DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
National Heart, Lung, and Blood Institute
FY 2005 Budget Justification

 Authorizing Legislation: Section 301 and title IV of the Public Health Service Act, as amended.

Budget Authority:

This document provides justification for the FY 2005 activities of the National Heart, Lung, and Blood Institute (NHLBI), including HIV/AIDS activities. A more detailed description of NIH-wide Fiscal Year 2005 HIV/AIDS activities can be found in the NIH section entitled "Office of AIDS Research (OAR)."

INTRODUCTION

The NHLBI provides leadership for a national program in diseases of the heart, blood vessels, lungs, and blood; sleep disorders; and blood resources. It plans and conducts—through work in its own laboratories and through grant- and contract-supported activities in extramural scientific institutions—an integrated and coordinated program of basic research, clinical investigations and trials, observational studies, and demonstration and education projects related to the causes, prevention, diagnosis, and treatment of the diseases under its purview and to the clinical use of blood and all aspects of the management of blood resources. Since FY 1993, the Institute has been the home of the National Center on Sleep Disorders Research and, since FY 1998, it has had responsibility for the NIH Women’s Health Initiative. The NHLBI supports research training and career development of new and established investigators in fundamental sciences and clinical disciplines to enable them to conduct research relative to its mission. In addition, it conducts educational activities, including development and dissemination of materials for health professionals, patients, and the general public, with a strong emphasis on prevention.

The following material summarizes the latest scientific progress and promising future opportunities.

SCIENCE ADVANCES

Study Finds Possible New Indicator of Heart Disease Risk

A recent study suggests that levels of a type of adult stem cell in the bloodstream—the endothelial progenitor cell (EPC)—may indicate a person’s risk of developing cardiovascular disease (CVD). When vascular endothelial cells (cells that line the blood vessels) are damaged or destroyed, the EPCs are thought to replace them. Scientists studying healthy men aged 21 and older found that the number of EPCs circulating in the blood was inversely related to CVD risk. In addition, they found that the EPCs of those at higher risk aged faster than the cells of those at lower risk, and that blood vessels were much less likely to dilate and relax properly in persons with low levels of the cells. Although much more research needs to be done, the findings suggest that it may some day be possible to test a person’s risk of developing CVD by taking a blood sample and measuring the level of EPCs.

Gradual Restoration of Blood Flow after Ischemia Benefits Heart Muscle Tissue

Scientists recently made progress in their search for safer ways of restoring blood flow to heart tissue damaged by ischemia (a deficiency of blood flow) caused by blockages in the coronary arteries. Time is critical in the restoration of blood flow to the heart muscle because its interruption for several hours leads to tissue death, and yet sudden restoration of blood flow (e.g., via balloon angioplasty) can exacerbate heart tissue injury. NIH-supported researchers recently reported a new approach to reduce injury to heart cells deprived of blood flow. Using a canine model, they found that applying a regimen of brief, nonlethal, ischemic periods immediately after blood flow was restored reduced the extent of heart muscle damage by approximately 50 percent. A similar decrease in lethal arrhythmias was also found. Since about 1.1 million people in the United States suffer heart attacks each year¹ and many of the survivors go on to develop debilitating heart failure, decreasing the amount of cardiac tissue damage from heart attacks could significantly reduce mortality and morbidity and also lower health care costs.

Magnetic Resonance Imagine (MRI) Provides Faster, More Accurate Way
to Diagnose Heart Attacks

More than 5 million patients with chest pain visit emergency departments each year.² Many who are suffering heart attacks must wait up to 12 hours for results of diagnostic blood tests before they can begin receiving life-saving treatment. Still others, with unstable angina, are sent home undiagnosed, only to have their angina later progress to a heart attack. A recent study (part of a collaborative program including the NHLBI, the NIH Clinical Center, and Suburban Hospital in Bethesda, Maryland) has shown that advanced MRI technology can detect heart attack and unstable angina in emergency room patients with chest pain more accurately and faster than standard diagnostic tests. Cardiac MRI allows clinicians to view the heart and arteries in “real time” and determine how well the heart is pumping, how adequate the supply of blood is to specific areas of the heart, and whether there is evidence of permanent heart damage. Since patients can be scanned in under 40 minutes, use of MRI technology could save many lives and reduce disability among those who survive by allowing doctors to diagnose cardiac emergencies and start appropriate treatment substantially faster than at present. Researchers estimate that diagnostic cardiac MRIs could be used in hospital emergency departments nationwide within just a few years.

Insulin-Sensitizing Drugs May Reduce Cardiovascular Disease (CVD) in Diabetic Patients

With the advent of effective approaches to regulate blood sugar levels, the greatest health threat for persons with diabetes has become CVD. New research suggests that thiazolidinediones—a class of insulin-sensitizing drugs often prescribed for diabetics to enable their cells to use insulin more efficiently—may also reduce CVD risk. Much scientific evidence links inflammation to CVD development, and researchers recently found that diabetics have higher blood levels of a protein known to trigger inflammation than non-diabetics. Moreover, when diabetic patients were treated with thiazolidinediones, levels of the inflammation-inducing protein fell by almost 30 percent. The results offer hope that treatment with insulin-sensitizing drugs like thiazolidinediones or other anti-inflammatory drugs might prevent or delay progression of CVD in patients with diabetes.

Scientists Find Better Predictor of Impending Aneurysm Rupture

If the aorta, the large artery that carries blood from the heart to the rest of the body, widens in the abdominal area—a condition known as abdominal aortic aneurysm (AAA)—it can rupture and cause fatal bleeding. Physicians do not know how to limit the growth of AAAs, and since surgery to repair them is risky it is usually recommended only when aneurysms reach a diameter of 4.5-5.0 cm. Smaller diameter aneurysms can also rupture, but heretofore no method was available for predicting whether a given aneurysm is likely to do so. In a recent study of 103 patients with AAAs, scientists used a non-invasive technology called computed tomography to produce 3-dimensional images of the aneurysms and to measure the amount of stress they impose on the artery wall. They found that the level of stress was directly related to the risk of rupture regardless of aneurysm diameter. If results are confirmed in a clinical trial, this technique could provide doctors better information concerning the relative risks of surgery and rupture.

