NATIONAL HEART, LUNG, AND BLOOD ADVISORY COUNCIL

MEETING MINUTES
June 14, 2001

I. CALL TO ORDER AND OPENING REMARKS - Dr. Claude Lenfant

Dr. Claude Lenfant opened the meeting and welcomed the Council to the 202nd meeting of the National Heart, Lung, and Blood Advisory Council (NHLBAC).

May was noted as National High Blood Pressure Education Month. This year’s emphasis was the need to control systolic blood pressure and the importance of lifestyle modification for prevention and treatment of high blood pressure.

ATP Guidelines

On May 17, there was a press conference to announce the release of the National Cholesterol Education Program’s Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). This is the third major update of the clinical practice guidelines for the prevention and management of high cholesterol in adults. The May 16 issue of the Journal of the American Medical Association featured the executive summary of the guidelines as well as a variety of educational materials and tools for professionals and patients.

Guests

Dr. Lenfant welcomed a member of the Board of Extramural Advisors, Dr. Robertson Parkman. Dr. Parkman is Head of the Division of Research in Immunology and Bone Marrow Transplantation at the Children’s Hospital of Los Angeles.

Personnel Announcements

Several personnel changes were announced. Mr. Robert Carlsen, who served as the Institute’s Director of the Division of Extramural Affairs and the Executive Secretary of the Council retired in April after serving the Institute for thirty-three years. Mr. Edward Donohue, Chief, Grant’s Operation Branch has been named as Acting Director of the Division. It was announced that Dr. C. James Scheirer, the Deputy Director of DEA and the primary contact for many Council activities, would retire at the end of June. He had been with the Institute since October 1984. The Institute is working hard to ensure the smooth and uninterrupted management of Council activities until these positions are filled.

New Publications

Dr. Lenfant noted that there were two new publications on the adult treatment panel report which included the ATP III Guidelines Executive Summary and High Blood Cholesterol: What You Need to Know. In addition, there were a number of new publications. One of the items was the Garfield Star Sleeper Fun Pad, a children’s activity book. The Garfield sleeper cat (stuffed animal) was shown and Council was told it was available through the NHLBI Public Web site. The Garfield star program is part of the Institute’s sleep education program efforts. There also was an updated fact sheet titled Facts about the DASH Diet that include DASH-sodium information. In addition, there was the Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. For health professionals, there were new issues of the Heart Memo and the Asthma Memo. Finally, there was the executive summary of the Gold Initiative for Chronic Obstructive Lung Disease.

II. REVIEW OF CONFIDENTIALITY & CONFLICT OF INTEREST - Dr. Claude Lenfant

The Council was reminded that according to Public Law 92-463, the Federal Advisory Committee Act, the meeting of the NHLBAC would be open to the public except during consideration of grant applications. A notice of this meeting was published in the Federal Register indicating that it would start at 8:30 a.m. and remain open until approximately 2:00 p.m. He also reminded the Council members that they are Special Government Employees and are subject to departmental conduct regulations. 

III. REPORT OF THE DIRECTOR - Dr. Claude Lenfant

Budget

Dr. Lenfant presented a series of slides showing the current FY 2002 NHLBI Presidential budget and contrasting it with prior year budgets. The FY 2002 budget (including the Women’s Health Initiative and AIDS) provides an increase of $268.3 million or 11.7 percent. The subsequent slides showed various breakdowns into budget categories. In FY 2000, NHLBI awarded $419,844,000 for competing research grants, $421,830,000 in FY 2001, and plans to award $405,992,000 in FY 2002 which amounts to a decrease of $15,838,000. Dr. Lenfant pointed out that there is a substantial increase in research contracts due to the NIH Loan Repayment Program. The number of competing research grants awarded this year is 987 which is better than anticipated in the beginning of the year. This will decrease for FY 2002, is primarily because of the increase in the average cost of new and competing grants. The number of research training grants increased for this year but will stay the same for FY 2002. This is because the stipend for the trainees has increased. Dr. Lenfant pointed out that there is no increase in the number of FTEs for the Institute staff despite the increased workload as a result of the increased number of grants.

Congressional Testimony

Dr. Lenfant described the Congressional testimony by the NIH which was organized into groups as opposed to individual testimonies by the various institutes. NHLBI was in a cluster on chronic disease with five other institutes (National Eye Institute, National Center for Complimentary and Alternative Medicine, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research and National Institute of Child Health and Human Development). Dr. Lenfant remarked that it was a very interesting process and that NHLBI had a significant portion of the time for its presentation.

NIH Loan Repayment Program

Dr. Lenfant reminded Council that Congress passed legislation which established new loan repayment programs. One program is for minorities, and is part of the legislation that establishes the Center on Minority Health and Health Disparities. This minority program will be developed and administered by that Center.

A second loan repayment program is for individuals engaged in clinical research. The legislation does not specify whether the recipients must hold clinical degrees. Therefore, some Ph.D.s, veterinarians, pathologists, or similar researchers might be eligible for the program if what they do is consistent with the definition of clinical research. This program may be largely dependent on the criteria for eligibility, which are still to be developed.

The third loan repayment program is for pediatric research. It does not specify clinical pediatric research, but it is assumed that the intent of the Congress is to include researchers who do either basic or clinical research related to pediatrics. This is the only one of the new programs where basic research is within the scope of the loan repayment.

NIH established a committee chaired by Dr. Lenfant which developed implementation guidelines. Dr. Lenfant apprised Council that a report was submitted to the Acting Director, NIH, for review and approval. The guidelines will then be sent to the Office of Management and Budget (OMB) for concurrence. Once OMB has developed the rules they will be published in the Federal Register for public comment. Dr. Lenfant commented that there are a number of issues such as eligibility that are under discussion and which will hopefully be resolved in the near future. In FY 2002, there will be a pilot of these programs to see how they will work.

FY 2004 and Beyond Committee

Dr. Lenfant discussed the fact that the Secretary of DHHS has stated that he will do whatever is possible to assure the doubling of the NIH budget by 2003, which will be the fifth year of the process. However, future budgets may not have such significant increases. Consequently, NIH has established a committee to anticipate and prepare for this budgetary shift, and Dr. Lenfant stated that he will keep the Council informed.

 IV.  INITIATIVES

Dr. Alving presented an overview of the Board of Extramural Advisors (BEA) meeting. The purpose of the BEA is to advise the Institute on the merits of initiatives which are under development. The BEA meets twice a year and Council members are welcome to attend.

1."Animal Models of Specific Tolerance for Heart, Lung, and Hematopoietic Stem Cell Transplantation"

The first initiative was presented by Dr. John Fakunding from DHVD and was entitled "Animal Models of Specific Tolerance for Heart, Lung, and HSC Transplantation." The objective of this RFA is to support the development of large animal models of specific tolerance induction for heart, lung and hematopoietic stem cell (HSC) transplantation (HSCT) and also small animal models of tolerance induction for lung transplantation. Transplantation is the only successful therapy for end-stage heart or lung failure and for many malignant and non-malignant blood diseases. The primary indications for heart transplantation are coronary artery disease and cardiomyopathy; those for lung transplantation are chronic obstructive pulmonary disease and cystic fibrosis. HSC transplantation is the only cure for thalassemia and sickle cell disease. These diseases affect millions of people, many of whom ultimately will need a transplant. The number of patients waiting for heart and lung transplants has increased in recent years, further exacerbating the organ shortage. The improvement in quality of life after transplant may be dramatic, but the benefits often are offset by the toxic side effects of long term immunosuppression and by complications such chronic rejection for heart and lung recipients and graft versus host disease for HSC recipients. Development of specific stable immune tolerance between donor and recipient would eliminate considerable morbidity and mortality. Reducing the number of patients needing a second transplant also would improve overall organ availability.

The Immune Tolerance Network, sponsored by the NIAID, NIDDK and the Juvenile Diabetes Foundation, will lead to clinical protocols of tolerance induction for islet cells and for kidney transplant patients. The immediate outlook for tolerance to heart and lung transplant recipients is not encouraging, however. In rodent models, numerous strategies have been used successfully to induce tolerance to heart transplantation and to study HSCT. However, for heart transplantation, these strategies are not reproducible in large animal models, such as non-human primates or miniature swine. For HSC transplantation, existing primate tolerance models need to be made specific for host tissues in order to eliminate the need for global immune suppression which leaves recipients with dysfunctional immune systems.

Although the rodent is an economical model for identifying unsuccessful strategies of tolerance induction, its immune system may be too different from that of the human to serve as a good pre-clinical model. For example, the age-related decline in T cell regeneration is much greater in humans than in mice, the role of the interleukin receptor common γ chain differs between mice and primates, and B cell and T cell development responds to different regulatory factors in these two species. Ethical constraints limit the kinds of experiments that can be performed on patients. Thus, a large animal model, with an immune system more reflective of the human immune system, is essential for testing heart, lung, and HSC transplantation protocols before moving into clinical studies.

