Cardiac Function in Patients With Hereditary Hemochromatosis
Condition: Hereditary Hemochromatosis
MeSH terms: Hemochromatosis; Hemosiderosis
Study type: Observational

Summary: 
      This study will examine the effect of iron buildup in the hearts of patients with hereditary
      hemochromatosis (HH), a genetic disease that causes the body to accumulate excess amounts of
      iron. The excess iron can damage the heart, liver, pancreas, skin, and joints. Generally,
      early treatment with phlebotomy (periodic removal of a unit of blood), and in some cases
      chelation (using a drug to remove iron from the body) slows down organ damage in HH patients.
      This study will try to elucidate the effect of iron buildup in the heart and determine if
      phlebotomy and chelation help keep the heart healthy.

      Patients with HH and healthy volunteers 21 years of age and older may be eligible for this
      study. (Normal volunteers will provide normal values of heart function that will be used to
      verify abnormalities detected in HH patients.) Patients must have a gene abnormality of Hfe
      gene Cys282Try homozygote. They may or may not be receiving treatment for HH and they must
      have no heart symptoms or serious organ damage due to HH. Candidates will be screened with a
      medical history and physical examination, blood tests, electrocardiogram (EKG), Holter EKG
      (24-hour EKG monitoring, see description below), and chest x-ray.

      Participants will undergo the following tests and procedures over 2 to 5 days:

        -  Exercise test: The participant exercises on a treadmill while wearing a mouthpiece,
           which is used to measure how much oxygen is used. Electrodes placed on the chest and
           arms monitor the heartbeat during the test.

        -  Echocardiography: This ultrasound test uses sound waves to take pictures. A small probe
           is held against the chest to allow a technician to take pictures of the heart and assess
           its function. A drug called Optison may be injected in an arm vein if needed to enhance
           the ultrasound images.

        -  Exercise stress echocardiography: The participant exercises on a stationary bike while
           heart function is measured with an echocardiogram, EKG, and blood pressure cuff.

        -  24-hour Holter EKG: The participant wears a small machine that records heart rhythm
           continuously for 24 hours. The recorder is connected by cables to electrodes placed on
           the chest.

        -  Magnetic resonance imaging: This test uses a magnetic field and radio waves to obtain
           detailed images of the heart and blood vessels. The participant lies flat on a table
           that slides inside the scanner, which is a large hollow tube.

      All tests are performed once in normal volunteers and in patients who have received standard
      treatment for HH. Untreated patients repeat the tests 6 months after beginning phlebotomy or
      chelation. Additional time points for these tests might be added if further evaluation is
      needed.

      ...
    

Detailed description: 
      Hereditary hemochromatosis (HH) is the most common hereditary metabolic abnormality among
      Caucasians. Homozygosity for the Cys282Tyr mutation, which is the most common known mutation
      with a predisposition to iron overload, occurs with an estimated frequency of 8 per 1000 in
      the Caucasians. Hemochromatosis in its advanced stages is associated with severe cardiac
      complications including congestive heart failure, premature coronary artery disease, and
      cardiac arrhythmias. The clinical manifestations of HH are due to increased iron absorption
      and abnormal iron cycling with excessive iron deposition in various organs. Mutations of the
      Hfe gene on chromosome 6 have been recently identified. Although the pathophysiology remains
      incompletely understood, a homozygote mutation in Cys282Tyr is present in 84 to 100% of
      clinically confirmed HH cases. This discovery permits the early diagnosis of this disease and
      could be used for screening to identify asymptomatic cases. Therefore, the NHLBI in January
      2000 launched a 30 million dollar project named HEIRS (HEmochromatosis and IRon overload
      Study) to screen 1,000,000 adults for HH, and recently completed enrollment.

      <TAB>

      Increased left ventricular wall thickness and mass has been found to be early cardiac
      manifestations of HH appearing before the onset of contractile dysfunction. Interestingly, a
      report also indicates that functional abnormalities of the heart can be seen in predominantly
      asymptomatic HH patient group. Such abnormalities of diastolic function are detected by
      Doppler echocardiography. Observations support the theory that asymptomatic cardiac
      dysfunction is detectable with non-invasive cardiac imaging in patients with HH. <TAB>

      <TAB>

      Although the pathophysiology of cardiac dysfunction in HH has not been well characterized, it
      is speculated that enhanced production of reactive oxygen species (ROS) may be responsible
      for tissue damage. Therefore, biochemical and/or genetic markers of oxidant stress might be
      helpful in determining whether this mechanism is involved in producing cardiac dysfunction.

      In this protocol, we propose a retrospective pilot study with a small-sized nested
      prospective study of cardiac function in patients with HH. The intention is to utilize
      obtained results to design a larger definitive study if results are warranted. The following
      hypotheses will be tested: Cardiac abnormalities 1) can be diagnosed with conventional
      non-invasive cardiac imaging in HH patients with New York Heart Association Functional Class
      I (asymptomatic), 2) limit patients' exercise capacity, 3) are associated with an elevated
      oxidant stress level, and 4) are improved by phlebotomy and its efficacy correlated with a
      reduction in oxidant stress.
    

Observational model: Case-Control
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Subjects will be recruited from the North American continent and United States possessions.
        The patients currently followed at the Transfusion Medicine Department under IRB protocol #
        01-CC-0045 will be informed of our study protocol. Also, subjects referred to IRB protocol
        # 01-CC-0045 from the ongoing genotyping study by the NHLBI (HEIRS trial) will be
        considered for the potential subjects. Advertisements of our study both on the Web and the
        NIH newsletters will be planned through the NIH Patient Recruitment and Public Liaison to
        recruit additional patients if necessary. There will be no exclusion from participation in
        the study on the basis of ethnicity/race/gender. Since HH is predominantly seen in
        Caucasian origins and the exact frequency in African, Asian, Hispanic population is too low
        to estimate, we assume that the study population will not be the same as the demographic
        representation of ethnic groups in this country because of the inheritance nature of this
        disease.
      
Keywords: Hereditary Disease; Diastolic Dysfunction; Exercise Tolerance; Exercise Stress Echocardiography; MRI; Natural History