Pathophysiology of Dilated Cardiomyopathy

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Brief Title

Pathophysiology of Dilated Cardiomyopathy

Official Title

Using Novel Blood and Imaging Biomarkers to Better Understand the Pathophysiology of Paediatric Dilated Cardiomyopathy

Brief Summary

      This will be a cross-sectional, observational study.

      Null hypothesis:

      There is no difference in the amount of extracellular volume (ECV or scarring) in the hearts
      of patients with heart failure as compared to control subjects.

      Heart failure occurs when the heart muscle has become too weak to work properly. It is
      associated with an increase in the amount of connective tissue (collagen) which replaces dead
      heart muscle cells (scarring). Currently a biopsy of the muscle is the only way to measure
      the amount of scarring. This is invasive and rarely done in children. Because of this, it is
      difficult to measure the amount of scarring in a particular patient or disease process, which
      is important for improving our understanding and treatment of the disease.

      Cardiac magnetic resonance imaging (MRI) is a non-invasive imaging tool which is routinely
      used to look at areas of local scarring in heart muscle. Because the scarring is so
      widespread in paediatric patients, we have not been able to use this method previously. Now
      new imaging techniques allow us to look at widespread scarring but these have not yet been
      validated in children.

      We plan to use late gadolinium enhancement (T1 mapping) to measure the amount of scarring in
      patients with heart failure (we have evidence that their heart biopsies show increased
      amounts of scar tissue) and children having MRI scans for other reasons. We will use measures
      of function including echocardiography and 6 minute walk test to compare to the amount of
      scarring. This will help us to know whether the amount of scarring will be clinically useful.

      We will look at the amount of various proteins in the blood of patients and control subjects
      which are related to the scarring and cell death processes. We already use blood tests to
      monitor heart failure and these tests may help us to refine our testing and improve timing of
      treatment (e.g. transplantation).

      This study will help us to design further research in this field.
    

Detailed Description

      All patients will be under the care of Great Ormond Street Hospital.

      Patient Groups:

      There will be three main patient groups:

        1. Heart Failure Patients (MRI Clinically indicated)

        2. Heart Failure Patients (Voluntarily recruited from clinic)

             1. 8-16 years of age

             2. Non-GA only

        3. Control subjects (Clinically indicated brain MRI with contrast)

      Patient recruitment

      We will include Great Ormond Street patients in this trial who are known to the heart failure
      team because they have been diagnosed with DCM for at least 3 months. They will have an
      established diagnosis of heart failure and will be under regular follow up. Where possible,
      we will attempt to align the research study review date with that of the patient's regular
      annual review.

      We will include patients who are to have a cardiac MRI scan with contrast for clinical
      reasons. These patients will be of any age and will have the scan under GA if appropriate, In
      addition, we will recruit patients from heart failure clinic who are not due to have scans
      for clinical reasons. These patients will be between 8-16 years to allow cooperation with the
      MRI scan protocol without the need for general anaesthetic (GA).

      Age-matched control patients will be those having routine MRI with contrast for non-cardiac
      MRI scans. They will also have blood tests for cardiac biomarkers at the time of insertion of
      the cannula for contrast injection. These will be patients identified as requiring gadolinium
      contrast for neurological imaging. They will include patients who are awake and those sedated
      or under GA. These patients will mainly be having routine brain MRI with contrast for
      epilepsy.

      Both groups will be fully consented.

      Heart Failure Patients:

      We will recruit patients being referred for cardiac MRI scanning for clinical reasons as well
      as inviting patients to volunteer for an MRI. Patients who do not require a cardiac MRI for
      clinical reasons will be over the age of 8 years to allow for cooperation with the MRI
      without general anaesthesia. Patients under follow up by the heart failure team will be
      contacted by their primary care consultant in the first instance to introduce the study and
      invite the patient to participate. It will be made clear there is no obligation to join the
      study and their treatment will be unaffected by their decision. They will be free to withdraw
      consent at any time. The patients will be invited to phone the study coordinator (DP) to ask
      questions, express willingness to participate or to decline. Non-responders will be sent one
      further letter of invitation.

      Control subjects:

      Patients being referred to the MRI department at Great Ormond Street Hospital will be
      identified once they have been allocated to a neurological MRI protocol with gadolinium
      enhancement. The radiologist allocating the patient will contact the patients' primary
      consultant to inform them about the study and request permission to contact the family. The
      family will be contacted once permission has been given, first by phone and then information
      sheets will be provided. The patients will be invited to phone the study coordinator (DP) to
      ask questions, express willingness to participate or to decline. Non-responders will be sent
      one further letter of invitation.

      Travel costs will be reimbursed where these are incurred specifically for participation in
      the study.

      Consent:

      Written, informed consent will be obtained from all participants if they choose to take part
      in this study. Information sheets will also be provided to the patients' GP and their
      cardiology physician, if they are under separate cardiology follow-up. Patients will be free
      to withdraw at any time.