The difficulty and expense of development of animal models, especially large animal models, has resulted in few researchers studying tolerance induction for heart and lung transplantation. Issuing an RFA to attract new investigators is essential to advance the field. Investigators currently using small animal models of tolerance induction for heart, lung, and HSC transplantation should be encouraged to move into large animal studies, and investigators studying HSC transplantation should consider its effect on heart and/or lung transplantation.

The Council supported this initiative and noted that while the target poplulation affected in the short term might be small, progress in understanding specific tolerance would have a much broader effect. There are also opportunities for collaborating with other institutes and networks.

2. "Clinical Research Consortium to Improve Resuscitation Outcomes" and

3. "Basic Research to Improve Cardiopulmonary Arrest Survival and Cognition"

Dr. John Watson from DHVD presented a group of initiatives. The first is entitled "Clinical Research Consortium to Improve Resuscitation Outcomes." This program concept was based on recommendations from the Post-Resuscitation and Initial Utility in Life Saving Efforts (PULSE) workshop, held in response to the grave public health consequences of poor cardiopulmonary and trauma resuscitation efforts in clinical practice. The workshop was organized under a multi-agency initiative with NHLBI, NICHD, NIGMS, and NINDS of the NIH, with FDA and DOD on June 29-30, 2000. One of the major recommendations of the participants was to establish a consortium of centers to conduct clinical studies and to expedite translation of promising strategies to the clinical setting. An important part of such approach includes pre-clinical testing of selected strategies in large animal investigations, which ideally would be conducted in parallel with clinical studies. One of the important anticipated features of the program is coordination of research spanning traumatic and cardiopulmonary arrest, with global ischemia offering a common link between the two areas. The advantages of such a coordinated effort include an integrated approach with common definitions, an opportunity to share strategies and organizational structure, and to reduce redundancies associated with several separate research structures. Because clinical investigations of resuscitation require commitment of substantial financial and human resources, central coordination and integration of hospital and emergency services, and community education and participation are paramount. The potential impact of such an effort on public health is great.

A proposed consortium of communities, institutions and organizations with scientific, clinical and technical expertise is necessary to (1) develop a long-term scientific agenda centered on designing and conducting Phase I-III clinical investigations to test the safety and efficacy of interventions for resuscitation of cardiopulmonary arrest and/or trauma victims, and (2) facilitate timely clinical translation of promising strategies. A consortium might include 10 to 15 medium-size cities. Each city will need a plan for gaining cooperation among emergency services and hospitals, and gaining community consent to perform resuscitation research over the program period. The consortium must present a clear vision how new scientific findings and new interventions will be integrated into the scientific agenda. The anticipated key elements of the program include: (1) organization around a central-resuscitation-theme; (2) collaborative efforts and interaction among investigators to achieve a common goal; and (3) a central data and logistical management center.

This Request for Information will request input from the relevant medical community. The NHLBI would request information concerning (1) key organizational and operational elements of the program, (2) anticipated barriers, (3) how to overcome barriers, (4) identification of resource needs and opportunities, and (5) anticipated outcomes. Responses that outline potential programs would be encouraged. The NHLBI would establish a website to exchange information about resuscitation research and to facilitate preparation comments in response to the RFI.

The Council was very supportive of this initiative despite the low rating given by the BEA and it was noted that there are no costs associated with this endeavor.

The accompanying initiative is entitled "Basic Research to Improve Cardiopulmonary Arrest Survival and Cognition." This RFA is designed to support novel basic research approaches to understand whole-body ischemia. The ultimate goal is to provide a basis for development of effective new therapeutic strategies for improving cardiac resuscitation outcomes. There were no additional comments raised by the Council for these initiatives.

4. "Centers for Reducing Asthma Disparities"

Dr. Gail Weinmann from the Lung Division described the initiative entitled "Centers for Reducing Asthma Disparities." Asthma is a serious chronic condition affecting over 14 million Americans, but the prevalence rates are higher in certain populations (e.g., 10 percent in inner-cities and 30 percent among the homeless vs. 5 percent in a general population of whites). African Americans and Hispanics from the Northeast are twice as likely to die from asthma as whites. African Americans are four times as likely to be hospitalized for asthma and are five times more likely than whites to seek care for asthma at an emergency department. Reasons for these higher rates are not certain, and most likely result from an interaction of risk factors such as environmental exposures, genetic predisposition, access to appropriate medical care, socioeconomic status, and cultural health practices.

The NHLBI supports a variety of activities to address the pressing public health problems posed by asthma. However, progress in reducing disparities has been disappointingly slow. Separate, independent research projects have generated important clues for understanding the nature and scope of the problem. A more coordinated, interdisciplinary and comprehensive approach to research is needed to take advantage of these clues, advance the science further and faster, and increase our capacity to improve health outcomes among minority and economially disadvantaged populations. Cooperative centers of research that foster partnerships among minority serving institutions, research intensive institutions, and the communities in which asthma patients live will promote such advancement.

The objectives are to promote interdisciplinary scientific investigation of factors that contribute to disparities in asthma, accelerate development and evaluation of strategies to promote effective asthma management among minority and economically disadvantaged populations, foster partnerships among minority serving medical institutions and research intensive institutions to enrich and expand scientific investigations in asthma, encourage development of greater capacity for asthma research in minority-serving medical institutions and encourage training and career development for minority clinical research investigators, and improve the effectiveness of NHLBI-supported research intensive institutions in developing and sustaining culturally appropriate research and demonstration activities focused on reducing disparities.

Council commented that having the centers be geographically close to each other and providing means for the trainees to continue in this endeavor would be beneficial. This program would also serve as a seed for minority investigators to get other support through other minority support mechanisms. There is also a web site that has a partial listing of some of the minority-serving institutions and there will be a clear definition of a minority-serving institution.

5. "Collaborative Programs in Endothelial Cell Heterogeneity"

Dr. James Kiley presented the next initiative which is seeking to improve the understanding of endothelial cell heterogeneity in normal vascular function and in the progression of vasculopathic diseases of heart, lung and blood. The program goal is to take the next necessary step towards integrating the existing knowledge in endothelial cell biology from the cardiovascular, pulmonary or hematologic systems. It encourages multidisciplinary collaborations that will help to understand how organ- and site-specific endothelial cell (EC) function may mediate the development of disease and lead to new therapeutic designs.

Investigators in the cardiovascular, pulmonary and hematologic communities have been independently working to understand the role of cell heterogeneity in the endothelium in normal function as well as in the diseased vessel. Such heterogeneity may arise from an inherent phenotypic distinction based on developmental origin of the cells or from diverse environmental cues. The origin of organ- and tissue-specific endothelium is still controversial. Investigations are on-going to examine the process of coronary vasculogenesis, that has been used as a model to study the embryonic origins of EC heterogeneity. Studies are also being conducted to identify and characterize circulating endothelial precursor cells in the blood that may give rise to different EC phenotypes. Studies in the pulmonary circulation have shown phenotypic and functional differences in macrovascular ECs compared to microvascular ECs. Further, there is a unique vasoconstrictive response to hypoxia in the pulmonary circulation elicited by EC mediators, that is unlike the response in the systemic system. Other studies have demonstrated that in sickle cell disease, circulating ECs and vessel wall ECs have an activated phenotype, although the activation pattern is complex and varies from organ to organ. Additionally, other work has identified unique sets of genes expressed in ECs of the systemic vasculature that are regulated by mechanical forces, while different genes have been identified in the pulmonary system. Given that the cardiovascular, pulmonary and hematologic systems are built to accommodate specific functions, it is not surprising that heterogeneity of the endothelium exists.

Although on-going studies have addressed important and complex pathways in ECs of each system, the heterogeneity of ECs from different systems have not been studied in a coordinated fashion. It is now crucial to integrate the existing data that has accumulated from the cardiovascular, pulmonary and hematologic communities. This Program is designed to encourage a focused, collective effort to systematically determine whether common themes exist that lead to functional differences of the endothelium. In the era of genomics and proteomics, it is only through this type of effort that the molecular complexity of the endothelium can be dissected and matrices can be developed to understand EC function and dysfunction. Ultimately, it is anticipated that a bridge between the heart, lung and blood communities will promote an understanding of the contribution of EC-based differences to clinical phenotypes and allow for the design of vascular bed specific therapies.

Council had modest enthusiasm for this initiative and emphasized that synergy among the participants should be required. One aspect of interest is that of signaling from the organ tissue which alters the endothelial cell and which could be important in terms of pharmacogenetics.

6. "Comparison of an Invasive Versus Conservation Strategy in Management of Coronary Patients  Scheduled for Non-Cardiac (Vascular) Surgery"

Dr. Jeffrey Cutler presented the next initiative which is to determine the efficacy in preventing myocardial infarction (MI) or death of an invasive strategy, including coronary arteriography and revascularization when appropriate, compared to a conservative medical approach alone in patients with coronary artery disease and inducible ischemia scheduled for non-cardiac (vascular) surgery.