Reducing Copper Levels May Help to Treat Injured Blood Vessels

A recent study in rats tested whether reducing levels of copper in the body would prevent injured arteries from narrowing and becoming blocked, a usual response to arterial injury. Copper was a likely candidate for testing because it has been shown to promote inflammation, a part of the body’s response to injury and infection that contributes to the development of CVD. Rats given tetrathiomolybdate (TTM), a drug that binds tightly to copper and helps remove it from the body, suffered less narrowing of the arteries after arterial injury than did rats that were not given the drug. Moreover, TTM appeared to promote reendothelialization—replacement of damaged blood vessel cells with new cells. The findings offer hope that drugs which reduce copper levels may eventually prove useful for preventing narrowing and blockage of blood vessels and promoting reendothelialization in humans as well.

Using Nanoparticles to Deliver Drugs Shows Promise for Preventing Restenosis

Angioplasty is a common procedure used to open up blocked coronary arteries and restore blood flow. Although it is initially successful in most patients, restenosis, or renarrowing, of the arteries often occurs weeks or months later. Restenosis is caused, in part, by proliferation of vascular smooth muscle cells (VSMCs) in the artery. Recently, scientists have begun using nanoparticles—tiny particles small enough to interact with DNA and proteins—to increase the effectiveness of drugs that stop VSMCs from proliferating. Scientists found that anti-proliferative drugs were more effective when inserted into nanoparticles specifically designed to stick to VSMCs. The improved performance is probably due to the nanoparticles ability to “target” the drugs directly to the VSMCs. If this technique can be applied in clinical studies, it holds promise for slowing restenosis after angioplasty.

Preventing Congenital Heart Disease in the Infants of Diabetic Mothers

Babies born to mothers who suffer from diabetes are three times more likely to have congenital heart defects than the newborns of non-diabetic mothers, and valve malformations are quite common. In a recent study using mouse embryos, researchers exposed the endocardial cushions—bulges of the heart lining in embryos that eventually develop into the heart valves—to varying levels of glucose. Findings showed that high levels of glucose during a narrow window of time prevented proper development, perhaps because glucose decreased the levels of a vascular growth factor (VEGF-A) needed for the cushions to form. When the growth factor was added, cushions grew properly despite the presence of high glucose levels. The study identifies a critical period of time in mice when the developing heart is sensitive to high glucose and a possible mechanism by which the resulting heart malformations could be prevented.

Findings May Help to Eliminate the Side Effects of Glucocorticoids

Glucocorticoids are widely prescribed drugs with highly beneficial anti-inflammatory and immunosuppressant properties, but their use can cause high blood pressure, a major risk factor for cardiovascular disease. Understanding the mechanism by which glucocorticoids raise blood pressure is an essential first step toward preventing this side effect. Findings from a recent study in rats suggest that glucocorticoids increase blood pressure because they decrease levels of the protein GTP cyclohydrolase 1 (GTPCH1) which is needed for the production of nitric oxide (NO), a compound known to dilate blood vessels. Scientists can now concentrate on GTPCH 1 as a possible target to treat the hypertension caused by glucocorticoid therapy.

Study Findings Suggest Revised Approach to Therapy for Atrial Fibrillation

Atrial fibrillation (AF) is a common type of heart arrhythmia affecting over 2 million people in the United States.³ It is increasingly prevalent, especially in the elderly, and is an important risk factor for stroke. The preferred and most frequently used initial therapy for AF has been a strategy to restore and maintain a normal heart rhythm. However, a recent clinical trial found that this strategy prevents deaths no better than the alternative, often secondary, approach of merely controlling the rate at which the heart beats. Moreover, the heart-rhythm strategy does not lower risk of stroke, enhance quality of life, or improve cognitive function, and may have some disadvantages, including more hospitalizations and adverse drug effects. These findings are expected to alter fundamentally the approach to preventing complications of AF in many patients.

All-in-one Approach to Lifestyle Changes Effectively Lowers Blood Pressure

Nearly 50 million American adults have high blood pressure⁴ and as a result they are at increased risk of having a stroke or heart disease. Lifestyle changes, such as losing excess weight, eating a heart-healthy diet, increasing physical activity, and quitting smoking, can lower high blood pressure. To date, most behavioral interventions encouraged people to make only one or two lifestyle changes at a time. However, findings from a recent clinical trial indicate that an all-in-one approach to lifestyle changes is feasible and effective in lowering blood pressure. Trial participants who simultaneously implemented healthy lifestyle changes also significantly reduced their weight and became more fit. These findings offer encouragement to Americans with above-normal blood pressure (120 to 139 mm Hg systolic and 80 to 89 mm Hg diastolic) by showing that multiple lifestyle changes can be made at once to lower blood pressure and in turn, reduce cardiovascular disease risk.

High Rates of Blood Pressure Control Are Obtainable

Uncontrolled high blood pressure (=140/90 mm Hg) raises risk of stroke and heart disease. Unfortunately, only a minority of Americans with hypertension have their blood pressure under control, despite the availability of effective antihypertensive medications. However, results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) show what can be achieved. Blood pressure control rates among ALLHAT participants increased from 24.7 percent at the beginning of the trial to 66 percent after five years of followup. Perhaps most notably, the ALLHAT gains in blood pressure control were achieved in a variety of clinical practice settings and in subgroups of people known to have difficulty controlling their blood pressure, such as blacks, the elderly, and patients with diabetes. These results offer patients encouragement that blood pressure control is obtainable and challenge physicians to continue working with their patients until adequate blood pressure control is achieved.

Hostility and Impatience Increase Long-term Risk of Developing Hypertension

Young adulthood and early middle age are critical periods for the development of hypertension and other risk factors for heart disease. A recent study examined the effects of personality characteristics and emotional states exhibited by younger people on long-term risk for hypertension. It found that hostility and impatience (two features of the so-called Type A personality) increased the risk. However, the other psychological and social factors examined, such as competitiveness (another Type A feature), depression, and anxiety, did not increase risk. These findings help researchers zero in on behavioral characteristics that require further study. They also highlight the need for people to be able to recognize, modify, and manage their harmful psychosocial behaviors so that they can thrive in the fast-paced U.S. society without compromising their cardiovascular health.

