Iron-mediated vascular disease in sickle cell disease.

Summary

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

Top Publications

  1. pmc Low-shear red blood cell oxygen transport effectiveness is adversely affected by transfusion and further worsened by deoxygenation in sickle cell disease patients on chronic transfusion therapy
    Jon Detterich
    Division of Cardiology, Children s Hospital Los Angeles, California 90027, USA
    Transfusion 53:297-305. 2013
  2. pmc Patients with sickle cell anemia on simple chronic transfusion protocol show sex differences for hemodynamic and hematologic responses to transfusion
    Jon A Detterich
    Division of Cardiology, Division of Pediatric Pulmonology, Division of Hematology, Children s Hospital Los Angeles, Los Angeles, California 90027, USA
    Transfusion 53:1059-68. 2013
  3. ncbi Analysis of light scattering by red blood cells in ektacytometry using global pattern fitting
    Miklós Rábai
    Department of Medicine, University of Pecs, Pecs, Hungary
    Biorheology 49:317-28. 2012
  4. pmc Fast approximation to pixelwise relaxivity maps: validation in iron overloaded subjects
    Antonella Meloni
    CMR Unit, Fondazione G Monasterio CNR Regione Toscana and Institute of Clinical Physiology, Pisa, Italy
    Magn Reson Imaging 31:1074-80. 2013
  5. pmc Sex differences and steroid modulation of cardiac iron in a mouse model of iron overload
    Casey Brewer
    Division of Pediatric Cardiology, Children s Hospital Los Angeles, Los Angeles, Calif
    Transl Res 163:151-9. 2014
  6. pmc Interdependence of cardiac iron and calcium in a murine model of iron overload
    Maya Otto-Duessel
    Division of Pediatric Cardiology, Department of Cardiology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    Transl Res 157:92-9. 2011
  7. pmc Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity
    Debbie Friedman
    Children s Heart Center, Newark Beth Israel Medical Center, 201 Lyons Avenue, Newark, NJ 07112, USA
    J Heart Lung Transplant 31:642-7. 2012

Scientific Experts

  • Debbie Friedman
  • John C Wood
  • Casey Brewer
  • Jon A Detterich
  • Miklós Rábai
  • Maya Otto-Duessel
  • Jon Detterich
  • Ani Dongelyan
  • Antonella Meloni
  • Herbert J Meiselman
  • Ruth I Wood
  • Suvimol Sangkatumvong
  • Alessia Pepe
  • Amber Jones
  • Roberta Kato
  • Adam Bush
  • John Wood
  • Thomas D Coates
  • MICHAEL KHOO
  • Massimo Lombardi
  • Hugh Young Rienhoff
  • Thomas Coates
  • Tamas Alexy
  • Rosalinda Wenby
  • HERBERT MEISELMAN
  • Heather Zmyewski
  • Jack Feinberg
  • Rosalinda B Wenby

Detail Information

Publications8

  1. pmc Low-shear red blood cell oxygen transport effectiveness is adversely affected by transfusion and further worsened by deoxygenation in sickle cell disease patients on chronic transfusion therapy
    Jon Detterich
    Division of Cardiology, Children s Hospital Los Angeles, California 90027, USA
    Transfusion 53:297-305. 2013
    ..We hypothesized that transfusion would improve HVR at high shear despite increased blood viscosity, but would decrease HVR at low shear...
  2. pmc Patients with sickle cell anemia on simple chronic transfusion protocol show sex differences for hemodynamic and hematologic responses to transfusion
    Jon A Detterich
    Division of Cardiology, Division of Pediatric Pulmonology, Division of Hematology, Children s Hospital Los Angeles, Los Angeles, California 90027, USA
    Transfusion 53:1059-68. 2013
    ..We hypothesized that transfusion would improve oxygen-carrying capacity, but that would be counteracted by a decrease in cardiac output due to increased hematocrit (Hct) and vascular resistance, leaving oxygen delivery unchanged...
  3. ncbi Analysis of light scattering by red blood cells in ektacytometry using global pattern fitting
    Miklós Rábai
    Department of Medicine, University of Pecs, Pecs, Hungary
    Biorheology 49:317-28. 2012
    ..Additionally, the relative concentrations of normal and non-deformable cells can be determined...
  4. pmc Fast approximation to pixelwise relaxivity maps: validation in iron overloaded subjects
    Antonella Meloni
    CMR Unit, Fondazione G Monasterio CNR Regione Toscana and Institute of Clinical Physiology, Pisa, Italy
    Magn Reson Imaging 31:1074-80. 2013
    ..Pixelwise (PW) fitting to the iron-mediated signal decay has some advantages but is slower and more vulnerable to noise than region-based techniques. We present a fast, pseudo-pixelwise mapping (PPWM) algorithm...
  5. pmc Sex differences and steroid modulation of cardiac iron in a mouse model of iron overload
    Casey Brewer
    Division of Pediatric Cardiology, Children s Hospital Los Angeles, Los Angeles, Calif
    Transl Res 163:151-9. 2014
    ..01). In summary, we found that estrogen increased cardiac iron loading in male mice, but not in females. Male mice loaded 25% more hepatic iron than female mice regardless of the hormone treatment...
  6. pmc Interdependence of cardiac iron and calcium in a murine model of iron overload
    Maya Otto-Duessel
    Division of Pediatric Cardiology, Department of Cardiology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    Transl Res 157:92-9. 2011
    ..Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related...
  7. pmc Systemic endothelial dysfunction in children with idiopathic pulmonary arterial hypertension correlates with disease severity
    Debbie Friedman
    Children s Heart Center, Newark Beth Israel Medical Center, 201 Lyons Avenue, Newark, NJ 07112, USA
    J Heart Lung Transplant 31:642-7. 2012
    ..Systemic endothelial function has not been explored in children with IPAH...