      Risks & Burdens from the study protocol

      The main risk arising from our study relates to the insertion of an IV line and
      administration of a gadolinium-based contrast agent. Such contrast agents are widely used in
      clinical practice and are extremely safe when administered within standard dosage guidelines.
      There are, however, potential complications of allergic reaction and development of
      Nephrogenic Systemic Fibrosis (NSF). Such allergic reactions are rare and when they occur,
      the majority are mild.

      To mitigate this risk we will exclude patients with a previous history of allergic response
      to gadolinium-containing agents as well as those with a severe atopic history or history of
      renal impairment. There are no known cases of NSF in patients with normal renal function(1).
      We will measure renal function in all patients within 1 month of the study.

      For patients being scanned specifically for the study, we will select patients over 8 years
      of age, to avoid the need for general anaesthetic. We will attempt to select mainly patients
      who require MRI scanning with contrast for clinical indications. The control group will only
      consist of those having MRI for clinical indications. In this case, the only burden will be
      increased time in the scanner of around 20 minutes to obtain the sequences required. Evidence
      from our institution shows that the increased duration of general anaesthetic is not harmful
      and does not lead to complications or adverse events.

      We will obtain blood samples for serum bio-marker measurement and haematocrit at the time of
      IV line insertion so this does not represent an additional intervention for the patient. We
      will use local anaesthetic cream or spray as requested by the patient and will use play and
      distraction techniques to minimise distress.

      There are no potential adverse effects of a properly conducted transthoracic echocardiogram.

      The 6 minute walk test will only be employed if the patient is able and willing to
      participate.

      There are no potential adverse effects of a properly conducted MRI scan. The magnetic field
      and RF pulses are not known to cause any physical harm in properly selected subjects. Such
      selection will involve careful screening of the patients' medical history for any surgery or
      accidents that might have introduced metal to their bodies e.g. cerebral artery aneurysm
      clips or a metal foreign body in an eye. This will require a review of the patient's notes
      once consent has been given and a written checklist at the time of MRI scan. Such patients
      are not scanned in standard clinical practice and would also be excluded from the study.

      Therefore, there is no realistic potential for pain, discomfort, distress, inconvenience or
      detrimental change to lifestyle anticipated for the participants from the MRI scan itself.

      1. Dillman, J.R., J.H. Ellis, R.H. Cohan, P.J. Strouse, and S.C. Jan, Frequency and severity
      of acute allergic-like reactions to gadolinium-containing i.v. contrast media in children and
      adults. AJR Am J Roentgenol, 2007. 189(6): p. 1533-8.

      Unexpected clinical findings

      If new abnormalities or medical issues come to light as a result of the study investigations,
      the patient's GP and hospital consultant will be informed. Medical follow-up of these issues
      will be through the patient's usual medical carers.
    


Study Type

Observational


Primary Outcome

Fibrosis

Secondary Outcome

 Biomarkers

Condition

Dilated Cardiomyopathy


Study Arms / Comparison Groups

 Heart failure
Description:  Patients will be recruited from the heart failure clinic by their consultant. These will include patients who are due to have a MRI scan for clinical reasons and those who volunteer to participate. Voluntary subjects will be over 8 years.

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

20

Start Date

January 2014


Primary Completion Date

June 2014

Eligibility Criteria

        Inclusion Criteria:

          -  Established diagnosis of DCM for 3 months

          -  Ability to cooperate with MRI scan without general anaesthesia (volunteers over 8
             years), or any age if cardiac MRi clinically indicated

          -  Provides written, informed consent

        Exclusion Criteria:

          -  Patient exclusion criteria:

          -  Estimated GFR <30mls/min

          -  Contraindication to MRI (see appendix 1)

          -  Chronic inflammation/ malignancy/ connective tissue disease

          -  Structural congenital heart disease/ previous cardiac surgery

        Control Group Exclusion Criteria:

          -  History of heart failure or congenital heart disease

          -  Contraindication to MRI (see below)

          -  Chronic inflammation/ malignancy/ connective tissue disease

          -  Previous malignancy

        Exclusion criteria for MRI

          -  Central nervous system aneurysm clips

          -  Implanted neural stimulator

          -  Implanted cardiac pacemaker or defibrillator

          -  Cochlear implant

          -  Ocular foreign body e.g. metal shavings

          -  Other implanted medical devices e.g. drug infusion ports

          -  Insulin pump

          -  Metal shrapnel or bullet

          -  Pregnant women (patients who are uncertain will be required to have a urinary or blood
             screening test)
      

Gender

All

Ages

N/A - 16 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Michael Burch, MD, , 

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT02001961

Organization ID

12CC23


Responsible Party

Sponsor

Study Sponsor

Great Ormond Street Hospital for Children NHS Foundation Trust


Study Sponsor

Michael Burch, MD, Study Director, Great Ormond Street Hospital


Verification Date

November 2013