FYI from the NHLBI Index
January 2013: Vol. 13, Issue 3
In the News
News from Capitol Hill
Science Advances from the NHLBI
- Stiffening of the Blood Vessels Precedes the Development of Hypertension
- Adult Stem Cells Help Regenerate Injured Lungs
- Pre-eclampsia is Linked to Altered Enzyme Activity
- Mouse Model of LAM Suggests Possible New Treatments
- Gene Therapy Helps Patients with Hemophilia B
- Scientists Find Link Between Abnormal Bone Marrow Cells and Pulmonary Arterial Hypertension
- Rutin Shows Promise as Blood Thinner
- Platelet Drug Shows Promise for Treating Severe, Unresponsive Aplastic Anemia
News from Capitol Hill
The Congress passed a continuing resolution (H.J. Res. 117) in September 2012 as a short-term measure to continue
funding for the NIH in fiscal year (FY) 2013, which began on October 1, 2012. The President signed the resolution into
law on September 28, 2012 (P.L. 112-175). The resolution, which will expire on March 27, 2013, will provide funding
under the same terms and conditions and at roughly the same level as in FY 2012 for most agencies, including NIH.
Asthma Legislation Introduced
On November 27, 2012, Representative Carolyn McCarthy (D-NY) introduced H.R. 6608, the Family Asthma Act, to require the
Secretary, acting through the Director of the Centers for Disease Control and Prevention, to collaborate with state and local
health departments to conduct activities on the dissemination of information and education on the prevention and treatment of
asthma. The bill includes a provision that would require the Secretary, in consultation with patient groups, nonprofit organizations,
medical societies, and other relevant governmental and nongovernmental entities, to submit to Congress a report, two years from the
date of enactment of the Act, that catalogs – with respect to asthma prevention, management, and surveillance – the activities of
the Federal government and other entities, and makes recommendations for the future direction of asthma activities, in consultation
with researchers from NIH and other member bodies of the National Asthma Education and Prevention Program.
NHLBI Director Recognized at Capitol Hill Reception
On December 12, 2012, the NHLBI Constituency Group, the National Coalition for Heart and Stroke Research, and Morehouse School of
Medicine hosted a Capitol Hill reception to welcome Dr. Gibbons. Dr. Regina Benjamin, the Surgeon General of the United States, and
Dr. Francis Collins, Director, NIH, provided remarks. Senators Mike Crapo (R-ID) and Richard Durbin (D-IL) and Representatives Lois
Capps (D-CA) and Todd Platts (R-PA), who serve as co-chairs of the Congressional Heart and Stroke Coalition, were honorary co-hosts.
NHLBI Director Speaks at Pulmonary Hypertension Luncheon
On November 13, 2012, Dr. Gibbons provided remarks at a Capitol Hill luncheon sponsored by the Pulmonary Hypertension
Association (PHA) to educate interested individuals. Other speakers included Senator Robert Casey (D-PA), staff from the
offices of Representatives Kevin Brady (R-TX) and Lois Capps (D-CA), Dr. John Berger of the Children’s National Medical
Center, and Ms. Diane Ramirez of the PHA.
NHLBI Deputy Director Speaks at Child Lung Health Briefing
On October 16, 2012, Dr. Shurin spoke at a congressional briefing on child lung health sponsored by the American
Thoracic Society, the Cystic Fibrosis Foundation (CFF), the Children’s Interstitial Lung Disease Foundation (chILD), and
the Congressional Cystic Fibrosis Caucus, which is co-chaired by Representatives Edward Markey (D-MA), Tom Marino (R-PA),
and Cliff Stearns (R-FL). Dr. Shurin provided an overview of research on neonatal respiratory conditions and cystic
fibrosis. Other speakers included Dr. Thomas Ferkol, Washington University School of Medicine, Dr. Stephanie Davis,
Indiana University School of Medicine, Mr. Mitchell Greenberg, CFF, and Mr. Greg Porta, chILD.
Science Advances from the NHLBI
Stiffening of the Blood Vessels Precedes the Development of Hypertension
A recent study shows that stiffening of the blood vessels precedes the development of hypertension, a discovery
that runs counter to the widely held belief that increased arterial stiffness is a consequence of hypertension.
