Goal 2: Reduce Human Disease

Inflammation and outcomes following pediatric cardiac operations

What is the contribution of the inflammatory response to postoperative recovery following pediatric cardiac operations and what strategies can improve outcomes?

Submitted by (@grahamem)

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

Details on the impact of addressing this CQ or CC :

Congenital heart disease is the most common cause of birth defects, with about 40,000 new cases born per year in the US. Affected individuals experience morbidity and mortality that generate health and economic consequences significantly out of proportion to their numbers. An estimated 10,000 of these patients will undergo cardiac surgery involving cardiopulmonary bypass (CPB). Furthermore, it is estimated that over 300,000 children in the US under age 21 have congenital cardiovascular disease and that 38% of these children will have had one or more surgical procedures. The use of CPB in neonates in particular has increased steadily over the past two decades. Further, neonates are generally sicker and consume more resources, including postoperative mechanical ventilation, ICU stay and hospital stay. Consequently, reducing the deleterious effects of CPB will have the largest impact in this group of patients.

Feasibility and challenges of addressing this CQ or CC :

Research has begun to assess the inflammatory response to cardiopulmonary bypass in pediatrics. However, the magnitude and importance of its contribution to complicating postoperative recovery remains elusive. Clinical trials have begun to assess the efficacy of generalized anti-inflammatory therapies, typically steroids, with conflicting results. No therapy has been recognized as the standard of care. It’s critical that we improve our understanding of the molecular and cellular mechanisms of this inflammatory response and resulting derangements in vascular permeability and develop novel treatment strategies for infants and children undergoing cardiopulmonary bypass.

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Goal 1: Promote Human Health

The Human Virome and Host Interactions in Heart, Lung, and Blood

What are the unknown elements of the human virome, and what host-virome interactions affect the heart, lung, and blood health and diseases? A major challenge has been the need for in vitro culture systems and animal models for studying the virome, which is a significant limitation that has forced current studies of the virome to be mostly descriptive. NHLBI has supported one research group to identify human virome and ...more »

Submitted by (@nhlbiforumadministrator)

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 virome contains the most abundant and fastest mutating genetic elements on Earth. The human virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. The virome may influence the host in profound ways independent of classical viral disease. The immune system is continuously stimulated by chronic systemic viruses and this aspect of host-microbiome interactions appears specific to the virome. The virome is considered one of the drivers of idiopathic systemic inflammation that has been linked to many of the most severe public health threats, including cardiovascular diseases. Disruptions in immunity by immunosuppressing events can undoubtedly alter the interactions of the virome with the host. However, little research has been done in all of these aspects other than limited descriptive studies to identify the presence or composition of the human virome. The NHLBI Microbiome Working Group in June 2014 clearly identified under-representation of studies of the human virome. Identification and characterization of unknown viral elements of the human virome and research on the interactions with the host will allow exploration of their impact on heart, lung and blood health and diseases, including impact in the presence of immunosuppression with the host such as in AIDS or HIV infection.

Feasibility and challenges of addressing this CQ or CC :

This initiative is feasible because of new technologies that have been developed recently such as the deep sequencing techniques. The initiative is also timely in that research supported by the NIH Human Microbiome Program and other programs has allowed us to better understand microbiome, especially bacteria in and on humans, and we began to realize the magnitude of the virome. This initiative will attract more investigators to not only identify more elements of the virome but more importantly to understand the roles of the human virome in heart, lung and blood health and diseases, and eventually to help develop diagnostic and intervention strategies.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Targeting Inflammation in Venous Thromboembolism

What is the role of inflamation in venous thromboembolism, both DVT and PE. If the inflammatory response can be controlled, then clot formation should be able to be decreased or eliminated without bleeding potential. The effect of the inflammatory response on the wall of the veins, both in the legs and the lungs, leads to changes that result in pain and swelling (legs) and pulmonary artery hypertension (lungs). Inhibiting ...more »

Submitted by (@thomasww)

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

Details on the impact of addressing this CQ or CC :

I would suggest that studies addressing this issue using new targeted anti-inflammatory medications be supported in both large animal models (close to human) and in clinical translational studies.