It would seem reasonable to reduce the perioperative risk by identifying patients with Coronary Artery Disease and performing revascularization on those with high grade stenosis. There is, however, no randomized, controlled trial that demonstrates the usefulness of such a strategy or that provides guidance as to what patterns of coronary disease and inducible ischemia predict benefit. The American College of Cardiology/American Heart Association guidelines that address the preoperative evaluation of patients with coronary disease coming to non-cardiac surgery listed the definition of the need for prophylactic revascularization as the highest research priority. Despite a lack of conclusive evidence of efficacy, revascularization is performed on thousands of patients before non-cardiac surgery to "get them through" the procedure. Does the technologic cascade of diagnosis and treatment reduce the risk of non-cardiac surgery? The answers to this and other questions such as who should be revascularized and whether the treatment effect in different definable subgroups varies are simply not known.

The fundamental question addressed in this trial is whether an aggressive strategy that includes coronary arteriography and revascularization, where appropriate, is superior to medical therapy alone in preventing death or MI in the period following randomization until 30 days after the non-cardiac vascular surgery. Death or MI at one year will be a secondary endpoint. Evidence of coronary disease may be by prior coronary arteriography, enzyme or q-wave documented MI, or abnormal stress-perfusion study. Evidence of inducible ischemia would be abnormal stress-perfusion study or the presence of angina.

A pilot study will be conducted first to determine the feasibility of the large scale randomized trial. This pilot should include about 10% of the estimated sample size (370 patients in about 40 sites). If the pilot study is successful, the trial would proceed incorporating any modifications that seemed appropriate. Additional sites would be selected for a total of about 200 sites and the full scale study, which would recruit about 3,330 patients, would then be conducted.

Council was not enthusiastic towards this initiative because the management of vascular diseases is changing which mitigates against the study. Also strong personal biases exist regarding revascularization when a high-risk lesion is found which would complicate randomization and would also deter compliance.

7. "Coordinated Behavioral Science Translational Research Project Grants"

This initiative was presented by Dr. Peter Savage and promotes the translation of basic behavioral science findings from studies of human cognition, motivation, emotion and other areas to advance disease prevention efforts and management of risk factors for heart, lung, and blood diseases and sleep disorders.

Lifestyle and behavior change remain among the most difficult challenges in prevention and treatment of heart, lung, blood diseases and sleep disorders. While a great deal of progress has been made in understanding why people adopt healthy or unhealthy lifestyles, implementing change in behavioral risk factors and maintaining change over time have proven difficult. A majority of individuals relapse soon after completing intervention programs. Clearly, new and innovative approaches are needed.

Studies of presentation of information have shown that when information on operative procedures is framed in terms of mortality rather than survival, patients are more anxious and less likely to elect surgery, even if other available choices result in less favorable outcomes.

Such studies may explain why patients sometimes seemingly act against their own self-interests, as when they exhibit poor adherence to medical and lifestyle recommendations. They may also suggest why providers often fail to successfully implement evidence-based practice guidelines, since cognitive and affective processes could also be expected to influence how a patient’s degree of risk is perceived and how treatment decisions are made and carried out by providers.

The implications of these findings for efforts to change behavior are obvious, yet no studies currently are investigating translating findings from cognitive research on cognitive biases, decision-making or information processing to the design and testing of interventions for CVD behavioral risk factor change or dissemination of practice guidelines. Translating findings from basic behavioral science research is vital for progress in designing more innovative disease prevention programs. For example, countering the rapid rise in overweight and obesity in our population and the associated increase in type 2 diabetes and hypertension will require new approaches, capitalizing on developments in the basic behavioral sciences. The objective of this initiative is to promote translation of new findings from basic behavioral research to the prevention and treatment of heart, lung, and blood diseases or to sleep disorders.

Council was enthusiastic about this initiative because there are so many good theories stemming from psychology, sociology, anthropology, communication and public health which can be brought together to deal with changing lifestyles and in maintenance of these changes. Also this initiative would bring behavioral scientists together with bench and applied scientists.

8. "Efficacy of the Total Artificial Heart in Selected Patient Populations"

Dr. John Watson presented the next initiative entitled "Efficacy of the Total Artificial Heart in Selected Patient Populations." The objective of this initiative is to evaluate the efficacy of implantable total artificial hearts in selected patient populations.

Despite improvements in survival with new medical therapeutics, 30,000 to 40,000 patients per year will eventually develop congestive heart failure unresponsive to any medical therapy. Although heart transplantation is an effective treatment for end-stage heart disease, the limited donor pool makes this an option for only 2,500 patients per year. As such, heart transplantation has only a limited impact on heart failure. In an attempt to fill this void, alternatives to transplantation have been sought, with mechanical circulatory assistance demonstrating therapeutic benefit in short term use. The purpose of this initiative is to encourage one or more small, investigator-initiated clinical trials of totally implantable artificial heart devices for selected patients requiring intermediate and/or permanent support.

The next logical step in the development of the total artificial heart (TAH) is the initiation of clinical testing in selected patient populations. The objective of this initiative is to solicit grants from appropriate clinical investigators to evaluate the efficacy of the Abiomed or Pennsylvania State TAH in selected patient populations. Potential patient populations include bridge to transplant, patients with a failed cardiac transplant, cardiac trauma patients and patients who desire an alternative to cardiac transplant.

This is a Program Announcement and there are no set aside of funds.

Council was very enthusiastic about this initiative because there is a clear need for such a device and it is very important for the government to provide leadership and support in this area.

9. "Emerging Asthma Therapies: Translation from the Bench"

Dr. Gail Weinman presented the next initiative entitled "Emerging Asthma Therapies: Translation from the Bench." This initiative seeks to support translational research for the development of novel asthma therapies.

The long term goal of a substantial portion of biomedical research is the development of safe, effective treatments for disease. However, the overwhelming majority of basic research findings, while providing a knowledge base for cellular and molecular function, do not translate into the clinical arena. For example, over the past several decades, intense basic research efforts have contributed enormously to the understanding of asthma pathogenesis, particularly in the area of inflammation. However, during that same time period, asthma prevalence and morbidity has risen sharply and only one novel treatment has been introduced into the marketplace for asthma. New results from the Childhood Asthma Management Program (CAMP) indicate that, although corticosteroid treatment is safe and effective for alleviation of inflammatory symptoms associated with asthma, it does not preserve lung function. Additionally, testing of several new therapeutic options have proved less promising than initially expected. Thus, while there are a variety of therapeutic options for controlling symptoms, there is not a single asthma treatment option that affects the natural history of the disease. Moreover, there are a subset of asthmatic patients whose disease is refractory to all available treatment modalities, substantially increasing morbidity, mortality and utilization of healthcare resources in this patient group.

Thus, it appears that there is a gap between the ever increasing body of knowledge on the mechanisms of asthma pathogenesis and clinical application resulting in improved patient care. The asthma research community now needs to focus on translating promising basic research into practical clinical application. This Program Announcement (PA) proposes to bridge that gap by supporting high-risk basic research with the specific goal of future therapeutic development. Both animal and human models are appropriate for the scope of this PA, but investigators must be able to demonstrate a specific target as well as a realistic potential intervention and mechanistic rationale. Areas of investigation that are appropriate include: immunomodulation, pharmacology, pharmacogenetics, cellular and molecular biology. Research aimed at therapeutic development could be directed at either the "induction phase" dealing with development of immunologic memory favoring allergic sensitization or the complex "effector phase" occurring in individuals with active disease. This PA will be in effect for 3 years in order to increase the volume of applications in this area as well as capitalize on new and emerging basic science findings. Applications to explore high risk, novel concepts will be encouraged. Studies that show the most promise for therapeutic development may be channeled to the Asthma Clinical Research Network (ACRN) or the Childhood Asthma Research and Education Network (CARE) for potential clinical testing.

Council was enthusiastic about this initiative and liked the fact that the emphasis was on the inductive phase as well as the effector phase of asthma. It was pointed out that the pharmaceutical companies have not been pursuing more novel therapies and that this would provide a means for developing innovative approaches.

"Innovative Concepts and Approaches to Developing Functional Tissues and Organs for Heart, Vascular, Lung, and Blood Applications; Exploratory/Developmental Awards (R21)

Dr. John Watson presented the next initiative entitled "Innovative Concepts and Approaches to Developing Functional Tissues and Organs for Heart, Vascular, Lung, and Blood Applications." The goal is to support innovative approaches leading to the development of new technologies, methods, devices, and materials that can be used to either engineer tissue as a biological substitute for implantation or to foster tissue regeneration and remodeling in vivo, with the purpose of replacing, repairing, maintaining, or enhancing patient function.

