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.

• INCLUSION CRITERIA:

HH Patients

Group A patients (untreated HH patients)

Adults 21 years or older

New York Heart Association Functional Classification Class I

Documented positive phenotyping for homozygote Cys282Tyr of Hfe gene with documented serum ferritin level above 400 ng/ml or documented % iron saturation more than 60%.

Patient has not received standard chronic phlebotomy or deferoxamine treatment. Individuals are allowed to have up to 3 emergency phlebotomies for alleviation of severe iron accumulation before enrollment.

Group B patients (treated HH patients)

Adults 21 years or older

New York Heart Association Functional Classification Class I

Documented positive phenotyping for homozygote Cys282Tyr of Hfe gene with documented serum ferritin level above 400 ng/ml or documented % iron saturation more than 60%.

Patient has been compliant with standard phlebotomy and/or deferoxamine treatment for 6 months or longer and in stable phase with iron saturation 50% or less.

Healthy Volunteers

Group C Patients (Age-Gender Matched Healthy Control Subjects)

Adults 21 years or older.

No symptoms suggestive of heart disease or any other medical conditions, negative Hfe genotyping for Cys282Tyr or His63Asp with normal ferritin and iron saturation.

EXCLUSION CRITERIA:

HH patients

Group A patients (untreated HH patients)

Pregnant or lactating women

History or present evidence of coronary artery disease, heart failure, peripheral vascular disease, coagulopathy, or uncontrolled hypertension (systolic blood pressure over 170 mmHg and/or diastolic pressure over 100 mmHg).

History of significant end-organ damage secondary to HH.

Serum creatinine greater than 2.0 mg/ml

LFT's more than 2.5 times above upper limit of normal

History of structural cardiac disease except mitral valve prolapse with mild mitral regurgitation

Uncontrolled glucose levels with hemoglobin A(1c) above 8 mg/dl or the use of more than one oral hyperglycemic agents or insulin therapy to control diabetes.

Current use of antioxidant treatment such as vitamin E and C. However, the cessation of this treatment 4 weeks prior to the study will allow for inclusion.

Evidence of impaired immunity including HIV

Chronic systemic inflammatory disease such as SLE, rheumatoid arthritis, collagen vascular disease.

Participation in unrelated research involving investigational pharmacological agent in past 30 days.

Current alcohol use (more than 26 grams averaged ethanol intake per day) or drug abuse.

Inability to provide informed consent

Smoking in past 3 months.

Use of beta-adrenergic blocking agents and calcium channel blockers with negative chronotropic effect within 1 week.

Inability to perform treadmill or bicycle exercise testing.

Inability to undergo MRI such as ferromagnetic implant.

Group B patients (treated HH patients)

Pregnant or lactating women

History or present evidence of coronary artery disease, heart failure, peripheral vascular disease, coagulopathy, or uncontrolled hypertension (systolic blood pressure over 170 mmHg and/or diastolic pressure over 100 mmHg).

History of significant end-organ damage secondary to HH.

Serum creatinine greater than 2.0 mg/ml

LFT's more than 2.5 times above upper limit of normal

History of structural cardiac disease except mitral valve prolapse with mild mitral regurgitation

Uncontrolled glucose levels with hemoglobin A(1c) above 8 mg/dl or the use of more than one oral hyperglycemic agents or insulin therapy to control diabetes.

Current use of antioxidant treatment such as vitamin E and C. However, the cessation of this treatment 4 weeks prior to the study will allow for inclusion.

Evidence of impaired immunity including HIV

Chronic systemic inflammatory disease such as SLE, rheumatoid arthritis, collagen vascular disease.

Participation in unrelated research involving investigational pharmacological agent in past 30 days.

Current alcohol use (more than 26 grams averaged ethanol intake per day) or drug abuse.

Inability to provide informed consent

Smoking in past 3 months.

Use of beta-adrenergic blocking agents and calcium channel blockers with negative chronotropic effect within 1 week.

Inability to perform treadmill or bicycle exercise testing.

Inability to undergo MRI such as ferromagnetic implant.

Healthy volunteers

Group C Patients (Age-Gender Matched Healthy Control Subjects)

Pregnant or lactating women.

History or present evidence of any structural cardiac disease except mitral valve prolapse with mild mitral regurgitation, heart failure, peripheral vascular disease, coagulopathy, and uncontrolled hypertension (systolic blood pressure over 170 mmHg and/or diastolic pressure over 100 mmHg).

Serum creatinine greater than 2.0 mg/ml.

LFT's more than 2.5 times above upper limit of normal.

Current use of antioxidant treatment such as vitamin E and C. However, the cessation of this treatment 4 weeks prior to the study will be included.

Uncontrolled glucose levels with hemoglobin A(1C) above 8 mg/dl or the use of oral hyperglycemic agents or insulin therapy to control diabetes.

Evidence of impaired immunity including HIV.

Chronic systemic inflammatory disease such as SLE, rheumatoid arthritis, collagen vascular disease.

Participation in unrelated research involving investigational pharmacological agent in past 30 days.

Current alcohol use (more than 26 grams averaged ethanol intake per day) or drug abuse.

Inability to provide informed consent.

Smoking in past 3 months.

Subjects with any chronic medical problems*

Inability to undergo MRI such as ferromagnetic implant.

*For the purpose of this protocol "chronic medical problems' is defined as any current condition not amenable to curative therapy and which requires long-term medical treatment and/or clinical monitoring.