Feasibility and challenges of addressing this CQ or CC :

This is feasible and doable - there is data suggesting that inflamatory inhibition with agents that target the selectins (for example) lead to a lessening of thrombosis, and decreases in vein wall damage, all without bleeding potential. These conepts in animals need to be evaluated in clinical studies. Additionally, there are other off-shoots such as studies with biomarkers of inflammation and how they can be helpful in making the diagnosis and predicting the response to therapies.

Name of idea submitter and other team members who worked on this idea : Thomas Wakefield

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Goal 2: Reduce Human Disease

Cellular senescence and age-related lung disease?

What is the role of cellular senescence in age-related lung disease? Do environmental factors, including smoking, contribute to the pathogenesis of lung disease through their ability to induce premature senescence? Does the accumulation of senescent cells in distal organs contribute to age-related lung disease through systemic inflammation?

Submitted by (@ferrucciogalbiati)

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

Name of idea submitter and other team members who worked on this idea : Ferruccio Galbiati

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Goal 2: Reduce Human Disease

What is the role of chronic inflammation in lung complications in the HAART era?

With the advent of HAART HIV-infected subjects are living longer. Lung infectious complications so common in the early stages of the HIV epidemic have been replaced by those associated with chronic inflammation (COPD, pulmonary hypertension, lung cancer). Furthermore, this chronic inflammation is likely contributing to premature vascular complications (i.e coronary disease) seen in this population. All of these complications ...more »

Submitted by (@htwig0)

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

Details on the impact of addressing this CQ or CC :

Addressing the role of chronic inflammation in chronic lung and vascular diseases will impact both the HIV population and our growing U.S. aging population. Approaches to the question could include:

1.. Causes of chronic inflammation

- Antiretroviral drugs, persistent HIV, persistence of other viruses, exogenous retroviral elements, exosomes, other epidemiologic exposures

2. Downstream mechanistic effects of chronic inflammation

- Alterations in gene regulation, alterations in oxidative stress, direct tissue damage

3. Clinical outcomes of chronic inflammation

- Lung – COPD, pulmonary HTN, cancer, interstitial lung disease, asthma.

- Vascular compartment - premature coronary and vascular disease

- Does HIV-infection itself require alterations in treatment modalities for lung disease

- Does HIV infection itself alter the outcome of chronic lung disease?

4. Therapeutic options

- Directed against the cause – i.e. antivirals.

- Immune specific targets against inflammatory mediators

Feasibility and challenges of addressing this CQ or CC :

The critical challenge for this question lies in the fact that complications caused by chronic inflammation such as COPD and coronary disease will by definition take years to develop. Intervention trials will take even longer. This is not like the early HIV epidemic, where complications were primarily infectious and could be seen and addressed quickly. Because of this chronic nature, it will necessary to try and establish cohorts with long term follow-up. Furthermore, it will be critical to have well defined appropriate HIV-uninfected cohorts to compare the HIV-infected population to.

Name of idea submitter and other team members who worked on this idea : Homer L. Twigg III on behalf of the INHALD Consortium

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Goal 2: Reduce Human Disease

The Use of Therapeutic Apheresis to Reduce Circulating Levels of Galectin-3 and other Cancer and Inflammation Promoting Factors

Inflammation plays roles in cancer initiation, promotion, and progression. Elevated circulating galectin-3 (Gal-3) protein and other cancer and inflammation promoting factors (CIPFs) such as C-reactive protein and VEGF are associated with tumorigenesis and may play causative roles. Plasma Gal-3 is a biomarker, prognosticator, and pathogenic mediator of diverse cancers and is emerging as a therapeutic target. Preliminary ...more »

Submitted by (@elaine)

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

Details on the impact of addressing this CQ or CC :

Apheresis therapy in a clinical setting, both alone and in combination with conventional protocols, shows great potential to enhance treatment regimens, reduce dosage and side effects, improve drug deliver to target tissues, reduce long term treatment related morbidity and improve outcomes with significant benefits for patients with a broad range of cancer types and stages.

Feasibility and challenges of addressing this CQ or CC :

The need for well designed, randomized clinical trials would be readily feasible with the appropriate IND. Grant support will be needed for further development of this concept, as well as to develop columns with more optimized and specific capabilities, in addition to clinical trials demonstrating efficacy.