Quality of Life Improved for Recent Heart Attack Patients Treated for Depression

Social isolation and depression are risk factors for death and recurrent heart attack in heart disease patients. Results from the first major study to evaluate the effects of treating depression and low social support in patients who recently suffered a heart attack surprisingly showed no reduction in deaths or second heart attacks. However, study participants experienced significant improvement in their social functioning, were less depressed, and enjoyed a higher quality of life. These findings show that treatment for depression and low social support can improve the quality of life of heart attack patients and underscore the importance of evaluating and treating heart attack patients who show signs of depression.

Sleep Disturbances Underrated by Healthcare Professionals

Insomnia is a common affliction characterized by difficulty falling asleep, difficulty staying asleep, or short sleep duration. The extent to which it is associated with medical and psychiatric disorders is only now being appreciated. Recent findings from the Women’s Health Initiative suggest a correlation between insomnia and depression. Other studies suggest that, for men, insomnia correlates with elevated levels of tumor necrosis factor-alpha, which at high levels is associated with higher risks for heart disease, high blood pressure, and insulin resistance. Since poor sleep is associated with decreased quality of life, increased physical complaints, and decreased work productivity, early assessment and treatment of insomnia symptoms, including depression, might reduce associated risks of psychiatric and cardiovascular disease.

Sleep Loss Is Coupled to Obesity in Children

Inadequate or disturbed sleep disrupts neuroendocrine, metabolic, and immunologic functions, and impairs motivational drive and cognitive functions. Of interest to researchers studying body weight, sleep loss disrupts hormonal regulation of glucose metabolism and interferes with satiety signals arising from food consumption. Previous studies found that carbohydrate craving associated with sleep deprivation is linked to obesity and that excessive daytime sleepiness due to sleep disorders is likely to decrease participation in physical activities and exacerbate weight gain. A recent study of adolescents found a link between poor sleep quality and obesity. Each hour of sleep disturbance decreased the daily physical activity level by 3 percent. More promising, however, was the finding that every hour of increased sleep time decreased the odds of obesity by 80 percent. These results suggest that developing strategies to help children overcome sleep disorders could be an important step in combating the obesity epidemic facing the United States.

Antibiotic Resistance During Cystic Fibrosis Linked to Local Condition in Airways

The lungs of cystic fibrosis (CF) patients become persistently colonized with Pseudomonas aeruginosa early in life. Despite a vigorous inflammatory response and the rapid influx of white blood cells into the CF airways to combat the bacteria, P. aeruginosa infections become chronic, airways are destroyed, and lung function declines, eventually resulting in death. An initiating event in the pathogenesis of CF is mucus stasis, caused by the inability of the airways to effectively expel mucus. Recent studies have revealed that this stagnant mucous environment becomes anaerobic (i.e., without oxygen) due to high oxygen consumption by bacteria, neutrophils, and CF airway cells. Although P. aeruginosa normally requires oxygen, it apparently adapts well to the anaerobic conditions in the mucus-rich environment of the lungs of CF patients. Furthermore, a class of antibiotics known as macrolides have shown efficacy against anaerobic P. aeruginosa, suggesting new possibilities for fighting infection, not just in patients with CF, but also in patients with asthma and chronic obstructive pulmonary disease.

Immunosuppressant Drug May Hold Key for Treating Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, progressive, ultimately fatal lung disease that affects several hundred young women in the United States. It is characterized by formation of cysts in the lungs due to excessive overgrowth of atypical smooth muscle cells. No treatments are available to halt or reverse the progression of LAM, and lung transplantation is the only established therapy for those with end-stage lung disease. Recently, investigators determined that rapamycin, an immunosuppressant drug used to prevent graft rejection in patients undergoing kidney transplantation, can effectively inhibit the overgrowth of LAM cells in vitro. Although clinical trials in humans will be necessary before its usefulness is established, rapamycin is the first drug to show potential for slowing or stopping the progression of LAM.

Therapeutic Effects of Immunostimulatory DNA Sequences (ISS)

Overstimulation of a key component of the immune system, called the Th2 lymphocyte, appears to play a significant role in the pathogenesis and propagation of allergic inflammation in asthma. Previous studies using mouse models of acute asthma have demonstrated that ISS, which are short segments of DNA that are identical to portions of certain bacterial genomes, can suppress Th2 expression, thereby reducing the undesirable infiltration of cells called eosinophils into the airways and reducing airway inflammation and hyperreactivity. Researchers have recently demonstrated that ISS are as effective as corticosteroids, the standard therapy for severe, acute exacerbations of asthma, in reducing airway inflammation in the mouse model. ISS appear to be well tolerated in humans, and trials will determine whether they could become an important immunotherapy for restoring immune balance to treat asthma.

Genotype Determines Asthma Patients’ Response to Beta Agonists

Beta agonists, the most commonly prescribed drugs for controlling asthma symptoms, relax airway muscles by binding directly to beta-receptors located on the muscle surface. However, researchers have demonstrated that certain patients who have mutations in the beta-receptors do not respond well to beta agonists; instead, their asthma control deteriorates. In the recent Beta-Adrenergic Responses by Genotype (BARGE) trial, investigators examined the genotype of patients and found that those with the receptor mutation had better peak flow response (a measure of breathing ability) while taking placebo than while taking the beta agonist albuterol. Based on BARGE, investigators suggest that patients with the mutation, who constitute one-sixth of the U.S. asthmatic population, may improve their asthma control when completely withdrawn from beta agonists. Identification of those with the mutation could lead to better management strategies for asthma.

Adenovirus Enhances Inflammatory Responses of Pulmonary Cells

Adenovirus infections of the respiratory tract are especially common in people with emphysema. This observation has led to speculation that adenoviral infection might be a risk factor for development or progression of emphysema, but cellular and molecular mechanisms that might explain the link between adenoviral infection and emphysema are not yet well defined. Researchers recently inserted the gene for the adenoviral E1A protein, a protein that controls virus replication, into cultured human bronchial epithelial cells. The investigators found that cells with E1A, but not controls lacking E1A, expressed high levels of transforming growth factor beta, intercellular adhesion molecule 1, and interleukin 8, all immune factors that play a part in inflammation. The critical role of the adenoviral E1A protein is especially significant since it suggests that strategies for inhibiting its expression could lead to better therapies and outcomes for emphysema patients.