Until very recently, most scientists and clinicians believed that damaged or diseased human tissue could only be replaced by donor transplants or with totally artificial parts. Today, however, tissue and organ engineering promises to revolutionize the treatment of patients who need new vital structures. It applies the principles of engineering and the life sciences in an effort to reach a fundamental understanding of structure-function relationships in normal and pathological tissues and to develop biological substitutes, with the capacity to grow and remodel, to restore, maintain, or improve tissue and organ function. The field has already made headway in the synthesis of structural tissues such as skin, cartilage, and bone. Furthermore, bladders have been successfully bioengineered and implanted in dogs. Thus, progress to date predicts future success in the bioengineering of more complex internal organs and the field is now poised for moving ahead in that direction. However, high risk, innovative research in a few critical areas could serve as a catalyst for engineering functional cardiovascular, lung, and blood tissue and help lay the foundation for success that could impact tremendously on human health.

In recognition of the nascence of this scientific area, and the need for the development of novel concepts and approaches to engineering functional tissues and organs, this Request For Applications is proposed. The primary purpose of the solicitation is to provide investigators with the opportunity to explore new approaches and test imaginative new ideas in areas that will have a significant impact on developing function cardiovascular, lung, and blood tissues and organs. In addition, it is intended to encourage the development of substantial and meaningful changes to existing technology. The proposed research should be at the frontiers of tissue engineering and should be unusually imaginative or dramatically different from past paradigms, and must have the potential for a broad impact on current efforts directed at growing tissues for repair or replacement. Applications from both individuals and groups interested in developing suitable novel approaches are encouraged, however team approaches to these efforts are especially encouraged in the belief that a synergistic blend of expertise and resources may be needed. It is expected that this research will require expertise from a variety of disciplines, including engineering, chemistry, physics, material science, biology, and medicine.

Council had a high degree of enthusiasm for this initiative because of the critical need for tissues and organs. Bringing scientists from the different disciplines together to accomplish this will be crucial. The issue of the use of embryonic stem cells was discussed and it was emphasized that NIH would follow all the policies and guidelines regarding human stem cell research.

10. " Interaction of Genes and Environment in Shaping Risk Factors for Heart, Lung, and Blood Diseases"

Dr. Peter Savage presented the next initiative entitled "Interaction of Genes and Environment in Shaping Risk Factors for Heart, Lung, and Blood Diseases." The purpose of this initiative is to identify genes which modify the impact of environmental exposures on heart, lung, blood, and sleep (HLBS) disorders, by quantifying the interaction between genetic variants and specific environmental changes. Short term, focused interventions will be used in families to assess the genetic component of the spectrum of the response of HLBS risk factor levels and disease manifestations to environmental change. The ultimate goal is to identify subgroups based on genotype who are most likely to benefit from targeted environmental changes designed to reduce the development or progression of HLBS diseases.

This initiative will support several studies to examine genetic influences on response to short term, focused interventions or environmental modifications with prior evidence of efficacy in families at risk of HLBS diseases. Studies of genetic variation are increasingly being used in clinical trials to evaluate the impact of polymorphisms in candidate genes on the response to intervention in unrelated individuals. This approach has not, however, been widely applied to families. The primary advantage of studying families is the ability to localize new genes related to response to environmental change, through genetic linkage methodologies, in addition to testing candidate genes. Identification of polymorphisms related to response to environmental change will be facilitated by studying them on a more homogeneous genetic and environmental background than is typical of clinical or population-based studies of individuals. Such "background" variation is reduced among families and in more discrete racial/ethnic groups. In addition, interventions adopted by family units may be more successful than when applied to individuals. For example, interventions involving allergen reduction, changes in diet, exercise or smoking cessation may have higher adherence when there is support from other family members who are also adopting healthy habits or changing the home environment.

Identifying genes that interact with modifiable environmental factors will have significant public health and clinical implications. Genotypic identification of individuals who respond favorably to a short-term intervention may enable targeted interventions to reduce chronic disease risk factors and may help to identify the most effective treatments in clinical practice. For example, the identification of genotypes that predispose individuals to thrombosis (such as Factor V Leiden mutations) in the absence of physical activity might lead to the recommendation for individuals with that genotype to maintain a strict exercise program. From the public health standpoint, individuals with modifiable genetic risk of disease could be identified prior to disease development. Effective, appropriate interventions tailored to the unique genotypic characteristics of an individual could then be initiated to prevent disease or modify its outcome. Recognizing that gene therapy approaches for complex common disorders may not be immediately forthcoming, identification of environmental modifiers of gene expression will permit direct application of human genome sequence information to improve the health of the public in the near future. Advances in this area might significantly enhance the effectiveness of clinical care and particularly of risk factor modification.

Council was enthusiastic about this initiative since the future of human genome epidemiology lies in understanding the gene environment interactions to facilitate phenotypic intervention. The initiative is innovative because of the use of families which will enhance background genetic homogeneity. It was pointed out that the phenotyping will have to be very carefully considered for this project to be successful.

12. "Minority Medical School Research Program"

Dr. John Fakunding presented the next initiative entitled "Minority Medical School Research Program." The purpose of this Request for Applications (RFA) is to augment and strengthen the research capabilities of faculty, students, and fellows at minority medical institutions that offer the M.D., or equivalent medical degree by supporting the enhancement of ongoing, and/or the development of new basic, clinical, and population-based research projects and programs related to cardiovascular, lung, or blood health and disease, transfusion medicine, or sleep disorders. The long-term objectives of this program are to: ensure that traditionally minority medical institutions that have not had a strong research infrastructure will have an opportunity to develop their research capabilities, increase the number of minority individuals involved in biomedical and behavioral research, and reduce health disparities.

The contributions that minority medical schools can make to fulfilling the promise of the NIH research agenda to reduce health disparities and increase the diversity of investigators are unique and essential. However, it is necessary to ensure that minority medical schools can develop the infrastructure and obtain the resources required to conduct state-of-the-art research and train the future cadre of scientists. Focused research programs and programs such as the Minority Medical School Research Program can help to achieve these objectives and foster the collaborative research affiliations needed to address heart, lung, blood, and sleep disorder research problems relevant to the communities and regions served by the minority medical schools.

Council was supportive of this initiative and there was discussion about the fact that it would be necessary to ensure the development of a critical mass of researchers and infrastruture at the awardee institutions. The idea of non-medical school minority institutions as examples was also discussed.

13. "Neural Modulation of Cardiovascular Function: Implications for Treatment"

Dr. Sonia Skarlatos presented the next initiative entitled "Neural Modulation of Cardiovascular Function: Implications for Treatment." This RFA is focused on elucidation of the complex role of neural influences on cardiovascular function and the exploitation of this basic research to develop effective new therapies for the treatment and prevention of cardiovascular disease. Multidisciplinary approaches are necessary, and collaborations between cardiovascular and neural scientists as well as between clinicians and bioengineers are encouraged.

Arrhythmias, circulatory responses to ischemia, and sudden cardiac death may all be provoked and modulated by changes in neural system interactions, yet these interactions remain poorly understood. In addition, the role of the nervous system is only just beginning to be understood in relation to long-term blood pressure control. Furthermore, beyond the cardiovascular actions of catecholamines and acetylcholine, little is known about the effects of novel neurotransmitters and modulator substances involved in mediating neural cardiovascular influences. Enticing new information about the cardiovascular effects of several newly recognized non-adrenergic, non-cholinergic neurotransmitters and modulator substances, such as neuropeptide Y and substance P, provide a number of new therapeutic sites to influence cardiovascular function and to control and prevent disease. For example, neuropeptide Y, normally co-released with norepinephrine from cardiac sympathetic nerves, has been shown to inhibit vagal nerve activity and potentiate the effects of catecholamines. Thus, changes in the level of this and other neuropeptides might contribute to cardiovascular disease in multiple ways. Targeting the sites of action of such novel neural compounds could offer therapeutic benefits that underlie undesirable effects associated with, for instance, generalized beta-adrenergic receptor blockade.

Other recent discoveries show that following ischemic injury to the heart and during development of heart failure dramatic remodeling of the distribution of myocardial neural inputs occurs. For instance, myocardial infarction results in nerve death and denervation near the site of myocardial damage, and more recent studies reveal that sympathetic reinnervation is highly heterogenous and associated with induction of lethal heart rhythm disturbances and sudden cardiac death. Similar forms of neural remodeling may also be associated with blood vessels and might be involved in development of vascular disease. It is not known whether therapeutic strategies developed to influence neural remodeling using, for instance, agents that modulate nerve growth factors may reduce neural heterogeneities and cardiovascular disease.

Thus, although the nervous system is known to play a critical role in the short- and long-term regulation of cardiac activity and vascular tone, its emerging role in development of cardiovascular disease remains poorly understood. Elucidation of this role is expected to provide a basis for development of better therapeutic strategies to treat and prevent cardiovascular disease.