It is well established that the walls of large arteries, especially the aorta, become stiffer with advancing age
and aortic stiffening is associated with many age-related cardiovascular diseases including coronary heart disease
and stroke. However, the relationship between aortic stiffening and blood pressure elevation has been less clear.
To learn more about the relationship, researchers measured aortic stiffness and blood pressure in participants in
a large cohort during two examinations separated by seven years. They found that aortic stiffness measured during the
first examination was significantly associated with the development of hypertension by the second examination. In
contrast, blood pressure measured during the first examination was not predictive of subsequently increased aortic stiffness.
The findings shed light on the mechanisms that cause hypertension and suggest potential new therapeutic approaches
to prevent or delay its development.
Adult Stem Cells Help Regenerate Injured Lungs
New research shows that adult stem cells residing in the lung may enable lung structures to regenerate after
catastrophic injury. Stem cell biology and regenerative medicine present unprecedented opportunities for developing
innovative treatments for lung diseases, but to realize their potential scientists need to understand the role of
stem cells in lung injury, disease, and repair.
In this study, researchers infected mice with influenza, which triggered massive airway damage that was followed
by robust regeneration. They showed that during regeneration, a type of stem cell from the small airways of the
lung proliferated rapidly, radiated to the injured regions, and assembled into alveoli-like structures. The results
also suggested that certain secreted factors stimulate and direct the lung progenitor cells after acute injury.
These findings provide critical new understanding that may aid in development of cell-based therapies for
chronic lung diseases that presently have no cure.
Pre-eclampsia is Linked to Altered Enzyme Activity
Investigators have found a link between pre-eclampsia and reduced activity of an enzyme called corin. Pregnant
women with pre-eclampsia had lower uterine corin levels than women with normal pregnancies. The researchers also
identified two mutations in the corin gene that reduce enzyme activity in pre-eclamptic patients.
Using genetically engineered mice, investigators determined that corin was involved in new blood vessel formation
at the maternal–fetal interface of the placenta and that loss of corin from the uterus led to impaired blood vessel
formation, which caused pre-eclampsia-like symptoms in mice.
Pre-eclampsia is diagnosed when a pregnant woman develops high blood pressure and protein is found in her urine
after 20 weeks of pregnancy. It occurs in about 10 percent of all pregnancies and, if left untreated, can develop
into eclampsia that may lead to seizures and death of the mother and/or fetus.
The findings from this work could generate new approaches, specifically those targeting corin, for treating
Mouse Model of LAM Suggests Possible New Treatments
Researchers have recently developed a mouse model of lymphangioleiomyomatosis (LAM) and found a two-drug
combination treatment that appears to be able to prevent, and to some degree reverse, lung damage caused by
LAM in that model. LAM is a rare, slowly progressive lung disease that almost exclusively affects women of
Researchers injected mice with cells lacking the tuberous sclerosis complex 2 (TSC2) gene and established
LAM-like lesions in the mouse lungs, suggesting that lung destruction in LAM is specifically associated with
loss of TSC2 function. Additionally, the investigators found that a regimen of two FDA-approved drugs, sirolimus
(rapamycin) and simvastatin (a commonly used cholesterol-lowering drug) prevented growth of lung lesions and
lung destruction and caused a dramatic regression of established lung lesions in the mice.
The study suggests the possibility of cellular therapy to restore TSC2 function in LAM patients, as well as
drug therapy to prevent lung damage and reverse or attenuate existing disease.
Gene Therapy Helps Patients with Hemophilia B
Researchers have developed an experimental gene therapy technique that was able to boost production
of a vital blood clotting factor in six adults with severe hemophilia B. The therapy could ultimately
give patients a long-term solution to the debilitating and life-threatening bleeding condition.
People with hemophilia B are prone to bleed abnormally because they lack factor IX (FIX), a protein
produced by liver cells that helps the body form clots to stop bleeding.
The new technique entailed joining the normal human FIX gene to a virus that naturally homes to liver
cells, thus allowing the gene to be delivered to the FIX production site simply and safely by injection
into a peripheral vein.