Transmission of Asthma Susceptibility

The prevalence of asthma began increasing in the United States in the 1960s, and today it is a major health problem that disproportionately affects children. Increasing evidence supports the hypothesis that in utero and perinatal exposure of mother and child to allergens increases the child’s subsequent risk of developing asthma. Investigators, using mouse models, found that asthma susceptibility can be transferred in utero from mother to offspring in a process that seems to be dependent on mediators that prime the immune system for asthma development. Defining the biologic mechanisms that drive the development of asthma will provide the basis for new interventions for treatment and prevention.

Women Benefit Even More than Men from Quitting Smoking

Cigarette smoking is a leading cause of chronic obstructive pulmonary disease (COPD), and smokers who develop COPD are strongly urged to quit. A recent study of middle-aged smokers with mild to moderate COPD found that in the first year after quitting smoking, women’s lung function improved more than twice as much as men’s. Among participants who quit smoking, improved lung function remained greater for women than for men throughout the duration of the five-year study. While both men and women benefit from quitting smoking, results of the study should be especially encouraging to women who are considering kicking the habit.

Fungal Infection Linked to COPD

Although chronic obstructive pulmonary disease (COPD) occurs almost exclusively among cigarette smokers, only a small proportion of smokers develop it, which suggests that factors other than smoking are likely to contribute to its pathogenesis. Mounting evidence suggests that inflammation due to infection in the lungs may play a role. Recent studies observed that the immune response in the lung tissues of persons infected with Pneumocystis carinii, a fungus that frequently causes pneumonia in AIDS patients and other immunocompromised individuals, is similar to that found in patients with COPD. Using sensitive detection techniques, investigators discovered that P. carinii was present in patients with COPD, even though they had no clinical signs of pneumonia. This new link between COPD and P. carinii, which responds to several antibiotics, opens the way for new prevention options for COPD.

Landmark Federal Cooperative Study Defines Role of Lung Volume Reduction Surgery

Lung-volume-reduction surgery (LVRS) was first used to treat emphysema during the 1950s. Although some patients seemed to benefit from the procedure, high mortality and morbidity discouraged its widespread use until the early 1990s, when some surgeons began performing LVRS again. The National Emphysema Treatment Trial (NETT), a collaboration between the NIH and the Health Care Financing Administration (now known as the Centers for Medicare and Medicaid Services, CMS), clarified the short- and long-term risks and benefits of LVRS and identified the characteristics of patients most likely to benefit from LVRS as well as those who are at greater risk of death and complications from LVRS. The NETT reflects a unique relationship in which the NIH funded and administered the study and CMS supported participants’ care costs. Additionally, the Agency for Healthcare Research and Quality contributed support for analysis of the cost-effectiveness of LVRS. The study results provide a scientific basis for reassessment of Medicare coverage for LVRS.

Genetic Variation Affects Severity of Acute Lung Injury

Sepsis, or “blood poisoning,” is the tenth leading cause of death in the United States⁵ and is the most common risk factor for acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). Patients with lung injury resulting from sepsis typically spend nearly 2 weeks in intensive care units, and only half come out alive. Although overall mortality rates from sepsis have decreased over the past 22 years, its incidence has risen. Both the death rate and incidence are nearly twice as high for black males as for white patients. Investigators have recently found polymorphisms, or variations, in DNA that are associated with an increased risk of developing ALI or ARDS from sepsis. Strikingly, they also determined that these polymorphisms are more common in black patients. Their findings emphasize the need for continued study of the association between outcomes and variations in DNA and may lead to better diagnosis and therapy for those patients at greatest risk for ALI/ARDS.

Improvements in Platelet Storage May Save Costs and Lives

When people weigh the risks associated with transfusions of blood or blood products, they usually think about the viruses that cause hepatitis, AIDS, or West Nile disease. For recipients of platelet transfusions, however, the major risk is bacterial infection. Unlike most blood products, platelets cannot be refrigerated. They must be stored at room temperature, which leads to rapid bacterial growth and a diminished shelf life. Although researchers had known for years that platelets stored at cool temperatures rapidly disappeared from the blood stream once transfused, no one understood why. Researchers recently noted that certain proteins on platelet surfaces rearrange when cooled, and that the rearrangement triggers removal of platelets by the liver. They also demonstrated that the rearrangement could be prevented upon refrigeration by storing platelets in a modified solution. Platelets transfused after being stored in the new medium and then refrigerated functioned as if they had been stored at room temperature and did not activate the removal process. This new approach to platelet storage could significantly improve the shelf life of platelets; reduce the number of units that must be discarded; limit the substantial expense of collecting, storing, and ultimately disposing of platelets that are not used; and protect patients by reducing the risk of infection.

Low-Intensity Warfarin Therapy Prevents Recurrence of Blood Clots without Adding Risks

Deep vein thrombosis (DVT) is the formation of a blood clot in an intramuscular vein. DVT typically arises in a leg vein, and, left untreated, it can lead to pulmonary embolism, a potentially fatal condition in which a detached clot travels to the lungs and enters a pulmonary artery. Risk factors for DVT include long periods of inactivity that decrease blood flow, such as immobilization after surgery and travel on long airplane flights. DVT patients are treated with heparin for 5 to 10 days to prevent clots from getting larger, then given warfarin, an anticoagulant drug, for several months to prevent DVT recurrence. However, 6 to 9 percent of patients develop additional clots after the therapy is completed. Prolonged use of warfarin is associated with an elevated risk of dangerous bleeding episodes. In 1998, the NHLBI launched a multi-center clinical trial to determine whether warfarin given at a dose that causes a lower intensity of anticoagulation could prevent the recurrence of DVT and pulmonary embolism following completion of the standard, higher-intensity warfarin regimen. The trial, called Prevention of Recurrent Venous Thromboembolism (PREVENT), showed a 64-percent reduction in episodes of DVT and pulmonary embolism in study participants taking low-intensity warfarin compared with those taking a placebo. In addition, researchers found no evidence of significant risks such as major hemorrhage.

Story of Discovery: Researcher Wins Nobel Prize for Solving the Mystery of Water Transport

Water constitutes 70 percent of the human body and, as a result, its organization and distribution in the body must be carefully controlled. To function properly, some cells must take on water quickly while others must keep water out. Many serious medical conditions are related to improper regulation of water. Some, such as congestive heart failure and pulmonary edema, are associated with excessive fluid retention. Others, such as diabetes insipidus, represent a failure (in this case, of the kidneys) to absorb sufficient amounts of water.

