cell Free DNA as a Marker of Cardiac Sarcoidosis
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : March 15, 2020
Estimated Study Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sarcoidosis

Arm Intervention/treatment
Active Comparator: Sarcoidosis patients without evidence of active myocarditis
A single blood draw.
Diagnostic Test: cell free DNA
All groups will have blood draws and cfDNA measured

Experimental: Sarcoidosis patients with evidence of active myocarditis
Two blood draws 2 months apart.
Diagnostic Test: cell free DNA
All groups will have blood draws and cfDNA measured

Active Comparator: Acute ST elevation myocardial infarction (STEMI)
Three blood draws, baseline, 6 hours and 24 hours.
Diagnostic Test: cell free DNA
All groups will have blood draws and cfDNA measured

Placebo Comparator: Healthy controls
A single blood draw
Diagnostic Test: cell free DNA
All groups will have blood draws and cfDNA measured




Primary Outcome Measures :
  1. cfDNA level [ Time Frame: cfDNA level at baseline and 2 months for sarcoidosis with heart disease compared to cfDNA levels at baseline for healthy controls and sarcoidosis without cardiac disease and cfDNA levels at baseline, 6 and 24 hours for STEMI patients. ]
    cfDNA level



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  1. Sarcoidosis patients without evidence of active myocarditis:

    • Inclusion:

      • Diagnosis of sarcoidosis based on the ATS/ERS criteria.
      • Normal 12 lead ECG within the past one year.
      • Non-smoker.
      • No immunosuppressive therapy for at least one year.
    • Exclusion:

      • Known cardiac disease.
      • Active smoker.
      • On immunosuppressive therapy.
  2. Sarcoidosis patients with evidence of active myocarditis:

    • Inclusion:

      • Diagnosis of sarcoidosis based on the ATS/ERS criteria.
      • Evidence of active myocarditis based on recent cMRI or cFDG-PET.
      • Non-smoker.
    • Exclusion:

      • Known cardiac disease other than sarcoidosis.
      • Active smoker.
      • On immunosuppressive therapy.
  3. Acute ST elevation myocardial infarction (STEMI):

    • Inclusion:

      • Diagnosis STEMI based on 1mm ST elevation in 2 or more contiguous leads.
      • Symptom onset within 12 hours.
      • Undergoing cardiac intervention for acute coronary syndrome.
      • Able to consent for blood draw.
    • Exclusion:

      • Active smoker.
      • Hemodynamically unstable.
  4. Healthy controls:

    • Inclusion:

      • No known cardiac disease.
      • No known cardiovascular risk factors: hypertension, diabetes.
      • Non-smoker.

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): NCT03858777


Contacts
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Contact: Brenda Werner, RN 319-353-8862 brenda-r-werner@uiowa.edu

Locations
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United States, Iowa
University of Iowa Not yet recruiting
Iowa City, Iowa, United States, 52242
Contact: Brenda Werner, RN    319-353-8862    brenda-r-werner@uiowa.edu   
Contact: Nabeel Hamzeh, MD    319-356-8343    nabeel-hamzeh@uiowa.edu   
University of Iowa Recruiting
Iowa City, Iowa, United States, 52242
Contact: Brenda Werner, RN    319-353-8862    brenda-r-werner@uiowa.edu   
Sponsors and Collaborators
Nabeel Hamzeh
Investigators
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Principal Investigator: Nabeel Hamzeh, MD University of Iowa

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Responsible Party: Nabeel Hamzeh, Associate Professor of Medicine, University of Iowa
ClinicalTrials.gov Identifier: NCT03858777     History of Changes
Other Study ID Numbers: 201812737
First Posted: March 1, 2019    Key Record Dates
Last Update Posted: August 27, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No
Keywords provided by Nabeel Hamzeh, University of Iowa:
sarcoidosis
Additional relevant MeSH terms:
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Myocardial Infarction
ST Elevation Myocardial Infarction
Myocarditis
Sarcoidosis
Infarction
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Cardiomyopathies