Genomes and Genes
Iron-mediated vascular disease in sickle cell disease.
Principal Investigator: John C Wood
Abstract: DESCRIPTION (provided by applicant): This proposal addresses broad Challenge Area (15) Translational and specific Challenge Topic, 15- DK-106: Translating Basic Hematology Concepts. Prolonged exposure to iron of the heart, liver, endocrine glands and other tissues results in severe oxidant damage, organ failure, malignant transformation and death, if unrecognized and untreated. Sickle cell disease (SCD) is a genetic disease that causes severe, lifelong pain, debilitating organ toxicity and early death. Many of the complications can be ameliorated by blood transfusions, which in turn cause significant iron overload. As humans have no effective way to remove excess iron, the iron remains throughout life unless chelation therapy is instituted. Patients who are on chronic transfusion programs and develop iron overload are routinely monitored at specialized centers and receive iron chelation. In contrast, a large number of patients only receive sporadic transfusions for treatment of acute events at different hospitals by providers unfamiliar with SCD and iron overload. Even though the number of sporadic transfusions may be high, these patients'iron status is largely unknown. In addition, patients who were chronically transfused when young, often stop transfusions in adulthood and are not treated for their iron overload. Thus, a significant number of SCD patients may have unrecognized iron overload and may not be aware of the associated risks. Very few studies have examined iron overload in SCD and most have used ferritin, clearly recognized as an inadequate measure of total body iron, for the assessment of iron burden. In fact, no study has examined the prevalence of iron overload in SCD adults by direct measurement of total body or tissue iron. We will determine the prevalence of iron overload in SCD patients using MRI methodologies that we developed and validated. These techniques permit easy, accurate, and non-invasive measurement of iron overload in multiple organs. Iron overload is associated with organ damage and poor outcomes in SCD patients;however, the mechanisms by which iron overload exert its toxicity have not been studied and the effects of damage from iron overload have not been separated from organ damage due to vaso-occlusion itself. SCD patients suffer from chronic, progressive vasculopathy leading to pulmonary hypertension, renal failure and stroke. Chronic intravascular hemolysis, which releases red cell components in the circulation, is a leading cause of vasculopathy and acts by impairing nitric oxide bioavailability. Iron-mediated oxidative stress and increased levels of labile plasma iron (LPI), may worsen intravascular hemolysis and impair endothelial function, as clearly seen in the thalassemia syndromes. Determination of the relation between non-invasive, standardized measures of vascular endothelial function, biomarkers of oxidant stress, modulators of nitric oxide metabolism and iron loading is critical for the understanding of sickle vasculopathy and must be accomplished before an interventional study to treat sickle vasculopathy can be designed. Hypothesis: We suspect that clinically significant iron overload is common in subjects with SCD and worsens with age. Furthermore, we anticipate that tissue localized and free plasma iron levels predict endothelial dysfunction, carotid intimal-medial thickening, and pulmonary hypertension, independently of hemolysis, inflammation, and night-time hypoxia. Specific Aims: 1) We will determine the prevalence, and magnitude of hepatic, pancreatic and labile iron elevation in patients with SCD. Liver iron concentration (LIC) and content measured by MRI will be used as a surrogate for total body iron. Pancreatic R2* will be measured as a surrogate for chronic labile iron exposure. Serum ferritin, transferrin saturation, and labile plasma iron (LPI) will be measured as acute markers of iron status. 2) We will determine whether iron overload exacerbates sickle vasculopathy. We will quantify sickle vasculopathy by measuring flow-mediated dilation of the brachial artery, carotid intimal-medial thickening, and pulmonary hypertension. We will determine if iron loading predicts vasculopathy independently of hemolysis (cell-free hemoglobin, lactate dehydrogenase), inflammation (high-sensitivity CRP), dysfunction of NO metabolism (arginine, ornithine &citrulline, vitamin C, tetrahydrobiopterin, dihydrobiopterin,) and night time hypoxia (overnight pulse oximetry). We anticipate that the results obtained during this granting period will solidly establish the prevalence of iron overload and its relation to biomarkers and endothelial function in SCD patients. This proposal represents an essential first step in the design of a subsequent clinical trial to improve vascular function. PUBLIC HEALTH RELEVANCE: We hypothesize that clinically significant iron overload is common in subjects with sickle cell disease (SCD) and exacerbates sickle vasculopathy. We will measure hepatic, pancreatic and renal iron overload by MRI in 150 SCD patients to determine whether iron overload predicts endothelial dysfunction, carotid intimal-medial thickening, and pulmonary hypertension, independently of hemolysis, inflammation, and night-time hypoxia. This proposal represents an essential first step in the design of a subsequent clinical trial to improve vascular function in SCD patients.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT
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