Despite water’s critical role in human health, cellular water transport remained a mystery of biological science until Dr. Peter Agre discovered aquaporin-1, a protein that plays a critical role in water transport. A hematologist supported by the NHLBI, Dr. Agre was not investigating water transport when he discovered aquaporins in 1991. Instead, he was studying the Rh antigen, a protein that is one determinant of blood type. Dr. Agre was trying to isolate Rh protein from red blood cells when he came upon an unknown protein in his samples. Rather than discarding the protein as a contaminant, however, Dr. Agre’s research group examined it and discovered that the protein closely resembled others found in abundance on cells from kidney tubules and plant stems. Although plant cells, kidney cells, and blood cells might not seem to have much in common, Dr. Agre and colleagues recognized that these three cell types share a propensity to take on water readily.

Researchers had speculated since the mid-nineteenth century that cells contain special pores through which water enters and exits. Believing that the new protein might be the heretofore undiscovered water channel, Dr. Agre performed a simple yet elegant experiment in which he modified frog eggs to express the protein on their surface. When he placed altered and unmodified eggs into a dilute, aqueous solution, the modified eggs rapidly expanded as they took on water and, within minutes, exploded; the normal frog eggs did not. Additional studies by Dr. Agre’s group and others confirmed that this protein, which was later named aquaporin-1, was the long-sought-after water pore, demonstrated that water was the only molecule that could flow through the channel, and identified members of the aquaporin protein family in a wide range of plant, animal, and even bacterial cells.

Twelve years after the discovery of aquaporin, researchers believe that defective aquaporin molecules play a role in a variety of human diseases and conditions, including diabetes insipidus, Sjogren's syndrome (a disease characterized by dry eyes and diminished production of saliva), and cataracts. The importance of aquaporin – which also has been discussed in the context of developing therapies to prevent or reduce lung injury, dangerous swelling of the brain after injury or stroke, and congestive heart failure – was recognized by the Royal Swedish Academy of Sciences. In 2003, the Academy presented the Nobel Prize in Chemistry, which Alfred Nobel designated for “. . . those who, during the preceding year, shall have conferred the greatest benefit on mankind . . . [by making] the most important chemical discovery or improvement,” to Dr. Agre for his role in solving the mystery of how the water flows into and out of cells.

Researchers Overcome Barrier to Safe, Effective Gene Therapy for Hemophilia Patients

One of many challenges facing gene therapy researchers is how to control where therapeutic DNA integrates into the genome. The risks associated with inserting a gene in the wrong place recently made headlines when two patients in a French gene transfer study developed leukemias that may have been caused when the new DNA disrupted the delicate mechanisms that control cellular growth and activity. Now, researchers studying hemophilia B appear to have identified a gene transfer approach, based on a mechanism that viruses use to infect bacteria, that specifies where the DNA is inserted. Animal testing indicates that the gene localizes to the proper site and produces therapeutic amounts of the replacement protein, Factor IX. Furthermore, protein production occurs only in the targeted tissue (i.e., the liver) and is maintained over several months in mouse models of the disease.

A Decade of NHLBI Intramural Research Leads to Safer, More Effective,
Bone Marrow Transplants for a Variety of Diseases

In the early 1990s, even the best candidates for bone marrow transplants had less than a 60 percent of being cured—and a 30 percent chance that the procedure itself would kill them. The prognosis was especially bad for patients over 30, people with advanced conditions, and those lacking identically matched sibling marrow donors. Therefore, when the NIH Clinical Center opened its bone marrow transplantation unit in 1993, researchers sought to minimize the risks associated with transplant; improve the likelihood that the procedure would be curative; and make the procedure more successful for a broad range of patients. Their studies answered questions about stem cell doses, methods to prevent donor cells from launching an immune response against a patient’s own tissues, and pre- and post-transplant regimens to prevent life-threatening infections. Thanks to these efforts, bone marrow transplants are more effective and safer for some patients today than ever before. The best suited bone marrow transplant recipients now face less than a 20-percent chance of succumbing to transplant-related complications, and have a 75-percent chance of being disease-free 5 years after transplant. Furthermore, whereas bone marrow transplant once was considered only for patients suffering from bone marrow or blood diseases, researchers have extended the procedure to treat some patients who have metastatic cancers.

Umbilical Cord Blood Is the Preferred Source of Stem Cells for
Patients with Thalassemia or Sickle Cell Disease

Stem cell transplantation is the only available cure for thalassemia and for sickle cell disease. Because other therapeutic options exist for both diseases, the risks associated with bone marrow transplantation have generally been deemed to be unacceptably high. Now, researchers have found that pediatric patients who receive stem cell transplants to cure sickle cell disease or thalassemia fare better if the donor stem cells come from the umbilical cord blood of a matched sibling rather than from a sibling’s matching bone marrow. Whereas sickle cell disease and thalassemia patients who receive bone marrow transplants from HLA-matched siblings have a 6- to 15-percent chance of dying from transplant related complications, each of the 44 umbilical cord blood recipients studied was alive 47 months after receiving the transplant. Moreover, 79 percent of the children who had thalassemia and 90 percent of those with sickle cell disease survived without any serious complications, and an even larger percent survived without developing chronic graft-versus-host disease.

Hydroxyurea Therapy Improves Survival in Most Severely Affected Sickle Cell Patients

Sickle cell disease (SCD) is an inherited disease that, in the United States, primarily affects people of African ancestry. Treatments for adults suffering from SCD did not exist until 1995, when the Multicenter Study of Hydroxyurea (MSH) in Sickle Cell Anemia showed that treatment with the drug hydroxyurea resulted in a 50-percent reduction in the number of painful crises and episodes of a life-threatening, pneumonia-like illness called acute chest syndrome. Moreover, during the 2½ year study, patients receiving hydroxyurea required 50 percent fewer blood transfusions and hospitalizations. After the MSH ended, trial participants, in consultation with their physicians, could choose to continue, stop, or start hydroxyurea therapy and to participate in a subsequent observational study. The follow-up study showed that hydroxyurea not only protects adults who have SCD from painful crises and acute chest syndrome, but also prolongs their lives. Even the sickest patients—those who suffered three or more crises a year—benefited. Because severely ill patients require more emergency room visits and hospitalizations than those who have less severe disease, the results have important implications both for improving patient care and for decreasing health care costs.

