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VMB Research Goals
- Studying the prevalence and causes of pulmonary hypertension (high
blood pressure in the lungs) in patients with sickle cell disease.
- Evaluating new treatments for patients with sickle cell disease, targeting:
- Pulmonary hypertension (high blood pressure in the lungs)
- Blood flow
- Inflammation
- Vaso-occlusive pain crisis
- Acute chest syndrome
- Study the reactions of nitric oxide in human blood.
- Using genomics and gene expression microarray technologies to understand sickle cell disease pathogenesis and to develop prognostic models.
VMB Research Studies
- 01-DK-0088 Determining the Prevalence and Prognosis
of Secondary Pulmonary Hypertension in Adult Patients with Sickle Cell
Anemia - PI: Mark Gladwin, M.D.; Point of Contact: James
Nichols, RN (301)435-2345
Précis:
Sickle cell anemia is an inherited blood disorder and the most common
genetic disease affecting African-Americans. Approximately 0.15%
of African-Americans are homozygous for sickle cell disease, and 8% have
sickle cell trait. Acute pain crisis, acute chest syndrome (ACS),
and secondary pulmonary hypertension (high blood pressure in the lungs)
are common complications of sickle cell anemia. Mortality rates
of sickle cell patients with pulmonary hypertension are significantly
increased as compared to patients without pulmonary hypertension. Recent
studies report up to 40% mortality at 22 months after detection of elevated
pulmonary artery pressures in sickle cell patients. Furthermore,
pulmonary hypertension is thought to occur in up to 30% of clinic
patients with sickle cell anemia.
This study is designed to determine the prevalence and prognosis of secondary
pulmonary hypertension in adult patients with sickle cell anemia, and
to determine whether certain genetic markers found in their genes contribute
to the development of pulmonary hypertension.
- 03-CC-0015 Collection of Blood from Volunteers and
Patients for Studies of Endothelial Function and Systemic Inflammation
- Mark Gladwin, M.D.; Point of Contact: James Nichols, RN (301)
435-2345
Précis:
We are evaluating the role of nitric oxide, inflammatory mediators,
and endothelial function in inflammatory diseases that involve the blood
vessels, such as sickle cell disease, coronary artery disease, and sepsis. The
collection of human blood from both patients and healthy volunteers is
necessary for the development of laboratory assays required for these
studies. This protocol defines in general terms the purposes for
which blood will be collected by members of the Clinical Center
Critical Care Medicine Department and Laboratory of Chemical Biology,
NIDDK, and the conditions under which sampling of blood collection will
be performed.
Précis:
This is a multicenter study for 150 patients with sickle cell disease
experiencing pain crisis. The trial will last for 12 months at an
estimated 8 centers nationwide. Patients with known sickle cell
disease will be identified and consented prior to their presentation to
the Emergency Room/Emergency Clinic. The trial will begin at the
time they present o the Emergency Room/Emergency clinic after meeting
entrance criteria. Qualifying patients will be randomized to either
nitric oxide (NO) for inhalation or nitrogen placebo in a double-blind
fashion. Patients will be treated for 6 hours with 80ppm via the
INOvent delivery system.
The objectives are to:
- Assess whether INO’s ability to reduce the severity and
duration of sickle cell vaso-occlusive pain episode when administered
acutely for 6 hours as measured by pain index scores compared
to placebo;
- Assess the impact of INO on rate of hospital admission;
- Assess the
safety of 80ppm of INO through the INOvent using a face mask
in sickle cell patients during a vaso-0cclusive epi
- 05-CC-0154 - Investigation of Mechanism of Sudden
Death in Sickle Cell Anemia – a Pilot Study, PI: Dorothea
McAreavey, M.D.; Point of Contact: Jill Sanko, RN (301) 496-9320
Précis:
Sickle cell anemia is an inherited blood disorder primarily affecting
groups with origins in endemic malarial areas, especially those
of African descent. SCA results from one of two single amino-acid substitutions
in beta-hemoglobin (Hb-S and Hb-C) that increases the propensity for hemoglobin
to polymerize, distorting, sickling and hemolyzing red cells. Individuals
homozygous for Hb-S (or double heterozygote Hb-S and Hb-C) develop sickle
cell anemia (SCA), while heterozygotes have sickle cell trait. SCA
is characterized by chronic anemia and crises of red cell sickling and
ischemia that are often painful and affect several organs and tissue types. SCA
confers considerable disability, morbidity and mortality.