 

Apheresis is highly underutilized and underfunded in the US, while Apheresis research and development is much more advanced and widely utilized in Europe and Asia.

Name of idea submitter and other team members who worked on this idea : Isaac Eliaz, MD

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Goal 2: Reduce Human Disease

Molecular effects of ischemia and reperfusion

What is the impact of total body ischemia and reperfusion on coagulation, inflammation, and endothelial function?

Submitted by (@rebecca.lehotzky)

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

Name of idea submitter and other team members who worked on this idea : AHA Staff & Volunteers

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Goal 2: Reduce Human Disease

Can transcutaneous carboxyhemoglobin measure endogenous heme oxygenase activity?

Non-invasive measurement of transcutaneous carboxyhemoglobin (SpCO) by CO-oximetry has been shown to reflect disease activity in asthma, allergic rhinitis, Staphylococcal pneumonia/sepsis and to correlate positively with lung function in cystic fibrosis. Given published studies of heme oxygenase activity in these diseases as a reflection of oxidant or inflammatory activity, does measurement of SpCO reflect endogenous ...more »

Submitted by (@lekurlandsky)

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

Details on the impact of addressing this CQ or CC :

Laboratory measurement of heme oxygenase activity in inflammatory and states of oxidative activity in multiple disease states, lung diseases for instance, has become important in measuring disease severity and activity as well as being an indicator of disease modification by gene polymorphisms of heme oxygenase. The simple measurement of transcutaneous carboxyhemoglobin if correlated with heme oxygenase activity would provide a ready assessment for clinicians in the clinical setting.

Feasibility and challenges of addressing this CQ or CC :

In a setting in which heme oxygenase activity is measured and clinical patients of varying diseases are available, this question could be answered reasonably easily without technical difficulty.

Name of idea submitter and other team members who worked on this idea : Lawrence E. Kurlandsky, MD

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Goal 2: Reduce Human Disease

What are the Determinants of Short Term Prediction of Heart Attacks?

In spite of many years of research, we still cannot predict the short term risk of a heart attack or sudden CHD death. Most CHD deaths occur outside of the hospital. In spite of improvement of out-of-hospital emergency care, most “sudden death events” are still not successfully resuscitated.

Submitted by (@kullerl)

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

Details on the impact of addressing this CQ or CC :

There is strong evidence of interrelationship between inflammation, thrombogenesis, especially activation of tissue factor and platelets, and risk of a heart attack or sudden death. This is especially true in individuals who have pneumonia, influenza, etc. but also perhaps in relationship to environmental factors such as air pollution. Development of early identification and treatment approaches could substantially reduce CHD mortality.

Feasibility and challenges of addressing this CQ or CC :

The NHLBI has certainly had a major commitment in studying the interrelationship between inflammation and CHD. However, there is a need to go into the field and evaluation the interrelationship between inflammation, especially infection, drug therapies and short term acute precipitation of heart attacks. For example, there is suggestive evidence that older individuals on aspirin who have pneumonia may have reduced risk of a heart attack and sudden CHD death. Further studies linking work at the National Institute of Allergy and Infectious Diseases and the Heart and Lung Institute should attempt to further understand the interrelationships between infection, inflammation, and activation of tissue factor and platelets, and risk of thrombosis and heart attack and whether specific drug therapies, especially in high risk older individuals or even among individuals who have had previous CVD or high atherosclerotic burden, whether newer drugs could substantially reduce the risk of a heart attack.