NIH ROADMAP

Because the NHLBI is a disease-oriented institute, clinical research is an essential component of its portfolio. Particularly with regard to clinical trials, the Institute has worked to develop efficient, less costly research approaches to evaluating therapeutic and preventive strategies. The ALLHAT (Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial), for example, involved 42,000 patients and could easily have cost more than $400 million if conducted in a traditional manner. Instead, it was conducted as a “large simple trial” with participation of physicians from many types of medical settings. As a result, the actual cost of the trial was markedly reduced. The NHLBI has also developed and refined the “clinical research network” concept and successfully applied it to study of conditions such as pediatric cardiovascular disease, asthma, acute respiratory distress syndrome, and Cooley’s anemia. The networks provide an infrastructure that enables rapid and efficient testing of new therapies as they come to light.

Thus, the NHLBI is an enthusiastic participant in the initiative titled Re-Engineering the Clinical Research Enterprise: Feasibility of Integrating and Expanding Clinical Research Networks, which was issued on December 2 as part of the NIH Roadmap for Accelerating Medical Discovery to Improve Health. This new contract solicitation encourages development of activities that demonstrate how clinical research networks can collaborate to conduct clinical trials and other multicenter clinical research studies. Once clinical researchers understand how networks can overcome challenges such as those presented by differences in study management, investigator interests, disease definitions, reporting procedures, data-and specimen-sharing policies, and informatics tools, they will be able to address more extensive research questions and to conduct clinical research more efficiently than the current system allows. By applying lessons learned from this roadmap initiative, the NHLBI will be better able to accelerate the pace of heart, lung, blood, and sleep research and to reduce barriers that prevent research advances from becoming incorporated into clinical practice and improving patient care.

NHLBI NEW INITIATIVES

Clinical Trials for the Prevention and Treatment of Infections after Cardiac Surgery

With greater numbers of cardiac surgeries being performed each year, cardiovascular infections caused by the bacterium Staphylococcus aureus are becoming a national medical problem. Results of a recent study of over 16,000 coronary artery bypass graft (CABG) surgery patients, published in the August 2003 edition of the Journal of the American Medical Association, found postsurgical infection to be the most common reason for readmission to the hospital within 30 days of CABG surgery. Statistics from the Centers for Disease Control and Prevention indicate that the presence of S. aureus in the blood of hospital patients is becoming much more common. Perhaps even more alarming is that S. aureus is becoming more resistant to antibiotics. The NHLBI plans to initiate two parallel randomized clinical trials to address the prevention and treatment of S. aureus in cardiac surgery patients. The main objective of one, the Prevention Trial, is to prevent infection of the sternum with S. aureus in patients undergoing cardiac surgery. The main objective of the other, the Treatment Trial, is to decrease mortality and morbidity for patients with an infection in a major wound that requires two or more days of antibiotic treatment within 30 days of surgery. Both trials will assess the costs and benefits of new anti-bacterial strategies compared with standard medical care and should provide a basis for improved control of such infections.

Reduction of Cardiovascular Risk in American Indians and Alaska Natives

American Indian/Alaska Native (AI/AN) communities bear a heavy burden of cardiovascular disease (CVD) and modifiable CVD risk factors. Despite extensive documentation of these problems in observational studies, few intervention studies have been launched to test possible solutions. Tribal leaders have urged that research in their communities focus on finding solutions for the most serious health issues they face, including obesity, diabetes, CVD, and sleep difficulties. To address their concerns, the Institute will test approaches to reducing CVD risk factors in AI/AN populations. A central feature of the initiative will be the development of interventions that can be incorporated into the clinical programs of community health care systems or delivered through other public-health avenues in native communities.

Cardiovascular Disease Risk in Jackson, Mississippi

The Jackson Heart Study (JHS) was initiated in 1998 to identify factors associated with increased prevalence and severity of CVD in 5,500 African American adults living in the Jackson, Mississippi, area. The study, which will be extended through FY 2009, is uniquely positioned to identify factors that influence the development and worsening of CVD in African Americans, with an emphasis on manifestations related to hypertension such as coronary artery disease, heart failure, stroke, peripheral arterial disease, and renal disease. Expansion of the JHS will enable support for additional clinical examinations and data collection of CVD risk-associated measures. It will also sustain and enlarge the Jackson-area community health education component, which uses data derived directly from the JHS cohort to develop and disseminate practical, up-to-date information on reduction of risk factors, practice of healthy lifestyles, and adherence to proven risk-reducing therapies.

Bioengineering Approaches for Prevention and Treatment of Overweight and Obesity

Bioengineering offers the promise of new approaches for addressing the obesity epidemic. For example, recent advances in imaging of body fat content should prove useful in improving specificity of diagnosis and treatment. Further progress is needed to allow cellular-level identification of lipids and application to animal models as well as humans. Potentially valuable methods are likely to include development of ultrasound, computed tomography, and MRI techniques in combination with appropriate spectroscopic approaches. A particularly difficult technical challenge is obtaining sufficiently precise measurements of energy intake and expenditure. What is needed is the equivalent of a “magic wristwatch” from which the wearer could easily determine whether an energy intake goal has been exceeded or an energy expenditure goal has been met. New approaches might provide accurate, convenient, easily understood, and inexpensive devices that would foster research, improve clinical management of adults and children, and help the public eat less and exercise more.

NHLBI Centers for the Application of Nanotechnology to
Heart, Lung, Blood, and Sleep Disorders

The rapidly advancing field of nanotechnology offers a wealth of opportunities for the diagnosis and treatment of heart, lung, and blood diseases and sleep (HLBS) disorders. Unfortunately, investigators with nanotechnology experience rarely focus their efforts on HLBS research, and investigators focused on HLBS disorders are generally unskilled in the development and use of nanomaterials and nanotechnologies. Therefore, a crucial need exists to foster partnerships between the nanotechnology and HLBS research communities. A new NHLBI program initiative will facilitate the interaction of scientists from a wide range of complementary disciplines, such as biologists, engineers, physicists, mathematicians, and physicians, with the overriding goal of creating nanotechnology applications for HLBS medicine. Each center will train young scientists and physicians and will be expected to make materials, reagents, and devices available to other researchers and to disseminate technological advances.

