Goal 2: Reduce Human Disease

To extend our knowledge of the pathobiology of heart, lung, blood, and sleep disorders and enable clinical investigations that advance the prediction, prevention, preemption, treatment, and cures of human disease.

Goal 2: Reduce Human Disease

Does lowering circulating lipoprotein(a) levels influence cardiovascular outcomes?

A comprehensive research strategy and plan is needed to determine the most efficient, safe, cost-effective and widely applicable strategy to decrease circulating levels of lipoprotein(a) and to determine whether lowering circulating lipoprotein(a) levels will reduce the risk of developing cardiovascular disease such as a heart attack or a stroke as well as the progression of atherosclerosis or aortic stenosis.

Submitted by (@serevill)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Approximately 20% of the population are characterized by elevated circulating levels of lipoprotein(a), regardless of age, gender or blood cholesterol levels. Estimates suggest that up to 90% of the variation in plasma lipoprotein(a) levels could be due to genetic factors, which makes lipoprotein(a) the most prevalent inherited risk factor for cardiovascular diseases (CVD). Large-scale genetic studies have shown that Lipoprotein(a) was the strongest genetic determinant of CVD such as atherosclerosis and aortic stenosis. Lipoprotein(a) is one of the strongest predictors of residual CVD risk and has been shown to improve CVD risk prediction in several population-based studies. Lipoprotein(a) is also one of the strongest known risk factors for spontaneous ischemic stroke in childhood.

A comprehensive research strategy aiming at identifying, evaluating interaction with other risk factors, treating and educating patients with elevated lipoprotein(a) levels would result in substantial reductions of health care costs in the US and around the globe by reducing the burden of CVD while simultaneously improving the quality of life of these patients.

Feasibility and challenges of addressing this CQ or CC :

The list of pharmaceutical agents that reduce lipoprotein(a) levels is steadily increasing. There are approximately half a dozen strategies that have been shown to significantly and safely lower lipoprotein(a) levels. One of the challenges of this research strategy will be to determine which of these strategies represent the most efficient, safe, cost-effective and widely applicable approach to lower lipoprotein(a) levels and CVD outcomes.

Increasing awareness on lipoprotein(a) and CVD will also be of utmost importance for this effort as relatively few physicians perform lipoprotein(a) testing and even fewer patients are aware of their lipoprotein(a) level. The first sign of high lipoprotein(a) is often a heart attack or stroke. Our challenge will be to identify patients with high lipoprotein(a) that could be enrolled in trials of risk characterization and lipoprotein(a)-lowering.

Name of idea submitter and other team members who worked on this idea : Sandra Revill Tremulis on behalf of the Lipoprotein(a) Foundation Scientific Advisory Board

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Goal 2: Reduce Human Disease

UNDERSTANDING SLEEP AND CIRCADIAN DISORDERS AT A BASIC MECHANISTIC LEVEL

We need to understand sleep and circadian disorders at a more mechanistic level. This applies to both the pathogenesis of these disorders and to their impact on health. New neurobiological and molecular tools facilitate this research. The focus needs to be not only in brain but also the impact of these disorders on future of peripheral organs. The elucidation of the fundamental functions of sleep and the impact of ...more »

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Much of the research on the consequences of sleep/circadian disorders has focused on their consequences or behavior. This type of research needs to be continued and there are new opportunities in this area. These behavioral studies need to be established in model systems to parallel studies in humans. In addition, new neurobiological approaches, including optogenetics and use of DREAD, provide new tools for this investigation. Moreover, we now have powerful molecular tools to evaluate effects of sleep/circadian disorders both in humans and animal models. These include microarrays, RNA seq, etc. Moreover, genetic studies, e.g., in restless legs syndrome, have identified gene variants conferring risk for the disorder. We do not know, however, how these particular genes are involved in the pathogenesis of the disorder or whether they represent potentially targets for drug intervention. There is a need for studies both in animal models and in humans to elucidate the function of these genes. Studies in other areas are obtaining stem cells from biopsies in patients and then turning these into relevant target cells such as neurons to elucidate gene function using in vitro approaches.