Annual mortality from SCA has been estimated at 3%. As a significant
number of deaths occur suddenly, a cardiac cause has been suspected. Despite
this observation, cardiac mechanisms of sudden death (SD) have not been
clearly identified. It has been demonstrated recently that SCA patients
with pulmonary hypertension have a higher incidence of SD than those with
normal pulmonary pressures. In many patients, pulmonary hypertension
occurs in association with elevated pulmonary arterial wedge pressures
and normal pulmonary arterial resistance, suggesting that the pulmonary
hypertension develops as the result of left ventricular (LV) abnormalities.
Furthermore, in other conditions in which pulmonary hypertension develops,
SD occurs only at pressures considerably higher than those observed in
SCA. These factors suggest that the pulmonary hypertension
of SCA is a surrogate marker for, rather than the cause of SD. Rather,
an SCA cardiomyopathic process may provide a unifying mechanism
that associates moderate degrees of pulmonary hypertension and high
risk of SD from cardiac causes.
We propose to describe the extent of cardiac involvement in SCA. Specifically,
we will (1) determine whether cardiac arrhythmias are common
in SCA patients with pulmonary hypertension and if they contribute to
SD; (2) describe the LV volume-pressure relations in SCA patients with
pulmonary hypertension in order to determine how elevated pulmonary
pressures are related to dynamic filling properties of the LV; and (3)
investigate whether the pathologic processes characteristic of SCA (such
as iron deposition or ischemia as the result of sickling) contribute
to the development of an SCA cardiomyopathy.
Improved understanding of the etiology and mechanisms of SD in SCA may
allow the development and testing of therapies for the primary prevention
of SD.
- 06-H-0054 - Evaluation of Synergy of Combining
Hydroxyurea with Recombinant Human Erythropoietin Glycoform alpha
(rhu Erythropoietin-α)
on Fetal Hemoglobin Synthesis in Patients with Sickle Cell Anemia, PI: Mark
T. Gladwin, M.D. Point of Contact: James Nichols, RN (301)
435-2345
Précis:
Sickle cell disease (SCD) is a genetic disease that afflicts over eighty
thousand Americans, 4 to 5,000 newborns per year in the US, and
100s of thousands of children and adults world-wide. This disease arises
from a single amino acid mutation of the beta globin chain of hemoglobin,
which results in abnormal polymerization of deoxygenated hemoglobin. The
deceptively simple biologic origin for SCD belies the debilitating chronic
multi-faceted clinical syndrome with which it is associated; SCD is characterized
by lifelong hemolysis, chronic anemia, recurrent painful vaso-occlusive
crises (VOC), hepatic, renal, musculo-skeletal, and central nervous system
complications, and a shortened life-expectancy. Our group has
found an up to 33% incidence of pulmonary hypertension in adult patients
with SCD who were screened and followed prospectively; with two-year
follow-up, this pulmonary hypertension is associated with a 10-fold
increased mortality rate.
Hydroxyurea has emerged as a useful therapy in sickle cell disease. It
is a cell-cycle specific agent that blocks DNA synthesis by inhibiting
ribonucleotide reductase, the enzyme that converts ribonucleotides to
deoxyribonucleotides. Hydroxyurea has been shown to induce the production
of fetal hemoglobin (HbF) in patients with sickle cell anemia, with associated
diminished morbidity and, likely, mortality in these patients. Any
HbF is good in SCD, although it is estimated that levels of 20 percent
HbF are required to substantially reduce the sickling propensity of red
cells and to modulate disease severity. The majority of patients with
SCD respond to hydroxyurea with a more than two-fold increase in HbF levels;
in some patients the percent of HbF exceeds 10 or 15 percent, but it is
not uniformly distributed in all cells, i.e. has a hetero-cellular rather
than a pan-cellular distribution. The mechanism through which hydroxyurea
augments fetal Hgb is incompletely characterized. An additional
benefit of hydroxyurea may be through effects on the nitric oxide (NO)
system. Recently, members of our group found that hydroxyurea
therapy is associated with the intravascular and intra-erythrocytic
generation of NO, and that NO increases HbF expression via the guanylyl
cyclase/cGMP dependent pathways.
