Cardiac Function in Patients With Hereditary Hemochromatosis

2014-07-24 14:33:37 | BioPortfolio


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.


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.

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.

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.

Study Design





National Institutes of Health Clinical Center, 9000 Rockville Pike
United States


Active, not recruiting


National Institutes of Health Clinical Center (CC)

Results (where available)

View Results


Published on BioPortfolio: 2014-07-24T14:33:37-0400

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Medical and Biotech [MESH] Definitions

A disorder due to the deposition of hemosiderin in the parenchymal cells, causing tissue damage and dysfunction of the liver, pancreas, heart, and pituitary. Full development of the disease in women is restricted by menstruation, pregnancy, and lower dietary intake of iron. Acquired hemochromatosis may be the result of blood transfusions, excessive dietary iron, or secondary to other disease. Idiopathic or genetic hemochromatosis is an autosomal recessive disorder of metabolism associated with a gene tightly linked to the A locus of the HLA complex on chromosome 6. (From Dorland, 27th ed)

A membrane protein and MHC class I antigen. It contains an IMMUNOGLOBULIN C1-SET DOMAIN and interacts with BETA 2-MICROGLOBULIN. It may also regulate the interaction of TRANSFERRIN with the TRANSFERRIN RECEPTOR. Mutations in the HFE gene are associated with cases of FAMILIAL HEMOCHROMATOSIS.

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The techniques used to draw blood from a vein for diagnostic purposes or for treatment of certain blood disorders such as erythrocytosis, hemochromatosis, polycythemia vera, and porphyria cutanea tarda.

Human histocompatibility (HLA) surface antigen encoded by the B locus on chromosome 6. There is a weak association between the presence of the HLA-B7 antigen and the diseases of narcolepsy and idiopathic hemochromatosis. HLA-B7 is in linkage disequilibrium with HLA-A3 and HLA-DR2.

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