The impact of this effort will be the following:

 

a. Taking our understanding of pathogenesis of sleep and circadian disorders to a new level.

b. Understanding the consequences of sleep and circadian disorders on different end organs at a more in-depth molecular level.

Feasibility and challenges of addressing this CQ or CC :

The sleep and circadian field have access to all the major cells systems for these studies—C. elegans, aplysia, Drosophila, zebra-fish, mice, etc. Moreover, there are already gene variants identified in human studies which require follow-up functional studies. The field has the expertise in all of the techniques described above. Moreover, there are more validated animal models for many of the common sleep disorders. Thus, this new approach is very feasible. 

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Goal 2: Reduce Human Disease

DEVELOPMENT OF A PERSONALIZED APPROACH TO SLEEP AND CIRCADIAN DISORDERS

There is developing evidence of major individual differences in pathways to different common sleep disorders such as obstructive sleep apnea. Moreover, there is evidence of different clinical presentations of disease and different outcomes. For example, some subjects with obstructive sleep apnea who get excessive sleepiness while others do not. The latter are still at risk for other consequences of the disorder such ...more »

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

There is a strong rationale for application of a personalized approach to sleep disorders. This requires approaching this question using multiple domains as in other areas of medicine—clinical features, physiological factors, application of the –omic approaches, genetics. The impact of this will be several:

 

a. A new way to classify sleep disorders.

b. Identification of subgroups of patients with apparently the same disorder who will have different outcomes of therapy.

c. Identification of subgroups of patients who will have different approaches to diagnosis.

d. Identification of subgroups of patients with apparently the same disorder who will have different therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

These sleep and circadian disorders are extremely common. There is a risk infrastructure for this type of research based on the large number of accredited sleep centers in the United States that could be used for subject recruitment and who can adopt similar techniques. There is also a rich set of data obtained from sleep studies that could be used to identify new patterns that reflect different subgroups of subjects. These studies need to be based on clinical populations of patients who present with the different disorders rather than on population-based cohorts.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Goal 2: Reduce Human Disease

SLEEP DISORDERS AS A MODIFIABLE RISK FACTOR FOR CHRONIC DISEASE

There is developing evidence that sleep disorders, in particular obstructive sleep apnea and inadequate sleep, can influence the course of other chronic diseases. Observational studies show that CPAP treatment of patients with pre-diabetes who have OSA reduces the incidence of future diabetes. Moreover, animal and human data indicate that insufficient sleep and sleep apnea can affect the rate of progression of neurodegenerative ...more »

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

This question will have considerable impact. Sleep apnea is an independent risk factor for insulin resistance. Moreover, observational studies show that treatment of OSA reduces the rate of future diabetes compared to that which occurs in untreated OSA. Therefore, identifying OSA and treating this could have a profound impact on reducing the rate of diabetes, i.e., a preventative strategy.

 

Both sleep loss and obstructive sleep apnea have also been shown to be risk factors for subsequent development of Alzheimer’s disease. This has been shown in mouse models and in epidemiological studies to address whether insufficient sleep and sleep apnea are independent risk factors for development of Alzheimer’s disease, in particular accelerating their onset. Determining whether this is so and whether interventions to treat these sleep disorders delay onset of diabetes and Alzheimer’s disease would have profound public health significance.

Feasibility and challenges of addressing this CQ or CC :

These disorders are extremely common so that recruitment of subjects is not challenging. Moreover, new technology reduces protocol burden to assess individuals. All studies can be done in the patients’ home. There are existing cohort studies focused on diabetes and the Alzheimer’s Center program that could be used for these studies. Thus, the studies are extremely feasible in the near term.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Goal 2: Reduce Human Disease

Apheresis Medicine in the Management of Sickle Cell Disease

Despite advances in care, patients with sickle cell disease have significant morbidity and mortality. One challenge is the optimal use of simple vs exchange transfusion vs no transfusion when managing these patients. Simple transfusions lead to iron overload while exchange transfusions may expose patients to increase numbers of red blood cell units. The mechanism of benefit from transfusion (oxygen delivery vs marrow ...more »