We have treated more than 30 patients chronically with hydroxyurea
to determine hematological changes Iongitudinally, and have established
the maximal HbF raising effect of hydroxyurea in these patients. We
have found that the levels of HbF that are induced by hydroxyurea
alone are insufficient, and insufficiently widely distributed, to ameliorate
the life-threatening complications of pulmonary HTN and of on-going
hemolysis in patients with sickle cell disease.
Earlier studies had suggested that the addition of erythropoietin (Erythropoietin)
therapy to chronic hydroxyurea therapy may induce fetal hemoglobin
at higher, more widely distributed, levels. We plan to test this in
patients with sickle cell disease who have chronic kidney disease, which,
presumably, leaves them with a depressed Erythropoietin reserve and an
inability to tolerate standard doses of F-inducing therapy with hydroxyurea,
and in patients with pulmonary HTN, which carries an ominous prognosis
in SCD. A secondary endpoint of this study will be to evaluate
if hydroxyurea plus Erythropoietin therapy can improve cardiovascular
aerobic capacity in general, and in particular minimize symptoms and
morbidity in patients with both chronic kidney disease and pulmonary
HTN.
- 06-H-0123 – Randomized, Placebo-controlled, Double-Blind,
Multicenter, Parallel Group Study to Asses the Efficacy, Safety and Tolerability
of Bosentan in Patients with Symptomatic Pulmonary Arterial Hypertension
Associated with Sickle Cell Disease (ASSET 1), PI: Roberto Machado,
M.D. Point of Contact: Lori Hunter, RN (301) 435-2345 (Z
number not assigned yet)
Précis:
The object is of this study is to demonstrate if bosentan improves
pulmonary vascular resistance (PVR) in patients with symptomatic pulmonary
arterial hypertension (PAH) associated wit h sickle cell disease. The study
population will include male and female patients with sickle cell disease
(SS, S-beta-Thalassemia) who have pulmonary arterial hypertension. Patients
will be randomized to receive either placebo or bosentan if they meet
all the inclusion criteria and not of the exclusion criteria. The
treatment medication or placebo will be administered for 4 weeks
and then the dose will increase for the remaining 12 weeks.
- 06-H-0124 – Randomized, Placebo-controlled, Double-Blind,
Multicenter, Parallel Group Study to Asses the Efficacy, Safety and Tolerability
of Bosentan in Patients with Symptomatic Pulmonary Hypertension Associated
with Sickle Cell Disease (ASSET 2), PI: Roberto Machado, M.D. Point
of Contact: Lori Hunter, RN (301) 435-2345 (Z number not
assigned yet)
Précis:
The object is of this study is to demonstrate if bosentan improves
pulmonary vascular resistance (PVR) in patients with symptomatic pulmonary
hypertension (PH) associated with sickle cell disease. The study population
will include male and female patients with sickle cell disease (SS, S-beta-Thalassemia)
who have pulmonary hypertension. Patients will be randomized
to receive either placebo or bosentan if they meet all the inclusion criteria
and not of the exclusion criteria. The treatment medication or
placebo will be administered for 4 weeks and then the dose will increase
for the remaining 12 weeks.
- 06-H-0165 - Evaluation of Endothelial and Hemodynamic
Function in HIV Associated Pulmonary Hypertension and a Phase
I/II Safety and Efficacy Trial of Sildenafil in HIV Associated Pulmonary
Hypertension, PI: Roberto Machado, MD/Christopher Barnett, MD
Précis:
HIV infection has been associated with an increased prevalence of pulmonary
hypertension. In addition, recent data suggests that a state of
endothelial dysfunction develops in HIV disease secondary to anti-retroviral
therapy and associated dyslipidemia or secondary to direct viral infection
of the endothelium. This leads to premature atherosclerosis and
possibly contributes to avascular necrosis of the hip. Similar
effects on the pulmonary vasculature may be involved in the development
of pulmonary vasculopathy.