Council considered this initiative to be an excellent proposal in an area which has not received much attention. It will bring together disciplines which will interact in innovative ways. 

14. "NHLBI Shared DNA Microarray Facilities"

Dr. Stephen Mockrin presented this initiative entitled "NHLBI Shared DNA Microarray Facilities." The objective of this initiative is to facilitate the application of DNA microarray technology to hypothesis-driven research in the areas of cardiovascular, pulmonary, hematological, and sleep disorders. This goal will be met by establishing (or expanding) shared DNA microarray facilities with the appropriate infrastructure, including equipment and expertise in relevant disciplines (molecular biology, robotics, bioinformatics, genomics, statistics, etc.).

Many heart, lung, and blood investigators are eager to apply microarray technologies to further their research questions. The major barriers to applying this technology are (1) the lack of funds to purchase or fabricate the microarrays, (2) access to bioinformatic resources and analytical tools to store, share and analyze data derived from DNA microarrays, and (3) access to a critical mass of investigators with the essential capabilities and sophistication for appropriate design and interpretation of experiments.

The proposed NHLBI Shared DNA Microarray Facilities are designed to overcome these barriers and enable multiple research groups to employ this contemporary technology in their approach to research problems. Each facility supported under this program must serve at least five NHLBI-supported research projects and the projects to be supported by any one Microarray Facility must include at least two of the four major scientific areas supported by the NHLBI (heart, lung, blood, and sleep). The primary intent is to enhance the capability of these groups to work at the cutting edge of contemporary biomedical science.

 The investment required to obtain essential equipment and personnel to establish DNA microarray technology is more than can easily be borne by a single investigator. This Request For Applicants is intended to support the cost-effective introduction of techniques to measure patterns of gene expression in specific tissues or cells of interest to NHLBI-supported investigators. In addition, to help assure the appropriate institutional commitment for the establishment, maintenance, staffing, and operation of a facility, the grantee institution must provide at least one dollar from non-Federal sources for every two dollars provided by the NHLBI.

Council considered this to be a superb initiative which the scientific community both needs and wants and which will provide a way of facilitating institutional fund cooperation with the NIH.

15. "NHLBI Administrative Supplements to Support DNA Microarray Applications and Analyses"

Dr. Stephen Mockrin presented the next initiative entitled "NHLBI Administrative Supplements to Support Microarray Applications and Analyses." The objective of this initiative is to supplement ongoing NHLBI funded research programs to utilize DNA microarray data and technologies.

The Administrative Supplement program will encourage and support microarray technology use for those investigators that need funds to purchase or fabricate arrays, purchase or develop analysis software, and/or to isolate appropriate tissues or cells for microarray application. In addition to generating new expression data, investigators can request funds through this Administrative Supplement to use DNA microarrays or analyze array data generated by the PGAs to ask hypothesis-driven questions specifically related to their own research. Funds may also be requested to follow-up on expression array analyses derived from the PGA array datasets. This can be done in two different ways: 1) to analyze the various PGA datasets asking hypothesis-driven questions related to the ongoing research project; and 2) to follow up on the data analysis generated by the PGAs, including polymorphism analysis in human subjects or animal models of genes of interest based on array clusters, and developing computational systems to model array data.

Council was stongly supportive of this initiative which gives the institutions that already have the technology to move ahead and the institutions that do not to start moving in that direction. 

16. "NHLBI Proteomics"

Dr. Stephen Mockrin presented the next initiative which is entitled "NHLBI Proteomics." This initiative will establish highly interactive, multi-disciplinary groups to enhance and develop innovative proteomic technologies and apply them to relevant biological questions that will advance our knowledge of heart, lung, blood, and sleep health and disease.

There are many areas that would benefit from proteomics, but are hindered by severe technological and methodological limitations. Protein profiling that can identify and determine the amounts of proteins in a cell or tissue offers exceptional promise for understanding complex molecular pathways and how they are involved in health and disease, and ultimately improve clinical decisions regarding detection, diagnosis, and treatment. However, no current technology allows both comprehensive identification of large numbers of proteins and sensitive quantitation of these proteins. Other technical challenges include the quantitation of membrane-bound proteins and very low-abundance proteins.

A second example are post-translational modifications, which have an enormous effect on the properties of many proteins, modulating their ability to interact with other factors, their sub-cellular localization, and their catalytic activity. Probably the most striking example is in signal transduction, where complex cascades of protein phosphorylation and other modification events transport signals from the cell periphery to the nucleus. Quantitative information about differentially modified proteins will allow investigators to gain increased understanding of the altered biological processes associated with various stages of heart, lung, and blood disease progression. However, considerable effort is needed to develop sensitive, efficient, and reproducible technologies that can provide a more global view of protein post-translational modification events.

Protein interactions is a third area, as many proteins function in concert with cellular factors or with other proteins as members of protein machines. It is important to determine protein interaction networks of interest to heart, lung and blood biology. Innovative platform technologies are needed to facilitate massively parallel functional proteomic studies, such as arrays that will identify all possible binding partners of a protein of interest.

In order to overcome these technological barriers and to make keen biological insights necessary for clinical benefit and utility, a significant and comprehensive approach is needed to create an environment in which innovative approaches are coupled to important biological problems. Hence, this initiative will establish local, highly interactive, multi-disciplinary groups (biology, chemistry, physics, engineering, proteomics, bioinformatics, statistics) to enhance and develop innovative proteomic technologies and apply them to relevant biological questions. In order to develop truly innovative technologies and apply them to biological issues, it will be important to provide a sustained period of uninterrupted support and a significant investment. Just as it took numerous years to overcome the genomic technological barriers, it will take many years for innovative approaches in proteomics to show its promise. The investment must also be sufficient to support the full range of possible novel approaches to the full range of heart, lung, blood, and sleep biological areas. In order to insure maximum benefit from this investment, the products (reagents, techniques, information) of this effort must be made readily available to the scientific community.

Council was supportive of this initiative which is the natural extension of the genomics initiative and, therefore, very important. This initiative is timely and NHLBI should be at the forefront.

17. "Nitric Oxide Biology in Health and Vascular Diseases"

Dr. Charles Peterson presented the next initiative which is entitled "Nitric Oxide Biology in Health and Vascular Diseases." The goal of this initiative is to stimulate research to measure and evaluate in a systematic way the effects of inhaled nitric oxide (iNO) gas and oral nitric oxide donors (NODs) on normal vascular biology, and on the abnormal vascular biology seen in disorders of the cardiovascular system and blood. Emphasis will be on evaluation of the importance of the nitric oxide (NO) pathway in normal vascular homeostasis, on evaluation of the potential of NO or NODs for routine therapeutic use in vascular disorders (e.g. sickle cell disease, congenital heart disease, and atherosclerosis), and on identification of the mechanistic basis of the well-known variation in patient responses to iNO.

In the area of blood diseases, there has been much recent excitement about the potential use of iNO and/or NODs for treatment of sickle cell disease, in particular for the pulmonary complications of this disease. Sickle cell disease has long been considered a blood disease, owing to its initiation by mutant sickle hemoglobin that polymerizes to decrease the deformability of red blood cells. However, it is now increasingly thought of as a vascular disease due to extensive evidence that the endothelium of sickle patients is activated (proinflammatory), and prothrombotic. The hallmark of this disease is widespread vaso-occlusion leading to transient acute pain crises and ultimately end organ failure, especially in the spleen, lungs, kidney, and brain. There are at least seven independent and compelling rationales for the investigation of iNO or NODs as potential therapeutics for this disease. All of these are well-supported in the scientific literature from the past 5 years. The rationales are: 1) reduction of pulmonary hypertension, which is becoming more of a problem as sickle cell patients live longer; 2) treatment (via NO-induced vasodilation) of the acute chest syndrome that is caused by vaso-occlusion in the pulmonary vessels, and is still the leading cause of mortality in this disease; 3) transport of iNO on hemoglobin resulting in peripheral vasodilation; 4) inhibition of the expression of endothelial adhesion markers (e.g. VCAM-1) now thought to be important early players in the formation of vaso-occlusive blockages; 5) increased solubility of sickle hemoglobin (i.e. melting of the sickle hemoglobin polymer); 6) increased oxygen affinity of sickle hemoglobin, potentially reducing the rate of its polymerization; and 7) improvement of poor glomerular hemodynamics linked to the chronic renal dysfunction that is associated with NO deficiency, and that is becoming more of a problem as sickle cell patients live longer.