Submitted by (@bsachais)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

SCD is the most common genetic disease in the United States affecting 100,000 individuals or 1 in 400 African American births. Pain, stroke, acute chest syndrome and priapism are common morbidities affecting patients with sickle cell disease, which often result in emergency room visits and/or hospitalizations. Despite advances in treatment, sickle cell disease is associated with significant mortality and shortened life expectancy. Defining the optimal role of red blood cell exchange and plasma exchange (which may be used to remove plasma molecules such as inflammatory factors and free hemoglobin) in the management and prevention of the complications of sickle cell disease and may not only prolong the life of these patients but is expected to improve the quality of their lives. In addition, clearly defining the indications for simple verses exchange transfusion therapy has the potential to minimize both alloimmunization to red blood cells (reported to occur in up to 75% of patients with sickle cell disease) and iron overload associated with transfusion.

 

Transfusion therapy may be efficacious to sickle cell patients by providing increased oxygen delivery to tissues and/or decreasing the amount of sickle hemoglobin present by suppression of erythropoiesis. Understanding the relative contributions of these mechanisms will assist with optimal use of transfusion therapy as well as inform the development of novel alternative therapies

Feasibility and challenges of addressing this CQ or CC :

Multi-center trials should be feasible, given the number of patients with sickle cell disease in the US. Participation by larger academic centers which care for sickle cell patients should facilitate trials. Methods for automated red cell exchange and plasma exchange are available and in common use at many centers. Great interest exists among physicians caring for sickle cell patients (as exemplified by the recent NIH consensus document and ASFA sickle cell consensus conference) which is a strength of this proposal. Challenges include agreement on standard treatment protocols across centers and long term follow up of patients. Maintaining vascular access in sickle cell patients is another challenge when performing apheresis procedures on sickle cell patients

Name of idea submitter and other team members who worked on this idea : Bruce Sachais on behalf of ASFA

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Goal 2: Reduce Human Disease

Funding for Hemostasis & Thrombosis Research

Thrombotic disorders, a result of the inappropriate activation of the hemostatic system, remain major causes of morbidity and mortality in the United States. Cancer, cardiovascular disease, trauma, and many of the other causes of death in the U.S. frequently culminate in a fatal thrombotic event. Notably, thromboembolic disease affects 500,000 people annually and leads to 100,000 deaths in the United States alone. Current ...more »

Submitted by (@abrams)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Following vascular injury, regulated hemostasis is both rapid and appropriate, thereby quenching hemorrhage. Nonetheless, it is clear that both hemostasis and thrombosis are dynamic processes, characterized by the sequential accumulation and removal of newly activated platelets and fibrin at sites of vascular damage. Over the past 10 years, research in hemostasis and thrombosis has been transformed, broadened and infused with new energy driven by novel technologies and ideas. NHLBI-funded science has revealed new pathways for platelet activation, for platelets in physiologic events outside of the hemostatic response, for coagulation proteases in modulating inflammation and tissue repair after injury, and new mechanistic insights into coagulation. Many tacitly accepted ideas in the field are yielding to these new mechanistic insights that suggest new ways to modulate coagulation leading to therapeutic gain. The NHLBI should continue its strong support of research to understand these mechanisms and should continue to bolster the training that will equip the next generation of scientists and physician-scientists to translate discovery from the lab to the bedside.

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Goal 2: Reduce Human Disease

HEALTH CARE DISPARITIES IN DIAGNOSIS AND TREATMENT OF COMMON SLEEP AND CIRCADIAN DISORDERS

There is evidence of a higher prevalence of sleep and circadian disorders in different ethnic groups. This is true for both adult and pediatric subjects. There is also evidence that minority populations in lower socioeconomic groups do not seek evaluation for sleep disorders as frequently as other segments of our population. There is also evidence that they are less adherent to treatments such as nasal CPAP for obstructive ...more »

Submitted by (@jnoel0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Sleep disorders are more common in minority populations. Moreover, these populations have higher rates of the known consequences of these disorders such as stroke, myocardial infarction, hypertension, resistant hypertension. Despite this, current population studies such as the Sleep Heart Health Study have included only a very small percentage of African Americans. The impact of this would be the following:

 

a. Elucidating the basis of barriers to case identification in these group

b. Designing specific intervention to overcome these barriers.

c. Developing methods to improve adherence to therapy in this group.

d. Removing sleep and circadian disorders as a risk factor for consequences such as stroke, cardiovascular disease and resistant hypertension in minority populations

Feasibility and challenges of addressing this CQ or CC :

There is a developing interest in this area in the field of circadian and sleep research. There is a developing knowledge base about health disparities in sleep and circadian disorders. Minority institutions such as Morehouse have developing programs in this area. We also have mobile technology that facilitates study of sleep and circadian disorders in minority populations.

Name of idea submitter and other team members who worked on this idea : Sleep Research Society

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Goal 2: Reduce Human Disease

The Importance of the Microbiome in Recovery after Hematopoietic Stem Cell Transplantation

Do modifications in the recipient gut or lung microbiome affect development of tolerance and immunologic recovery after allogeneic hematopoietic stem cell transplantation (HCT) and can re-institution of a more normal microbiome lead to improved outcomes?

Submitted by (@marymh)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

HCT leads to profound changes in the host microbiome. Some small studies indicate that differential recovery of the gut microbiome is associated with differential outcomes, including graft-versus-host disease and mortality. Less is known about the pulmonary microbiome. Better understanding of the role of the microbiome in facilitating posttransplant recovery could lead to easily administered interventions and provide important insights into the role of different subpopulations of the microbiome on the health of all people.

Feasibility and challenges of addressing this CQ or CC :

Preclinical and clinical studies of this area would be greatly facilitated by a microbiome repository linked to high quality clinical data and would provide opportunity for insight into the role of the microbiome in health and disease.

Name of idea submitter and other team members who worked on this idea : Mary Horowitz

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Goal 2: Reduce Human Disease

What is the place of curative therapies in the management of Sickle Cell Disease

Advances in the care of pediatric patients with sickle cell disease ( SCD) have resulted in improved survival to adulthood.However, adulthood is marked by rapid disease progression, impaired quality of life and premature mortality. Hematopoietic cell transplantation(HCT) from matched sibling donor has curative potential, but has been offered mainly to children. Refinements in the conditioning regimen, supportive care, ...more »

Submitted by (@lakshmanankrishnamurti)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

To overcome this obstacle to progress in the field, we propose the creation of the funding mechanisms for a multicenter clinical trial consortium which would bring together investigators in field and facilitate study the outcomes of CT for patients with different types of donors and stem cell sources and compare them to outcomes in phenotypically matched controls receiving best available standard of care.Answering the compelling question about the role of CT in the management of SCD has the potential to have a catalytic effect in progress in this field. Patients are are then more likely to receive CT or standard of care at the appropriate time and in the manner in which they are most likely to have a positive outcome. This has the potential to reduce morbidity and premature mortality and in the long run, to decrease the burden of the disease on the healthcare system. The advent of clinical trials of gene therapies for SCD offers the prospect of even greater applicability of curative therapies. Thus, a consortium developed to answer this CQ would serve as a crucial vehicle for providing access to a greater proportion of patient to these personalized curative therapies . Such studies would also be powered to answer the question about who should receive the curative therapy, when they should receive it, and how it would impact their SCD related complications, late effects, survival and quality of life and help families make informed choice appropriate for their situation.

Feasibility and challenges of addressing this CQ or CC :

The increasing applicability and acceptability of HCT for SCD is evidenced by the doubling in the number of such procedures reported to CIBMTR in the decade starting 2001. Refinements in conditioning regimen and supportive care continue to improve outcomes in children and now in adults with SCD undergoing HCT from HLA matched related donors. Recently, HCT from unrelated donors and from haplo-identical donors have further increased the applicability of HCT. Opening of gene therapy trials has further raised the prospect of cure for a greater proportion of patients. These developments are evidence of the feasibility of recruitment to large multi-center comparative trials of SCD and standard of care. Recently, there has been increasing collaboration among investigators in the field with informal consortia being developed by investigators coming together to study HCT for children, adults or HCT from haplo-identical donors. These groups are also increasingly working with SCD hematologists, families and other stakeholders. There is also increasing cross-cutting collaborations with other medical specialists and behavioral and translational scientists Thus, the convergence of several factors described above suggests that the time is fortuitous for a major initiative from the NHLBI to bring investigators together and create the infrastructure that will enable these investigators to seek definitive answers to the challenging question “What is the place of curative therapy in SCD?”.