Interstitial Lung Fibrosis Clinical Research Network

The NHLBI will develop an Interstitial Lung Fibrosis Clinical Research Network to conduct clinical trials of treatments for patients who have idiopathic pulmonary fibrosis (IPF). IPF, an interstitial lung disease with an especially severe course, has a high fatality rate and no predictably effective treatment. A lack of success from clinical trials of promising compounds is leading clinicians and researchers to believe that a multi-pronged attack with several agents may be required to treat IPF. Although combination therapies have not been tested carefully, they are gaining acceptance by the medical community and rigorous evaluations of new therapeutic approaches are urgently needed. This initiative will establish centers to evaluate the efficacy of several antifibrotic and anti-inflammatory drugs in stabilizing lung disease.

Pulmonary Complications of Sickle Cell Disease

Implementation of comprehensive clinical care programs for children, prophylactic penicillin therapy to prevent life-threatening infections, and transfusion programs to prevent stroke have helped many children with sickle cell disease to survive to adulthood. As adults, however, many suffer from chronic organ damage, especially in the lungs, and are at risk for a life-threatening condition known as acute chest syndrome. Even if the episodes of acute chest syndrome are not themselves fatal, adults who frequently experience acute chest syndrome tend to die at younger ages than those who have fewer events. A program will be initiated to stimulate basic and clinical research on the pulmonary complications of sickle cell disease by funding interactive large grants that integrate basic research on the relationship between red blood cell sickling and lung injury with clinical investigations.

An NHLBI/National Hemophilia Foundation Cooperative Research Program
for Improved Hemophilia Therapy

The NHLBI and the National Hemophilia Foundation are planning a cooperative research program to improve treatments for bleeding disorders such as hemophilia or von Willebrand disease. Although desmopressin, a hormone that increases the availability of proteins essential for blood clotting, can help control bleeding in many people with von Willebrand disease and some who have a mild form of hemophilia, not all patients respond to it and most become progressively less responsive after repeated doses. Most people who have hemophilia receive regular intravenous injections of replacement clotting factor to prevent undesirable bleeding, but this regimen is difficult for small children and unpleasant for older children and adults. In addition, many individuals with severe hemophilia develop inhibitors that neutralize the ability of replacement factors to clot blood. The new program will address the inadequacies of current therapies by supporting research in several areas identified in discussions with the Foundation. Examples include research to control or reduce the immune response against coagulation factors so that people who have hemophilia can continue to benefit from prophylactic treatments of replacement clotting factors; to improve delivery of replacement clotting factor and improve the effectiveness of clotting factors themselves so that patients do not have to receive the frequent, unpleasant injections associated with current hemophilia therapy; and to develop new molecules that interfere with the uncontrolled bleeding associated with von Willebrand disease and hemophilia without causing undesirable clotting so that patients who do not benefit from current treatments have other options.

Genetic and Cellular Discovery in Myelodysplastic Syndromes (MDS)

The increasing prevalence of MDS in the United States is largely due to the aging of the American population and the greater consequent opportunities for exposures to cytotoxic and mutagenic chemicals. MDS, which increasingly are being found in patients following successful cancer therapy or transplantation procedures, have highly variable disease processes. Their heterogeneity makes them difficult to characterize and has limited the development of new therapeutic approaches. A new initiative to support the profiling of biologic and clinical markers of MDS is expected to lead to a better understanding of the diseases and to the discovery of molecular therapeutic targets for different stages of disease.

Genetic and Cellular Discovery in Myeloproliferative Disorders (MPD)

The prevalence of MPD is increasing in the U.S. population, but no curative therapies other than hematopoietic stem cell transplantation exist. The heterogeneous nature of MPD has complicated efforts to characterize and to study the highly variable disease processes in MPD and has limited the development of new therapeutic approaches. This new program would support analysis of genes that are expressed in MPD and identification of gene products that are associated with or responsible for the development or progression of MPD to a malignant and fatal outcome. Such discoveries will be critical to the development of new therapies for MPD patients who are not suitable candidates for hematopoietic stem cell transplantation.

OTHER AREAS OF INTEREST

New High Blood Pressure Clinical Practice Guidelines Issued

A special committee of the National High Blood Pressure Education Program, representing professional, voluntary, and Federal organizations, developed new clinical practice guidelines for the prevention, detection, and treatment of high blood pressure. Called The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), the guidelines feature updated blood pressure categories, including a new “prehypertension” level. The guidelines also streamline the steps by which doctors diagnose and treat patients and recommend the use of inexpensive diuretics as part of the drug treatment plan for high blood pressure in most patients. Results from more than 30 clinical studies provided the foundation for the new recommendations and demonstrated the critical importance of lowering blood pressure, irrespective of age, gender, race, or socioeconomic status. Special web pages and educational materials have been developed for health care professionals, patients, and the public to inform them of the JNC 7 guidelines and to raise awareness about the dangers of high blood pressure.

Study Tests Ways to Help Americans Keep Weight Off

The NHLBI launched a major study that could help solve one of the hardest aspects of weight control – keeping lost pounds off. In phase I of the Weight Loss Maintenance Trial, participants will receive counseling to help them make lifestyle changes to reduce their weight. In phase II, participants who lost 9 or more pounds in phase I will be randomly assigned to one of three weight-maintenance strategies: self-directed/usual care, personal contact, or interactive technology. Phase II participants will try to maintain their weight loss for 2 ½ years. To be eligible for the study, participants must be overweight or obese, aged 25 years or older, and taking medication to control high blood pressure and/or high blood cholesterol. About 60 percent of the study participants will be women and 40 percent will be African Americans. The study will determine which weight-maintenance strategies help people achieve long-term success and what effect these strategies have on heart disease risk factors and quality of life.

