Goal 2: Reduce Human Disease

Pulmonary Vascular Diseases

Does anticoagulation with warfarin improve outcomes (time to clinical worsening, qualtiy of life, exercise capacity) in patients with pulmonary arterial hypertension treated with current oral/inhaled therapies? There are substantial "unknowns" and practice variation in anticoagulation in PAH. Resource utilization is also a factor here. We may either be helping patients (or hurting them with side effects) by using anticoagulation. ...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 :

This is a view of problems in the field.

Pulmonary Hypertension Clinical Research: Current Problems and Possibilities

Current studies limited to the short term, with soft outcomes.

No mechanistic studies embedded in trials.

Control of phenotype is weak.

Small n: lumping of cohorts.

No factorial of advanced design.

No biological samples obtained for study.

Failure to study basic management issues.

Name of idea submitter and other team members who worked on this idea : ATS Member

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Goal 2: Reduce Human Disease

Understanding the Role of the Vasculature in Dementia

Dementia is traditionally grouped into vascular dementia, Alzheimer's dementia, Parkinson's dementia and other causes of dementia. Vascular dementia is generally thought to be a consequence of strokes but there are some recent studies indicating that even Alzheimer's dementia may have a vascular underpinning. Vascular permeability is increased in the early stages of Alzheimer's disease and it is possible that similar ...more »

Submitted by (@jalees)

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 NHLBI could fund programs which enable vascular biologists to collaborate with neuroscientists and neurologists in order to understand whether the vasculature has a causal role in the progression of dementia.

 

 

 

Can interventions that improve vascular function prevent the progression of dementia? Instead of using broad interventions such as statins which affect numerous signaling pathways, vascular biologists could target selected aspects of vascular health such as improving vascular barrier function and vascular regeneration.

 

If these interventions that have been shown to be efficacious in other vascular beds outside of the brain are also effective in the brain, then important new therapies could be developed for dementia which is likely to become one of the leading cause of death in the next decades.

Feasibility and challenges of addressing this CQ or CC :

A key challenge for targeting the brain vasculature will be the blood-brain barrier. Understanding the role of the blood-brain barrier in dementia will be a prerequisite to developing novel vasculature-directed therapies.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

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Goal 3: Advance Translational Research

Vascular disease awareness

Increase awareness of vascular disease in the population. Public recognition and understanding is poor, despite high prevalence. ­ Improve public education about vascular diseases, the risk factors, early signs, and treatment.

Submitted by (@societyforvascularsurgery)

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

Name of idea submitter and other team members who worked on this idea : Society for Vascular Surgery

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Goal 3: Advance Translational Research

Animal models of vascular diseases

How can we better model human vascular disease in all its complexity?

­This is key to more effective translation of both diagnostics and therapeutics. Develop improved animal models of vascular diseases including PAD, aneurysm, venous diseases, to facilitate fundamental research and preclinical development.

Submitted by (@societyforvascularsurgery)

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 : Society for Vascular Surgery

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Goal 3: Advance Translational Research

Direct Upregulation of Antioxidant Defenses as a Therapeutic Strategy

Clinical trials involving administration of antioxidants such as vitamin C or vitamin E as therapeutic strategies for cardiovascular diseases associated with oxidant stress have proven to be surprisingly disappointing. A particularly attractive alternative approach is direct upregulation of endogenous antioxidant defenses such as NRF2 via dietary approaches. NRF2 is a master antioxidant and cell protective transcription ...more »

Submitted by (@jlombard)

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

Details on the impact of addressing this CQ or CC :

Direct upregulation of endogenous antioxidant defenses such as NRF2 via dietary approaches will avoid the well known caveats of drug-based approaches such as off target effects and detrimental side effects. Dietary supplements such as Protandim are already available; and beneficial effects of other NRF2 up-regulators such as resveratrol and sulforaphane are beginning to be recognized. The dietary approach is minimally invasive and has high preventative value.

Feasibility and challenges of addressing this CQ or CC :

Addressing this CQ is clearly feasible, as dietary supplements are currently available for humans, and the beneficial effects of foods containing compounds that upregulate the NRF2 system, e.g., broccoli, cauliflower, red wine, and grape juice are currently recognized. One challenge in addressing this question in animal models to date is that the only genetic model lacking NRF2 is a knockout mouse model, which have substantial limitations for in vivo physiological studies due to their small size. However, a recent R21 grant (#1R21OD018309-J. H. Lombard, P.I.) has allowed the development of a NRF2 knockout rat model which is better suited for physiological studies than the mouse model. In addition, the techniques used to develop the NRF2 knockout rat can be applied to multiple disease-sensitized strains, e.g., the Dahl salt-sensitive rat. Fawn Hooded Hypertensive rat, Obese Zucker rat, etc. Similar disease sensitized rodent genetic strains are not available in mice.