Name of idea submitter and other team members who worked on this idea : Lakshmanan Krishnamurti, MD, Allistair Abraham MD, John Horan MD and members of the Sickle cell Transplantation and Research Alliance

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Goal 2: Reduce Human Disease

Transplantation across HLA barriers in aplastic anemia

Allogeneic stem cell transplantation is curative in aplastic anemia with much less intrinsic toxicity than transplantation in hematologic malignancies. The recent BMT-CTN trial demonstrated 97% survival at one year with little subsequent decline. However patients without matched related or unrelated donors have graft-rejection rates of up to 50%. Preliminary data from the Netherlands suggests that anti-thymocyte globulin ...more »

Submitted by (@jantin)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The use of umbilical cord blood or haploidentical donors has proven effective in patients with hematologic malignancies, but in non-malignant disorders outcomes are limited by graft rejection. Overcoming rejection in this context would be applicable to other non-malignant disorders such as thalassemia, sickle cell anemia, and other congenital disorders of hematopoiesis.

Feasibility and challenges of addressing this CQ or CC :

It will require a large coordinated network like BMT-CTN to obtain sufficient patients studied in a uniform fashion to provide consistent reproducible data. .

Name of idea submitter and other team members who worked on this idea : Joseph Antin

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Goal 2: Reduce Human Disease

Support for Cardiothoracic Surgery and Pediatric Heart Clinical Trial Networks

Continued and expanded support for the Cardiothoracic Surgical Trials Network (CTSN) and Pediatric Heart Network (PHN) is essential as both design, conduct, and analyze multiple, collaborative clinical trials that evaluate surgical interventions, and related management approaches for the treatment of cardiovascular disease. To date both networks have reported on and developed a portfolio of studies which need continued ...more »

Submitted by (@meaton)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The work and support provided to date have allowed for the creation of an infrastructure for both the CTSN and PHN. Each network is now providing valuable results to the cardiothoracic surgery specialty which will allow an increase in quality patient care in the years and decades to come. The continued support is essential for the success of these networks as any reduction will limit the resources available for site participation and ultimately results. Due to the existing infrastructure for each network, the financial burden associated with de-funding and then restarting the networks in future years would be at least triple the financial commitment currently in place.

Feasibility and challenges of addressing this CQ or CC :

Conducting multi-center clinical trials is a substantial financial commitment but a vital part for the future of the cardiothoracic surgery specialty.

Name of idea submitter and other team members who worked on this idea : Matt E.

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Goal 2: Reduce Human Disease

Funding for Cardiothoracic Surgery Research

The continued development of new technologies requires cardiothoracic surgeons to maintain a strong level of research to ensure the highest quality of patient care and surgical outcomes are received across the world. The level of support for CT surgery within the NIH has continued to drop over the last decade. This is a substantial problem for the specialty as the limited funding available creates difficulty in the continued ...more »

Submitted by (@meaton)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

CT Surgeons are performing procedures on some of the sickest patients while effecting some of the most dramatic favorable outcomes and the continue support for research in this specialty is essential to ensuring improvements in quality patient care. CT surgeons are provided the opportunity to participate in both the research lab and operating room which provides an important opportunity for a role in both the scientific discovery and implementation of new outcomes.

Feasibility and challenges of addressing this CQ or CC :

Cardiothoracic diseases are one of the top health issues facing the global population and the research being conducted is integral in helping cure the issues facing the current generation. With expanded support for research, new areas of the heart, lung, and esophagus can be studied with the hopes of identifying new technologies and procedures to help ensure the next generation is given the highest quality of care possible.

Name of idea submitter and other team members who worked on this idea : Matt E.

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