Hearts N’ Parks Program Brings Science and Skills to 50 Communities

The Hearts N’ Parks program, a community-based lifestyle initiative, transfers research knowledge about the health risks associated with overweight and obesity to the community level and empowers people to make better lifestyle choices in order to improve their overall health. Data collected during the first year of the program show that it is positively influencing health-related behaviors. For example, children, adolescents, and adults reported adopting healthier eating behaviors after participating in a Hearts N’ Parks program. Additionally, adults reported boosting their level of regular physical activity after the program. Hearts N’ Parks, sponsored by the NHLBI and the National Recreation and Park Association, incorporates science-based information about lifestyle choices that can reduce the risk of coronary heart disease and skills for adopting heart-healthy behaviors into regular activities offered by park and recreation departments and other community-based agencies. The program encourages Americans of all ages to seek a healthy weight, follow a heart-healthy eating plan, and engage in regular physical activity. More than 50 Hearts N’ Parks sites are now active in 11 states throughout the country.

Trial Seeks to Lower Risk of Heart Disease and Stroke in Adults with Type 2 Diabetes

The NHLBI is moving forward with a full-scale, landmark, clinical trial to test the best approaches to lowering the risk of heart disease and stroke in adults with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial will enroll 10,000 adults with type 2 diabetes in 70 clinics around the United States and Canada. The trial will evaluate the effects of intensively controlling blood sugar along with aggressively controlling blood pressure and blood lipid levels. Results from the ACCORD trial will help physicians determine the best ways to treat diabetic patients to prevent the most common and serious consequence of diabetes – cardiovascular disease. The NHLBI is sponsoring the trial in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases.

Red Dress Raises Heart Disease Awareness for Women

Employing the power of symbolism, the NHLBI has recruited an influential ally in its fight against heart disease – the red dress. As a national symbol for women and heart disease awareness, the red dress is paired with the message that “heart disease doesn’t care what you wear, it’s not just a man’s disease.” Women are getting the message; more than 55,000 red dress pins, created by a noted jewelry designer, were requested and distributed in the initial six months. Additionally, red dresses from America’s leading fashion designers are being displayed across the nation as featured exhibits at community events designed to alert women to their heart disease risk. The Red Dress Project is a component of The Heart Truth, a national awareness campaign to motivate women 40-60 years of age to take their heart health seriously and take steps to lower their risk of heart disease. The Heart Truth is being conducted in partnership with the American Heart Association, the Office on Women’s Health of the U. S. Department of Health and Human Services, WomenHeart–the National Coalition for Women with Heart Disease, and other organizations committed to the health and well-being of women.

Interrelationships Between Sleep, Fatigue, and HIV/AIDS

As new therapies extend the life expectancy of HIV-infected patients, the long-term adverse effects of HIV infection on quality of life are becoming increasing apparent. Although relatively unstudied, sleep disturbances and fatigue are highly prevalent and disabling symptoms in a majority of HIV-infected individuals. Indeed, sleep complaints are among the first symptoms of HIV infection and are correlated with decreasing CD4+ lymphocyte counts in otherwise asymptomatic HIV seropositive individuals. Studies indicate that HIV infection disrupts the normal cycle of alternating rapid-eye-movement (REM) and non-REM periods associated with restorative sleep. The impairment in sleep quality may diminish immunological and cognitive-motor function, as well as produce fatigue that interferes with the ability to perform daily activities. The NHLBI, in collaboration with the National Institute of Mental Health, has initiated a new research program to elucidate the etiology of sleep disturbances and fatigue
associated with HIV/AIDS. Knowledge gained from the program is likely not only to benefit HIV/AIDS patients, but also to improve fundamental understanding of the relationship between sleep and chronic disease in general.

NHLBI-ICRH Collaboration

The National Heart, Lung, and Blood Institute is the first of the NIH components to develop collaborative research programs with its counterpart institute, the Institute of Circulatory and Respiratory Health (ICRH), of the Canadian Institutes of Health Research (CIHR). To advance research in areas of importance in heart, lung, and blood diseases, the two institutes are together initiating programs to address new strategies to resuscitate heart attack and trauma patients; develop new cellular and molecular imaging of heart, lung, and blood systems; and improve management of thrombotic disorders such as heart attack, stroke, deep vein thrombosis, and pulmonary embolism. Each of the programs will be conducted at multiple sites in Canada and the United States for several years, beginning in 2004. The collaboration will accelerate research progress in these areas by enabling support for more investigators than either Canada or the United States could support separately.

Budget Policy

The Fiscal Year 2005 budget request for the NHLBI is $2,963,953,000, an increase of $85,847,000 and 3.0 percent over the FY 2004 Final Conference Level. Also included in the FY 2005 request, is NHLBIs support for the trans-NIH Roadmap initiatives, estimated at 0.63% of the FY 2005 budget request. This Roadmap funding is distributed through the mechanisms of support, consistent with the anticipated funding for the Roadmap initiatives. A full description of this trans-NIH program may be found in the NIH Overview.

A five year history of FTEs and Funding Levels for NHLBI are shown in the graphs below. Note that the Fiscal Year 2001 FTE figure is not comparable to the figures in the succeeding years due to NIH’s consolidation of its Human Resources function in FY 2003.

NIH’s highest priority is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while providing new research opportunities. The FY 2005 NIH request provides for an aggregate 1.3 percent increase in average cost for Research Project Grants, consistent with the Gross Domestic Product deflator. The NHLBI is providing an average cost increase of 1.9 percent for direct recurring costs in noncompeting continuation awards. Competing RPGs are based on an average cost increase of 1 percent.

Advancement in medical research is dependent on maintaining the supply of new investigators with new ideas. In the Fiscal Year 2005 request, NHLBI will support 2,009 pre- and postdoctoral trainees in full-time training positions. Stipend levels for pre-doctoral and post-doctoral recipients supported through the Ruth L. Kirschstein National Research Service Awards will remain at FY 2004 levels.

The Fiscal Year 2005 request includes funding for 67 research centers, 658 other research grants, including 579 clinical career awards, and 195 R&D contracts. Intramural Research and Research Management and Support receive increases to support increased pay and estimated inflationary increases in FY 2005.

NHLBI plans to support several initiatives on obesity in FY 2005 including; allocating $1,000,000 for an initiative with NICHD on prevention and treatment of pediatric obesity in primary care settings and $1,500,000 for bioengineering approaches for prevention and treatment of overweight and obesity.

The mechanism distribution by dollars and percent change are displayed below:

National Heart, Lung, and Blood Institute
Budget Mechanism - Total