The researchers studied six people with severe hemophilia B who had been producing FIX at less than 1
percent of normal levels and needed to take infusions of manufactured FIX several times a month. After
receiving the FIX gene therapy, each participant produced FIX at 2 to 11 percent of normal levels. In
the short-term follow-up period (6 to 16 months), four of the six participants no longer required FIX
infusions for routine bleeding, and the other two required them less frequently than before the study.
These results are more promising than prior attempts at gene therapy for hemophilia. If future studies support
the findings, the approach could offer significant improvement in quality of life for patients with hemophilia B.
Scientists Find Link Between Abnormal Bone Marrow Cells and Pulmonary Arterial Hypertension
Investigators have uncovered a new clue to the cause of pulmonary arterial hypertension (PAH), a progressive
and frequently lethal disease that in many cases arises mysteriously. PAH is characterized by lung vascular
injury that involves disorganized and abnormal endothelial cells (cells that line blood vessels).
Looking back to the origins of pulmonary endothelial cells, the investigators found abnormalities in
the endothelial progenitor (stem) cells in the bone marrow of PAH patients.
Further, they showed that mice receiving transplanted pro-genitor cells derived from the bone marrow of
PAH patients went on to develop features of PAH, including endothelial damage, abnormal vessel growth, blood
clot formation, and eventual heart enlargement and failure. None of these features was observed in mice
receiving transplanted cells from healthy individuals.
Coupled with the observation of a high incidence of PAH among patients with bone marrow diseases, the
findings suggest that bone marrow-derived endothelial progenitor cells play a role in causing vascular
injury in the lung that underlies PAH.
Rutin Shows Promise as Blood Thinner
Researchers have determined that rutin, a substance found in plants, is a promising candidate for development of
a new drug to prevent blood clots.
Anti-clotting drugs, also known as blood thinners, are used to prevent thrombosis, a potentially life-threatening
condition in which a clot forms in a vein or artery and blocks blood flow. They are routinely prescribed to individuals
who are prone to form blood clots in their vessels because they have irregular heart rhythms, artificial heart
valves, or other predisposing conditions. Although blood thinners have been used clinically for many years, administering
them in a way that is both effective and safe for a given patient can be tricky.
Recently, scientists hoping to develop better blood thinners tested a large number of molecules for their ability to
block the action of an enzyme, protein disulfide isomerase, that is needed for clot formation. The search identified
rutin, which is found in many common foods including berries, buckwheat, and some vegetables. Blood from mice that
had been fed rutin was less likely to clot than blood taken from control animals, and intravenous infusion of rutin
into mice resulted in a nearly complete inhibition of clot formation.
The experiments suggest that rutin could be developed into a new type of blood thinner. Since it occurs naturally
in many foods and is well tolerated by humans, researchers hope that it may prove beneficial for many patients while
sparing them the harmful side effects that sometimes occur with currently available blood thinners.
Platelet Drug Shows Promise for Treating Severe, Unresponsive Aplastic Anemia
An early-phase study at the NIH Clinical Center has shown that eltrombopag, a drug that was designed to stimulate
production of platelets in patients with bleeding disorders, can raise blood cell levels in some people with severe
aplastic anemia who have failed to benefit from standard therapies.
Aplastic anemia results from the destruction of bone marrow stem cells, which mature into red blood cells that carry
oxygen, white blood cells that fight infection, and platelets that prevent excess bleeding. Although some patients are
helped by immune-suppressing therapy or, failing that, bone marrow stem cell transplantation, the disease can be fatal
in severe unresponsive cases.
Eleven of 25 participants enrolled in the study showed improved production of at least one type of blood cell after
12 weeks of oral eltrombopag therapy. Among the seven volunteers who continued taking the drug long-term (8–32 months),
six eventually produced higher levels of all three types of blood cells and were able to maintain safe blood counts
without needing transfusions. Overall the drug was well tolerated, with few side effects.
The researchers tested eltrombopag because it had previously been shown to boost platelet levels both in healthy
people and in patients with low platelet counts due to hepatitis C infection or immune thrombocytopenia.
The encouraging finding in this study was improvement in red blood cell and white blood cell counts in some aplastic
anemia patients, suggesting that eltrombopag can stimulate bone marrow stem cells and perhaps have wider utility than
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