In this study we plan to invasively characterize the status of pulmonary
and systemic endothelial function and determine the mechanisms
of pulmonary vascular endothelial dysfunction in HIV disease. To this end we
will catheterize healthy volunteers and volunteers with HIV infection
with and without pulmonary hypertension and directly measure acetylcholine-dependent
blood flow in the pulmonary and brachial artery to assess pulmonary and
systemic endothelium-dependent blood flow. Simultaneous measurement
of exhaled NO and pulmonary capillary artery NO2- will allow for complete
characterization of the contribution of NO production to endothelium-dependent
vasomotor control. We will also use recently developed MRI techniques
to measure pulmonary artery blood flow during infusion of acetylcholine
(ACH), sodium nitroprusside (SNP) and NG monomethyl-L-arginine (L-NMMA)
to establish responsiveness to an endothelium dependent vasodilator, endothelium-independent
vasodilator and an NO inhibitor, respectively. Volunteers with
pulmonary hypertension will have the option to undergo open label phase
I/II treatment with sildenafil for 16 weeks and return for a repeat
assessment of pulmonary hemodynamics as well as pulmonary and systemic
endothelial function.
Endothelial cells will be isolated using novel flow-cytometry methodologies
developed over the last two years at the NIH intramural division
utilizing combinations of positive and negative selection based on specific
surface markers for activated T cells and endothelial cells and markers
of cell viability. Endothelial cells will subsequently be interrogated using
amplified real time PCR methodologies and affymetrix based gene expression
profiling developed in our laboratories. The levels of expression
in endothelial cells of HIV virus, HHV8, eNOS, caveolin, HO-1,
endothelin receptors A and B, and endothelin 1, in addition to other
proteins regulating vascular homeostasis and cellular host defense (i.e.
epidermal growth factor, transforming growth factor beta, platelet derived
growth factor and interleukin-6), will be assessed.
These studies will provide insights into the mechanisms of pulmonary
artery endothelial dysfunction and suggest rationally designed
therapies targeting viral load, HHV8, and/or the NO/endothelin pathways. These
studies have the promise of opening the door to the study of
pulmonary artery endothelial dysfunction at the physiological, cellular
and molecular level.
- 06-H-N189 - Prevalence of Secondary Pulmonary Arterial
Hypertension (PAH) in Patients with Sickle Cell Disease in Nigeria
and the Role of HIV/AIDS and Endemic Parasitic Infections in the Natural
History of Pulmonary Hypertension in Sickle Cell Disease, PI; Zakari
Aliyu, M.D.
Précis:
Sickle cell disease (SCD) is an autosomal recessive disorder and the
most common genetic disease in the world. SCD is the most common
inherited blood disorder in the United States, affecting 70,000 to 80,000
Americans. Secondary pulmonary arterial hypertension (PAH) has been
shown to have a prevalence of 30% in patients with SCD with mortality
rates of 40% at 40 months after diagnosis in the United States. The
burden of disease of SCD is highest in Nigeria (West Africa) where approximately
4% of the 140 million people in that country are homozygous for SCD, but
the prevalence and outcomes of pulmonary hypertension in Africa have not
been investigated. Many known infectious risk factors for PAH are
also highly prevalent in Nigeria, including Human Immuno Deficiency Virus/Acquired
Immune Deficiency Syndrome (HIV/AIDS), malaria, chronic hepatitis B and
C, schistosomiasis and hookworm. Our first clinical hypothesis is
that interactions between these infectious complications and sickle cell
related hemolysis would lead to an even higher prevalence of PAH in Nigeria. Our
study is therefore designed to determine the prevalence of PAH in Nigerian
patients with SCD using echocardiographic measurements of the tricuspid
regurgitant jet velocity. We aim to determine the associations and
epidemiological interactions that might lead to PAH, of endemic infectious
disease co-morbidities, especially HIV/AIDS, with SCD by screening for
these infectious diseases in control subjects and in SCD patients with
and without PAH. Our second translational hypothesis is that genetic
polymorphisms in candidate genes that regulate endothelial function and
adhesion contribute to the development of PAH phenotype in African SCD
patients. Using both candidate gene and genome wide association
approaches, we will identify and selectively characterize single nucleotide
polymorphisms (SNPs) in genes important for endothelial function, vascular
inflammation and cardiac function (functional VCAM1 SNPs and steady state
soluble VCAM-1 levels, SELP, SELE, SELL, ICAM1, ITGA4, and CD36, TGF-β superfamily
gene polymorphisms - specifically bone morphogenic protein receptor II,
and CORIN, the serine protease which, cleaves the natriuretic peptide
precursors secreted by the heart, proANP and proBNP, to the physiologically
active ANP and BNP). Finally, our study using the SELDI-TOF-MS
system and 2D differential gel electrophoresis (DIGE), will examine differential
patterns of plasma protein expression, in particular the apolipoproteins
and arginase I and II enzymes, as potential biomarkers or therapeutic
targets in sickle cell patients with pulmonary hypertension. Our
proposal uniquely integrates international clinical, epidemiologic and
molecular studies to determine the burden of SCD related PAH, decipher
the mechanism of interactions of PAH and infectious diseases and identify
genetic and protein markers and potential therapeutic targets for PAH. Our
collaboration will provide an opportunity for the rapid transfer
of appropriate technology and knowledge relevant to the provision of
the highest quality care to sickle cell patients in Nigeria and the
world.