Name of idea submitter and other team members who worked on this idea : Lewis H. Kuller, MD, DrPH

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Goal 3: Advance Translational Research

Develop Targeted Therapeutics to Treat Venous Thrombosis and Inflammation in Venous Thromboembolism

Venous Thromboembolism (VTE) afflicts nearly a million Americans yearly, has a mortality of 6-12% and has costs of more than $15 billion. Current treatment regimens, systemic anticoagulation and compression stockings, fail patients in multiple ways: risk of major bleeding episodes; failure of clot resolution in up to 50% of patients; failure to prevent the development of post-thrombotic syndrome (PTS) in up to 40% of ...more »

Submitted by (@chanduvem)

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

Details on the impact of addressing this CQ or CC :

Venous Thromboembolism (VTE) is a common disease with established treatment regimens that have been repeatedly proven to fail patients. The disease process affects a million Americans, and projections are that this will increase to 1.82 million by 2050. VTE affects a wide range of the U.S. population including young pregnant women, cancer patients ,hospitalized patients and the ever expanding elderly sector. Despite recent advances the incidence of the disease is unchanged and treatment failures include failure to resolve clot, failure to prevent long-term recurrence and failure to treat vein wall inflammation which results in the development of post-thrombotic syndrome (PTS) in up to 40% of patients. There are significant complications from the approved systemic treatment regimens including bleeding from anticoagulation therapy and potentially fatal complications from inferior vena cava filters. In cases of severe chronic venous insufficiency (CVI), a common sequela of VTE, quality of life survey results mirror those of chronic lung disease, coronary disease and debilitating arthritis. The cost of VTE is nearly $15.5 billion in the U.S. alone. PTS significantly affects patients and up to 42% of patients lose workdays with a cost per patient of $11,667 and a cost to the overall system of $16 billion. Addressing this critical challenge will help to decrease mortality and morbidity in a large, active sector of the U.S. population and save the healthcare system billions.

Feasibility and challenges of addressing this CQ or CC :

This critical challenge comes at an opportune time as multiple platforms for targeted therapies have been tested, proven to be efficacious and nearing approval for use in patients. Basic science research in venous thrombosis has advanced significantly with well established in-vitro and in-vivo models. Furthermore, significant work has been done to reveal multiple targets for clot resolution and for the treatment of vein wall inflammation. Thus the critical information is known and therapeutics available to make addressing this challenge highly feasible.

There will be challenges to addressing this clinical need. The first challenge may be developing and/or identifying the most relevant animal model. There are multiple established animal models and these may need to be modified to provide the best simulation of the clinical situation being addressed. Secondly, there are multiple delivery platforms that would be suitable to this project including nanomedicine based therapies. These would have to be optimized and tested in this research realm and then would need FDA approval . Lastly, following pre-clinical studies it will take large scale clinical studies to prove the efficacy and then require re-education to adopt this approach in the treatment of patients with thrombosis. Fortunately understanding and addressing these challenges will ultimately result in an improved therapy for patients with venous thromboembolism.

Name of idea submitter and other team members who worked on this idea : Chandu Vemuri

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Goal 2: Reduce Human Disease

Impact of lung remodeling on congestive heart failure progression

End stage congestive heart failure (CHF) causes intensive lung remodeling beyond the type-2 pulmonary hypertension. CHF induced lung remodeling includes profound lung fibrosis, lung vascular remodeling and lung inflammation. Understanding CHF-induced lung remodeling is also critical to understand the right ventricular failure. However, this area is largely unstudied. Regulating CHF-induced lung remodeling and the underlying ...more »

Submitted by (@chenx106)

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

Details on the impact of addressing this CQ or CC :

To deal end-stage CHF will need team efforts from heart, lung, blood and immunology.

Name of idea submitter and other team members who worked on this idea : Yingjie Chen, Associate Professor, University of Minnesota

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Goal 2: Reduce Human Disease

Modulation of cardiac contraction and relaxation in heart failure: role of systemic inflammation

Is cardiac contraction and relaxation in heart failure modulated by the systemic inflammatory response? There is overwhelming evidence that inflammatory biomarkers predict worse outcome in acute and chronic heart failure. Despite the wealth of evidence, clinical trials in this area have either not been completed, failed, or provided inconclusive results. The questions that remain are: 1) Is inflammation a mechanism ...more »

Submitted by (@aabbate)

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

Details on the impact of addressing this CQ or CC :

Addressing this question may fill a decades-old gap in our understanding of the role of inflammation in heart failure, and potentially lead to novel prognostic biomarkers and/or improved therapeutics.

Feasibility and challenges of addressing this CQ or CC :

All the preclinical and clinical tools are available.

Name of idea submitter and other team members who worked on this idea : Antonio Abbate

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