Name of idea submitter and other team members who worked on this idea : Julian H. Lombard

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Goal 1: Promote Human Health

Mechanisms of Vascular Stiffness

Increased vascular stiffness has been identified as an important cardiovascular event that accompanies aging and cardiovascular disease. Although multiple vascular changes have been identified and suggested to cause increased vascular stiffness, our understanding of the underlying mechanisms needs to be refined in order to develop useful therapeutic strategies to prevent or reverse these changes. An example of critical ...more »

Submitted by (@meiningerg)

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

Details on the impact of addressing this CQ or CC :

Ultimately, addressing this CQ would impact treatment of CV disease, reduce incidence of significant and life threatening CV events and improve quality of life. This area of investigation is relevant to therapeutics and potentially lifestyle changes that will improve CV health and slow CV age related changes linked to disease.

Feasibility and challenges of addressing this CQ or CC :

Current advances in our technologies make it very feasible to address new questions to improve our knowledge of the mechanisms underlying vascular stiffness. Challenges will include developing multi-scale and cross disciplinary strategies that will, by design, facilitate an integrated understanding of the process leading to altered vascular stiffness.

Name of idea submitter and other team members who worked on this idea : Gerald A. Meininger

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Goal 2: Reduce Human Disease

How gene mutations contribute to defects in vascular development

How do gene mutations in endoglin and alk 1 create arteriovenous malformations leading to disease. Alk 1 and endoglin are receptors in TGFB/BMP family signaling. TGFB/BMP have roles in vascular development, remodeling and maintenance in vascular integrity. Understanding the downstream effect will lead to advancements in reducing genetic diseases such as HHT as well as vascular malformations in general

Submitted by (@mariannes.clancy)

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 : Marianne Clancy MPA, Chris Hughes PhD

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Goal 1: Promote Human Health

New Approaches to study interactions of blood cells with components of the vascular wall

To eventually modulate pathologic communication processes employing new therapeutics, there is a need to better understand the transcellular communication between blood cells and components of the vascular layer in vivo.

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

A better understanding of this largely unrecognized and underappreciated form of transcellular communication would allow us to use the information to not only detect disease at its very earliest stages, but perhaps also modulate pathologic communication processes employing new therapeutics.

Feasibility and challenges of addressing this CQ or CC :

It is now feasible to address this CQ because of the availability of techniques such as atomic force microscopy, multi-photon intravital microscopy, computational and experimental approaches.

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

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Goal 3: Advance Translational Research

Scientific priorities for HIV-related cardiovascular research

Millions of virally suppressed patients with HIV/AIDS survive to older ages and will become increasingly vulnerable to inflammation-associated cardiovascular disease. The critical challenge is to determine whether age-driven cardiovascular declines that occur HIV-infected people are exacerbated by the persistent systemic inflammatory drive that occurs in virally suppressed patients. Studies that document cardiovascular ...more »

Submitted by (@bgelman)

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 impact of this critical challenge would be to heighten the translational impact of HIV-related cardiovascular research. Key facets of this challenge are: 1) To give high priority to studies that use human tissue specimens that have been carefully annotated and biobanked, 2) To be certain that proposed studies employ tissue from age-appropriate comparison patients who were not HIV infected, and 3) To avoid giving undue credence to acute infection or in vitro infection models (as with tat and gp120 toxicology) that do not reflect immunologic and virologic mechanisms in virally suppressed patients. Millions of virally suppressed patients with HIV/AIDS survive to older ages, and become increasingly vulnerable to cardiovascular disease. Ischemia-related disease causes dysfunction especially in organs that depend on abundant blood flow such heart, brain and kidneys. All these organs are affected to some extent by persistent inflammation in virally suppressed HIV-infected patents. The compelling question/critical challenge is to determine whether age-associated cardiovascular changes are exacerbated by persistent mild systemic inflammatory drive that are found in blood vessels of virally suppressed patients. Studies that document the presence of cardiovascular changes in older infected people without controls, or in vitro models of acute infection, both do not address issues of high translational relevancy. Using human tissue specimens from age-appropriate controls does.