In the area of cardiovascular diseases, it is believed that NO has much potential to improve the homeostatic properties of the arterial wall, such as inflammation and hemostasis, in patients with endothelial dysfunction (e.g. as in atherosclerosis, or diabetes) and reduced regional NO bioactivity. Moreover, recent reports have clearly documented in normal human subjects the importance of locally produced NO on regional vascular dynamics in the periphery. Hence the development of strategies for local delivery of NO might lead to useful new therapies. Our understanding of the role of NO as a therapeutic agent, causative agent, or protective agent in the pathogenesis of cardiovascular diseases is limited. One area where iNO has been successful as a therapeutic in the critical care setting is in the improvement of pulmonary hypertension linked to congenital heart disease. However, patient responses have been variable, and the mechanistic basis of the benefit has not been extensively documented. Another emerging area of interest is that of mechanisms contributing to the increased peripheral vascular resistance that is associated with congestive heart failure (CHF), and that is thought to contribute to the high mortality of CHF. The increased resistance is believed in part to be due to decreased NO-mediated vasodilation in an environment of increased basal NO production (i.e. resistance to the action of NO). The increased levels of NO derive from increased activity of a specific isoform of nitric oxide synthase, inducible nitric oxide synthase (iNOS). Understanding the mechanisms involved in the switching in NOS isoforms, and mechanisms of resistance to the action of NO could lead to new treatment modalities for CHF. A third area of interest addresses atheroprotective genes. Recent evidence suggests that atherogenic-determinant genes exist whose expression may offset or even ameliorate the pathogenesis of atherosclerosis. Cases in point are the genes for the isoforms of nitric oxide synthase (NOS). An important question is the role of shear stress and how various types of flow (e.g. laminar, pulsatile flow) along the vessel wall may differentially regulate genes (e.g. NOS) associated with NO metabolism in vascular cells (endothelial and smooth muscle). Studies are needed to delineate the coordinate induction of genes that promote an anti-thrombotic, anti-inflammatory and anti-oxidant environment helping to prevent the formation of atherosclerotic lesions on the vessel wall. NHLBI currently supports less than five grantees working in these cardiovascular areas of interest.

 Council expressed enthusiasm for this initiative. Although there is a lot of research on nitric oxide, interactions with other anti-radicals is considered novel and further research is warranted.

18. "Nonhuman Primate Models of HIV-Associated Pulmonary,Cardiovascular and Hematologic Disorders"

Dr. James Kiley presented the next initiative entitled "Nonhuman Primate Models of HIV-Associated Pulmonary, Cardiovascular and Hematologic Disorders." The purpose of this RFA is to encourage investigators to utilize nonhuman primate models to explore Human Immunodeficiency Virus (HIV)-associated pulmonary, cardiovascular and hematologic disorders. These primate models (e.g., Simian Immunodeficiency Virus (SIV) and Simian-Human Immunodeficiency Virus (SHIV)-infected) should be designed to facilitate the study of the biological and clinical characteristics of disorders associated with infection and co-infections of lung, heart, blood and bone marrow, as well as novel methods for prevention and treatment of these disorders.

By altering local immunity in the lung, HIV infection can also result in harmful inflammatory responses and infiltrates that may cause acute or chronic lung injury (e.g., pulmonary hypertension). HIV-associated immune dysfunction increases the likelihood and severity of other lung infections and also appears to alter the pathogenesis and clinical course of these respiratory infections in ways that are different from other immunodeficient states. The presence of concurrent lung infections other than tuberculosis, for example Pneumocystis carinii pneumonia and pneumococcal pneumonia, can also increase the replication of HIV and accelerate the course of AIDS. Nonhuman primate models are well suited to determine immunological correlates of tuberculosis and other lung co-infections during different stages of disease, something that is currently not well understood. Other research needs that can be addressed in these model systems include immunological and microbiological mechanisms associated with latent and active tuberculosis, the pathogenesis of granuloma formation, and host-microbial interactions that lead to lung injury. Models of SIV/SHIV-mycobacterial coinfections are likely to provide essential information needed to understand synergistic interactions between Myocardium tuberculosis (Mtb) and HIV.

Blood and marrow-related disorders have been observed in SIV-infected monkeys, and parallel findings have been found in humans infected with HIV-1. Therefore, the nonhuman primate model system is useful for furthering our understanding of the mechanism(s) associated with these disorders and for exploring strategies for prevention and treatment. Hematopoietic abnormalities associated with HIV infection include: decreased proliferation of hematopoietic stem and progenitor cells, increased destruction of mature cells, and alterations in the supportive marrow stromal environment and in the production of regulatory cytokines. The pathophysiologic mechanisms of these abnormalities are poorly understood, and require rigorous study. Also, it is known that thrombocytopenia is one of the earliest manifestations of HIV infection in human and primates. HIV infection is likely to compromise the function and interaction of cytokines, matrix proteins, migration of megakaryocytes and the production of platelets leading to thrombocytopenia.

This initiative will stimulate collaborations among scientists devoted to the study of simian immunodeficiency virus/simian-human immunodeficiency virus (SIV/SHIV) disease in primates as a model for human AIDS and investigators whose expertise is in the areas of, but not limited to, tuberculosis, and other pulmonary and cardiovascular disorders and the role of blood cellular components in the genesis and progression of the disease, including the genesis of thrombocytopenia and thrombotic events during HIV infection. Such collaborations would take advantage of both the large wealth of knowledge and the physical resources (e.g., biological and immunologic reagents) that have been assembled in the past 15 years in response to the AIDS epidemic. In addition to R01s, this RFA would include career award grant mechanisms (K01, K08) that will encourage and facilitate the ability of junior investigators to acquire the skills needed to conduct research in primate models.

Council considered this to be an important initiative which is clearly relevant to human disease.

19. "Novel Biomarkers of Chronic Obstructive Pulmonary Disease (COPD)"

Dr. Gail Weinmann presented the next initiative entitled "Novel Biomarkers of Chronic Obstructive Pulmonary Disease." The objective of this initiative is to stimulate research to identify and characterize biomarkers of COPD presence, severity, and exacerbation.

Identification and characterization of biomarkers of COPD would yield multiple benefits. Such markers could facilitate investigations of the natural history and epidemiology of COPD, aid phenotyping in studies of associated genetic factors, and clarify the relationships of existing animal models to the human disease. Clinical applications could lead to earlier diagnoses and more accurate prognoses and allow targeting of intensive smoking cessation interventions to those at greatest risk. Validated biomarkers might serve as surrogate indicators in clinical trials and thereby enable the development of novel therapeutic agents. Finally, a clearer understanding of the relationship between specific biomolecules and disease status would advance basic COPD research by providing clues to the underlying pathogenetic mechanisms involved. It is notable that the discovery of a biomarker in alpha1-antitrypsin deficiency was instrumental in leading to an explanation of susceptibility and a possible treatment in that group of individuals.

Recent research suggests that chemicals or biochemicals related to oxidative stress (e.g. exhaled 8-isoprostane or hydrogen peroxide), to inflammation (myeloperoxidase or human neutrophil lipocalin), or to elastin degradation (desmosine or elastase/elastase inhibitor complex) may be altered in COPD. The discovery of other novel markers is possible using methods of proteomic analysis or gene expression profiling. Finally, advances in imaging technologies such as positron emission tomography (PET) may now allow in situ measurements of relevant markers of COPD. Given the importance of biomarkers for COPD research, the encouraging early results with putative markers, and the recent availability of powerful molecular methods, a concerted effort to identify biomarkers of COPD is warranted at this time.

Investigations of biomarkers for COPD would serve as a bridge between basic studies of pathogenetic mechanisms and clinical studies of disease risk and progression, two areas of strength in the COPD Research Program. Translation of research results from one area to the other would likely be enhanced. Most prior studies of biomarkers for COPD have been performed outside the U.S. and NHLBI currently funds very little research on this topic.

Council was strongly enthusiastic about this initiative.

20. "The Role of Genomic Variation in Progression, Outcome, and Treatment of Heart, Lung, and Blood Diseases"

Dr. Stephen Mockrin presented the next initiative entitled "The Role of Genomic Variation in Progression, Outcome, and Treatment of Heart, Lung, and Blood Diseases." This initiative will stimulate the translation of information on genomic variation to clinical applications. The goal is to use knowledge about DNA variations to predict the clinical progression and outcome of cardiovascular, pulmonary, hematologic, and sleep disorders, and to guide prevention and treatment strategies.

Research efforts to use DNA-based markers to aid in gene discovery have produced a large number of polymorphic markers, such as restriction fragment length polymorphisms (RFLPs) and simple tandem repeats polymorphisms (STRPs). More recently, numerous studies and programs are involved in the discovery of single nucleotide polymorphisms (SNPs), including the NIH SNP Initiative (http://grants.nih.gov/grants/guide/rfa-files/RFA-HG-98-001.html), the SNP Consortium (http://snp.cshl.org/), and the NHLBI Programs for Genomic Applications (PGAs) (http://www.nhlbi.nih.gov/resources/pga/index.htm). Some of these projects focus on random SNP discovery, while others focus on SNPs within and surrounding genes of interest. There are now approximately 1.6 million human SNPs in the public database (SNPdb) (http://www.ncbi.nlm.nih.gov/SNP/).