- 06-H-0220 - Long-term, Open-label, Multicenter, Extension
of Bosentan in Patients with Pulmonary Hypertension Associated
with Sickle Cell Disease Completing a Double-blind ASSET Study (AC-052-368
or AC-052-369) (ASSET 3) PI: Roberto Machado, M.D. Point of Contact: Lori
Hunter, RN (301) 435-2345 (Z number not assigned yet)
Précis:
The object is of this study is to assess long-term safety, tolerability
and efficacy of bosentan in patients with pulmonary hypertension
(PH) associated with sickle cell disease (SCD). The study population
will include male and female patients with sickle cell disease (SS, S-beta-Thalassemia)
who have previously completed the 16-week treatment period of the double-blind
study of bosentan (ASSET 1 or ASSET 2). Patients who meet all the
inclusion criteria and not of the exclusion criteria will be started on
62.5 mg bid for 4 weeks and then start the maintenance dose of 125 mg
bid (or stay on 62.5 mg is their weight is less than 40kg/90lbs). Patient
will be divided into two groups. Group A will consist of patients
who begin this study within 4 weeks of completing ASSET 1 or ASSET 2. Group
B will consist of patients who begin this study longer than 4 weeks after
completing ASSET 1 or ASSET 2. Patients will remain on drug until
the FDA approves the drug for use in patients with pulmonary
hypertension or until the sponsor decides to stop the study.
- 06-H-0202- Cardiopulmonary Function Assessment and
NO Based Therapies for Patients with Hemolysis-associated Pulmonary
Hypertension PI: Roberto Machado, M.D. Point of Contact: Lori Hunter, RN (301)
435-2345 (Z number not assigned yet)
Précis:
Sickle cell anemia is an autosomal recessive disorder and the most
common genetic disease affecting African-Americans. Approximately 0.15%
of African-Americans are homozygous for sickle cell disease, and 8% have
sickle cell trait. Acute pain crisis, acute chest syndrome (ACS),
and secondary pulmonary hypertension are common complications of sickle
cell anemia. Pulmonary hypertension has now been identified as a
major cause of death in adults with sickle cell disease. Similarly,
pulmonary hypertension has been identified as a chronic complication of
hemolytic disorders such as thalassemia, hereditary spherocytosis and
paroxysmal nocturnal hemoglobinuria. Sildenafil has been proposed
as a possible therapy for both primary and secondary pulmonary hypertension
and recent phase I/II studies from the intramural NIH suggest it is well
tolerated and efficacious in this population. Furthermore, a number
of recent studies have suggested that NO based therapies may
have a favorable impact on sickle red cells at the molecular level and
could improve the abnormal microvascular perfusion that is characteristic
of sickle cell anemia.
This clinical trial is designed with three major objectives: 1) to assess
cardiopulmonary function in patients with sickle cell disease and thalassemia
with and without pulmonary hypertension, to better characterize the effects
of chronic hydroxyurea therapy on cardiopulmonary function, 2) to determine
the relative acute vasodilatory effects of sildenafil, and inhaled NO
in patients with hemolysis-associated pulmonary hypertension and 3) to
determine the chronic effects of the addition of inhaled NO on pulmonary
hemodynamics and functional capacity in patients with hemolysis-associated
pulmonary hypertension chronically treated with sildenafil.
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