Feasibility and challenges of addressing this CQ or CC :

Feasibility:

1) Obtaining well-annotated organ specimens from HIV infected and noninfected people is feasible. The National NeuroAIDS Tissue Consortium (NNTC) collection goes well beyond the CNS and includes heart, lung, kidney, gut, liver, spleen and other organs. Many of the organs specimens in the collection have been annotated with virological and immunological markers already.

2) Over 900 autopsies on HIV infected patients are banked by the NNTC and over 100 of these decedents were over the age of 50. Over 200 controls are effectively banked. These specimens and related clinical data are in the public domain at this time.

3) Age appropriate autopsies were done by the NNTC, and a large number of NIA sponsored tissue repositories have accumulated tissue from elderly patients.

Challenges:

1) The limitations of using autopsy material and the limits of a cross sectional view need to be better understood and appreciated. These studies should not be written off scientifically as "observational" or "not hypothesis driven."

2) The lessons of not using age-appropriate controls have NOT yet been learned in the HIV/AIDS research community. A prime example is an overabundance of brain aging surveys in HIV infected populations that did not contain age-appropriate controls. A controversial and inconclusive brain aging pathology literature was produced because of that.

Name of idea submitter and other team members who worked on this idea : Benjamin Gelman

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Goal 2: Reduce Human Disease

Lipid apheresis as adjunct therapy in peripheral vascular disease

What is the roll of inflammation and how does lipid apheresis alter inflammation in peripheral vascular disease when added to standard therapy and/or when used alone? Does lipid apheresis result in long-term improvement with reduced morbidity, mortality, and expense compared to standard therapy?

Submitted by (@winters.jeffrey)

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 prevalence of peripheral vascular disease (PVD) in the United States is estimated to be 5.9%, affecting up to 20% of adults over the age of 65. Therapy for PVD is vascular surgical intervention for limb ischemia; combined with medical therapy and anti-platelet agents but morbidity and mortality remains high. Low density lipoprotein cholesterol (LDL-c) is associated with increased risk for development and progression of PVD. Preliminary studies of the use of lipid apheresis have demonstrated improvement in symptoms and a variety of laboratory measures with decreased morbidity when added to standard therapy. The mechanism of this treatment may go beyond reducing LDL-c as the columns also affect levels of inflammatory cytokines, alter blood rheology, and affect other lipids.

Feasibility and challenges of addressing this CQ or CC :

Currently two lipid apheresis devices have been cleared by the Food and Drug Administration and are in use in the United States. The presence of cleared devices, the large number of affected patients, and availability of testing for lipoproteins, fibrinogen, CRP, PAI-1, IL-6, IL-17, IL-1, IL-10, INF-γ, VEGF, PGI2, IGF-I and rheology factors make the enrollment and evaluation of patients into a clinical trial examining the use of this treatment of PVD feasible. Challenges for the performance of a clinical trial would include the limited number of centers offering lipid apheresis, the chronic nature and length of time needed to perform lipid apheresis, and the expense of the lipid apheresis devices and disposables.

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

Vascular biology and the pathophysiology of sepsis

Unravel the cellular & molecular mechanisms related to the vascular biology of sepsis and related cardiovascular collapse. The goal is to develop a new scientific framework for the prevention of sepsis related morbidity and mortality by applying novel approaches to discover new targets for biomarkers and therapy by promoting multidisciplinary research required for scientific cross-talk between complementary research disciplines ...more »

Submitted by (@greg.martin)

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 : Society of Critical Care Medicine Executive Committee/Council

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Goal 2: Reduce Human Disease

what endogenous anti-inflammatory mechanisms can improve vascular diseases

the role of pro-inflammatory mechanisms of vascular disease are well characterized, but we know little about potentially protective endogenous anti-inflammatory mechanisms.

Submitted by (@mautieri)

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 will identify new therapy or targets of therapy to improve our understanding of most vascular disease and lead to improved human health.

Feasibility and challenges of addressing this CQ or CC :

this is quite feasible; if we know so many pro-inflammatory mechanisms which for years we have tried to reduce or prevent, we can just as easily identify endogenous anti-inflammatory mechanisms that we can identify and enhance.

Name of idea submitter and other team members who worked on this idea : Mike Autieri

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