This concept is not designed to be a gene discovery program. Rather, this initiative will encourage investigators to combine the available data on genomic variation (STRPs, SNPs, RFLPs, etc.) and the vast clinical information on heart, lung, and blood diseases to better understand clinical progression and outcome, to predict response to drugs, and to explore novel intervention strategies (prevention and therapeutic) at the level of the individual. Applicants may propose to use existing clinical and epidemiological studies to apply genotyping in relevant candidate genes, their surrounding genomic areas, and other genomic regions of high interest to study the variation in relation to clinical progression, outcome, prevention, or treatment of cardiovascular, pulmonary, hematologic, and sleep disorders. As the goal of this initiative is to apply genomic information to clinical application in the individual (or subsets of individuals), each application must have sufficient statistical power to accomplish this goal.

Council was strongly enthusiastic about this initiative since it is likely to make a difference at the interface of biology and medicine.

21. "Role of Infectious Agents in Vascular Diseases"

Dr. Sonia Skarlatos presented the next initiative entitled "Role of Infectious Agents in Vascular Diseases." The role of infectious agents in the development of vascular disease continues to be supported by studies showing an association between vascular diseases and certain bacterial and viral infections. The objective of this initiative is to encourage the careful design of in vitro and in vivo studies that will clearly delineate the specific cellular and molecular mechanisms by which infectious agents contribute to atherogenesis. A secondary objective of this initiative is to encourage the development of therapeutic interventions that target these molecular mechanisms.

Mechanistic studies suggest that gene products of infectious agents can act directly on vascular cells. Nevertheless, an important question is whether infectious agents--only sometimes found in atheroma--can exert vasculopathic effects without infecting vascular cells. For example, the atherogenic changes seen in infected endothelial and smooth muscle cells can be caused by systemic inflammation due to chronic infection and activation of circulating inflammatory cells. In addition, another important mechanism by which infectious agents might increase vascular disease without directly infecting vascular cells is through exacerbation or augmentation of well known risk factors such as hypercholesterolemia.

Several animal models have been developed for vascular diseases including atherosclerosis in non-human primates, rabbits and mice. The establishment of infectious disease/vascular disease animal models opens the opportunity to test specific inhibitors of the disease process, which can provide solid evidence of causality. Also, these models allow rational development of antiviral and antibacterial therapies including drugs, vaccines, and other novel approaches that target specific pathogenic mechanisms. A preventive CMV vaccine has been available for a number of years, but it has limited efficacy and is unlikely to effect latent CMV. A Chlamydia vaccine is not yet available. While traditional vaccines may be beneficial for uninfected individuals, they may be ineffective against existing latent and chronic pathogens. Therefore, the testing of a variety of therapeutic possibilities that target direct, indirect, or systemic atherogenic mechanisms of infectious agents seems warranted.

Council was strongly enthusiastic about this initiative since there are a tremendous number of practical implications and there is significant technology which exists to accomplish these goals.

22. "Thrombophilic Factors in Thromboembolic Disease"

Dr. Liana Harvath presented the next initiative entitled "Thrombophilic Factors in Thromboembolic Disease." The objective of this initiative is to encourage basic and translational research in venous thrombosis and pulmonary embolism. The specific goals are to: (1) support targeted research on hemodynamics, blood coagulation and on the cellular and inflammatory processes that are involved in venous thrombosis; (2) investigate clinically relevant familial and environmental thrombophilic conditions; (3) study venous tone and the properties of venous vascular beds, (4) apply basic science knowledge to improve clinical issues related to anticoagulation and rethrombosis, and (5) evaluate the effect of flow and naturally occurring models of thrombosis in low flow or low oxygen environment.

Recently, progress has been made in better understanding of thrombophilia, defined as an increased tendency or predisposition to thrombosis. It can be inherited or acquired. Inherited deficiencies of antithrombin, protein S, or protein C are known predisposing factors; however, less than 10% of patients with suspected thrombosis have a defect associated with one of these proteins. A change in the level of FVIII, FXIII or PAI-1 has also been implicated in thrombosis. Major progress was made with the discovery of activated protein C (APC) resistance that is caused by a mutation at the protein C cleavage site of the coagulation factor V (also known as Factor V Leiden). This mutation is present in 5 to 7% of the Caucasian population and in about 30% of patients with familial venous disease. A second molecular alteration in the prothrombin gene has been linked to an enhanced risk of venous thrombosis. The A20210 allele is present in about 6% of the patients and in 2% of the general population. While the above molecular abnormalities can result in clinical thrombophilia, penetrance is incomplete. For example, only about 10% of patients with factor V Leiden develop thromboembolic disease in their lifetimes. DVT is a complex disease often caused by the occurrence of two or more coagulation defects or by gene - environment interactions. Advanced genetic technology e.g. large scale screening, genomics for assessment of the underlying genetic factors predisposing to thrombosis seems to be suitable for this purpose, and eventually a "thrombophilia chip" may be developed. In addition to studies in patients with DVT/PE, the development of an appropriate animal model of thromboembolic disease utilizing genetic tools is encouraged and may allow testing of specific prophylactic regimens.

Venous thrombi may form in low flow or low oxygen environment such as may occur in the placenta or in sickle cell disease. Thrombophilia is known to be an important contributor to complications of pregnancy and fetal loss. Research is needed on the characteristics of blood flow, regulation of the venous tone, and the nature of the endothelial surface in susceptible areas. New methods are needed to monitor the major risk factors of trauma and surgery that may expose tissue factor and create stasis leading to prothrombotic conditions. The interrelationship between venous thrombosis and the inflammatory response and how this leads to the sequelae of chronic venous insufficiency is not completely understood. The involvement of leukocytes, cytokines, and adhesive proteins, such as selectins, in this process needs to be defined. New approaches to platelet function inhibition, e.g. Gas6 is needed.

Patients with DVT receive both initial treatment with heparin and long term oral anticoagulant therapy for at least 3 to 6 months. Although the patients have diverse disease etiologies, the current treatment modality and the drugs involved are the same. Better data on subsets of patients and a possible relationship to thrombophilic factors could be very valuable in developing preventive measures and specific prophylaxis, rather than non-specifically shutting down all vitamin K-dependent proteins with Warfarin. The complications and morbidity related to warfarin are significant and represent a patient subset that does not require this anticoagulation regimen. Monitoring the efficacy of oral anticoagulation is based on the prothrombin time and can be misleading. This anticoagulant effect is influenced by individual variations, including diet, absorption, genetic make-up, and interaction with other drugs. The need for close monitoring and repeated hospitalizations significantly add to the total cost of anticoagulant therapy. Application of the existing knowledge of basic blood coagulation to the duration of treatment of DVT and method of monitoring is clearly needed to optimize treatment of thromboembolic disease.

Council was very enthusiastic about this initiative since it is an incredible problem which, if solved, would have a tremendous implication in terms of public health.

23. "Tuberculosis Curriculum Coordinating Center"

Dr. Dorothy Gail presented the next initiative entitled "Tuberculosis Curriculum Coordinating Center." The purpose of this RFP is to encourage a coordinated national effort to strengthen, expand, and increase access to the best ongoing educational and training opportunities related to public health efforts against tuberculosis (TB).

Tuberculosis, one of the oldest known human diseases, kills approximately 3 million people annually despite the existence of an effective, although cumbersome, antibiotic therapy and a safe, but often ineffective, vaccine. TB is the most common opportunistic infection in AIDS patients around the world and it is estimated that one-third of the world's population, mainly in underdeveloped countries, carries the causative organism, Mycobacterium tuberculosis. The high incidence of TB in underdeveloped countries and the large numbers of people immigrating from those countries to the United States raise doubts that TB can be completely eliminated in this country unless major financial resources are deployed in those countries where TB is endemic. As a result of implementing more aggressive prevention and control programs in the United States over the past 10 years, the total number of TB cases diagnosed annually has been declining (but proportionally increasing in the immigrant population); however, it is feared that these recent successes are creating a false sense of public health security. As a consequence, it is becoming more difficult for medical and health professional students to receive the specialized instruction that will allow them to diagnose and treat patients with TB. The need for better TB education was identified by the Institute of Medicine report on tuberculosis, titled "Ending Neglect." At a meeting of the TB Task Force organized to respond to the Institute of Medicine recommendations, the unique role that the NHLBI has had in promoting TB education in medical and health professional schools was highlighted.

The proposed RFP will have two phases:

In the first phase of the award faculty members of medical and nursing schools, media and education experts, selected to represent the best TB expertise in the country, will be responsible for the preparation of items such as: 1) surveys of the levels of knowledge of students of medicine and allied health professions about TB, through standardized and validated questionnaires; 2) analysis of the educational materials utilized at the different schools; and 3) elimination of outdated materials and selection of appropriate ones for students and young health professionals at different levels of educational attainment.

In the second phase of the award, faculty members from the different schools will be funded to work with the coordinating center in implementing the best TB curriculum at their schools. The faculty members must have documented TB expertise and leadership skills and must hold an academic appointment at a level sufficient to enable them to exert an influence on curriculum

preparation and coordination. The center would complement existing and planned TB educational efforts supported by the Center for Disease Control and Prevention (CDC).

Council was supportive of this initiative since it is timely and will allow the opportunity to extend what has been learned from the Tuberculosis Academic Awards (TBAA) Program.

24. "Transfusion Medicine/Hemostasis Clinical Research Network"

Dr. Liana Harvath presented the next initiative entitled "Transfusion Medicine/Hemostasis Clinical Research Network." The goal of this initiative is to establish a clinical research network of interactive groups in the area of transfusion medicine/hemostasis that will allow for efficient evaluation of the efficacy of new blood products for treatment of hemostatic and hematopoietic disorders and newer immunomodulatory agents in the treatment of immune-based bleeding disorders.

The objective of this RFA is to establish a Transfusion Medicine/Hemostasis Clinical Research Network that will accelerate research in the clinical use of newer blood products that have undergone viral inactivation or that are recombinantly based. The management of immune-based hemostatic disorders, such as idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura is not well defined and novel growth factors as well as immunomodulatory agents need to be evaluated with respect to their roles in these diseases. The network will standardize the approach to the existing diagnosis and treatments, and evaluate new ones. The emphasis will be on clinical trials with a goal toward facilitating optimal therapy. Therapeutic trials may involve investigational drugs, devices or blood products, including those already approved but not currently used, and those currently used.

 Council supported this initiative since it will translate the results from the scientific findings pertaining to hemostasis to clinical studies. There was a suggestion to include studies of existing blood products as well as studies on rare but serious transfusion reactions. This initiative will bring together groups to be able to recruit enough patients to answer relevent clinical questions.

25. "von Willebrand Factor, Shear Stress, and Arterial Thrombosis"

Dr. Liana Harvath presented the next initiative entitled "von Willebrand Factor, Shear Stress, and Arterial Thrombosis." The goal is to support research on the plasma protein von Willebrand factor (VWF) with emphasis on (1) biosynthesis, processing and secretion, (2) factors regulating the level and multimeric distribution, (3) effect of shear, and (4) mechanism of platelet interactions. These processes are essential in arterial thrombosis.

Platelet adhesion and shear-induced aggregation are initiated by an interaction between VWF and the glycoprotein complex Ib-IX-V. VWF is a glycoprotein synthesized by endothelial cells and megakaryocytes and is stored in Weibel-Palade bodies and secretory granules. The protein is secreted by both constitutive and regulated pathways. VWF is synthesized as a monomer of 2813 amino acids. The signal peptide and propeptide are rapidly cleaved and a homodimer is formed within the cell by disulfide linkage. These dimers are then processed in the Golgi apparatus resulting in large polymers of very high molecular masses. Upon secretion, these polymers are processed into smaller subunits by a metalloprotease. Normal plasma contains a spectrum of VWF polymers with the largest polymers having the highest platelet aggregating and hemostatic activity. Both the plasma concentration of VWF and its polymeric distribution are considered to be important in the biological activity of this critical protein. A dysfunction in the metalloprotease has recently been reported in some patients with thrombotic thrombocytopenic purpura. This deficiency leads to the presence of large VWF polymers in plasma that can spontaneously cause aggregation of platelets probably explaining the microangiopathy observed in these patients. These patients when in remission showed normal protease activity and normal VWF polymer distribution.

The biosynthesis and processing of VWF, the identification and characterization of the protease, regulation of VWF polymer formation, response to shear force, interaction with platelets, possible regulation of vessel-bound VWF and fluid phase VWF are research areas to be defined. Platelet aggregation inhibitors directed to glycoprotein IIb-IIIa have proved to be valuable adjuncts in the treatment of cardiovascular diseases. Inhibitors to platelet adhesion based on interaction of VWF with the GPIb complex could provide additional opportunities for the treatment of arterial thrombosis.

Council was very supportive of this initiative to increase the support for VWF studies.

26. "Asthma Clinical Research Network (ACRN)"

Dr. James Kiley presented the next initiative entitled "Asthma Clinical Research Network (ACRN)." The goal of this network is to continue a network of clinical centers and a data coordinating center to conduct controlled clinical trials of new and existing treatments for adult asthma.

In order to address this major public health problem, the NHLBI established the ACRN in 1993 to conduct clinical trials to rapidly evaluate new and existing therapeutic approaches for asthma, and to disseminate the clinical findings to the health care community. The ACRN consists of six clinical centers and one data coordinating center. To date, the ACRN has completed seven clinical trials with an additional three trials currently underway and two more pending implementation. Since its inception, the ACRN has published 14 papers and 10 abstracts. The completed and ongoing trials include: The Addition of Regular-Use to Intermittent Rescue Beta-

Agonist for Patients with Mild Asthma; Colchicine In Moderate Asthma; Salmeterol Off Corticosteroids; Salmeterol + or - Inhaled Corticosteroids; Dose of Inhaled Corticosteroids with Equisystemic Effects; Measuring Inhaled Corticosteroid Efficacy; Beta Adrenergic Response by Genotype; Improving Asthma Control Trial; and Smoking Modulates Outcomes of Glucocorticoid Therapy in Asthma.

Progress is continuing in basic research and new hypotheses and potential therapies are evolving from small clinical trials. There are many future possibilities for evaluating new and existing therapies for asthma, including modulators of innate immunity/tolerance induction, the role of anti IgE therapy, predictors of response to steroids, the heterogeneity and variabilty of response to various asthma medications, identification of non-invasive markers of inflammation, relationship of changes in lung function with asthma exacerbations, the role of obesity in the response to inhaled corticosteroids, pharmacogenetics on the steroid receptor, phenotypic characterization of adult onset, non-atopic asthma, asthma in the elderly, leukotriene receptor antagonists, and optimal therapy for severe asthma. Another important approach is evaluation of adherence and asthma outcomes for new anti-asthma agents and with combination therapy. An NHLBI-supported asthma network is the ideal environment to address all of these and many other timely clinical topics. As the list of possible future studies changes over time, the network concept provides flexibility to rapidly respond to new and emerging concepts.

Council was very supportive of extending this initiative.

27. "Clinical Network for Acute Respiratory Distress Syndrome (ARDS) - ARDSnet. (Renewal)"

Dr. Dorothy Gail presented the next initiative entitled "Clinical Network for Acute Respiratory Distress Syndrome (ARDS)." The goal of this initiative is to continue a network of clinical centers and a clinical coordinating center to conduct controlled clinical trials of treatments for acute lung injury (ALI)/ARDS.

The NHLBI ARDSnet was established in 1994 to hasten the development of effective therapies for ARDS by evaluating new treatments and management practices in a rigorous way. The ARDSnet originally consisted of 10 clinical sites and a clinical coordinating center and 10 additional clinical sites were added following a competition to conduct a new protocol that is evaluating the efficacy and safety of the pulmonary artery catheter.

The ARDSnet has had a major impact on the care of critically ill patients with ALI/ARDS. The results of the ventilator management study have been heralded as signaling a new era of research and management of the critically ill. The ARDSnet has demonstrated that well designed, collaborative clinical studies with sufficient power can be undertaken in critically ill patients. The results call into question commonly used endpoints other than survival and bring attention to lung injury as a factor influencing systemic inflammation and organ dysfunction. In addition to the six network protocols, several ancillary studies will provide needed information on pathogenesis and natural history of ARDS. Progress is continuing in basic research and new hypotheses and potential therapies are evolving from small clinical trials.

The new Network would be structured as the original, with a Steering Committee composed of Principal Investigators responsible for protocol selection, development, and conduct; a Clinical Coordinating Center; an independent Protocol Review Committee; and a Data Safety and Monitoring Board. Because of the complex nature of the clinical trials to be undertaken, some requiring 2-3 years to complete, 7 years of support are proposed.

Council was very enthusiastic about continuing this initiative.

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CLOSED PORTION

This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. appendix 2).

There was a discussion of procedures and policies regarding voting and confidentiality of application materials, committee discussions and recommendations. Members absented themselves from the meeting during discussion of and voting on applications from their own institutions, or other applications in which there was a potential conflict of interest, real or apparent. Members were asked to sign a statement to this effect.

 REVIEW OF APPLICATIONS  

The Council considered 1,333 applications requesting $1,621,964,332 in the total direct costs. The Council recommended 907 applications with total direct costs of $1,279,890,796. A summary of applications by activity code may be found in Attachment B.

ADJOURMENT

The meeting was adjourned at 5:30 p.m. on June 14, 2001.

CERTIFICATION

I hereby certify that the foregoing minutes are accurate and complete.

Claude Lenfant, M.D.

Chairperson

National Heart, Lung, and Blood Advisory Council

on 09/05/01