Goal 3: Advance Translational Research

Advanced Models for Translational Cardiovascular Research and Drug Development

Although the study of the cardiovascular (CV) system has benefited significantly from the use of gene-targeted and transgenic mouse models, small rodents do not always accurately reflect human cardiovascular physiology. Many discoveries using mouse CVD models failed to translate into human applications.

Submitted by (@echenum)

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

Details on the impact of addressing this CQ or CC :

Outcomes from large animal studies are likely to translate into more favorable results in human studies. Historically, some of the most significant advances in modern CV medicine are indebted to large animals.

Feasibility and challenges of addressing this CQ or CC :

Recent advances in mammalian genome projects and gene targeting technologies enable the production of large animal models. Genome information is now available for many animal species including pigs, rabbits, dogs, cats, horses and cows. Customizable nucleases, such as Zinc Finger Nuclease (ZFN), Transcription Activator-Like Effector Nuclease (TALEN), CRISPRs (clustered regularly interspaced short palindromic repeats) associated protein-9 nuclease (Cas9) has enabled the production of gene targeted animals in many of these species lacking germline transmitting embryonic stem (ES) cells, with satisfactory results. Integration of these novel knowledge and technologies in non-primate large animals will lead to production of an array of novel models of human CVD. Research in these models will help identify and establish suitable animal models that faithfully predict the outcomes in human clinical trials of new medicines and treatments. This is believed to have a major impact in the medical research field in general and significantly move cardiovascular research and drug development forward.

Name of idea submitter and other team members who worked on this idea : Eugene Chen from University of Michigan

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16 up votes
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Goal 2: Reduce Human Disease

Defining critical elements for irreversible myocardial injury

What are the critical mechanisms that account for progression from reversible to irreversible ischemia and reperfusion injury?

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 :

Understanding the mechanism of how myocardium becomes irreversibly injured will provide clarity for therapeutic intervention.

Feasibility and challenges of addressing this CQ or CC :

Advances in proteomics and databases of post-translational modifications may support the feasibility of discoveries in this area.

This information is key for designing novel therapeutic strategies for acute myocardial ischemic injury. This understanding will define the critical timing, location, and distribution of modulators, and amplitude required for activation of components involved in protective pathways.

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6 up votes
10 down votes
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Goal 2: Reduce Human Disease

Treatment Options for Diabetics and Impact on Cardiovascular Health

As a clinician, over the years I have noted major differences in adverse cardiovascular outcomes in diabetics who are treated with insulin +/- oral agents compared to those only treated with oral agents. Cardiovascular events occur much less often and at a much later timeframe in diabetics ("Type 2/adult onset") treated with insulin as the primary method. Even with newer agents, there may be slight improvement, but ...more »

Submitted by (@patty.gladowski)

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

Details on the impact of addressing this CQ or CC :

Delaying the onset of injury to vasculature in Type 2 diabetics would have a major impact on quality of life for the diabetic and costs to the healthcare system. Dialysis and related costs are around $200,000/yr and interfere with life and ability to work, leg ulcers are often chronic and in many cases result in amputation.

Feasibility and challenges of addressing this CQ or CC :

This study could be performed in the clinical setting or could be completed with chart review to determine diabetics on insulin on insulin and review outcomes. If access to charts for patients continuously treated for five years or longer were available, this study could be done in a shorter timeframe and at less cost. A long term and costly alternative would be to begin a clinical trial. Medical claims data may be an alternative, but it would be important to identify onset of diabetes and treatment for a minimum of five years.

Name of idea submitter and other team members who worked on this idea : Patricia Gladowski

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3 net votes
7 up votes
4 down votes
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Goal 2: Reduce Human Disease

Transforming Clinical Practice through Patient-Centered Medical Nutrition and Lifestyle Education

The fact that diet contributes significantly to prevention and treatment of disease is now a foregone conclusion. National and international guidelines offer evidence based recommendations advocating nutrients, foods and eating patterns that are most closely associated with reduced risk. Patients assume that physicians are knowledgeable regarding the role of diet in health and that they are trained to counsel patients ...more »

Submitted by (@lvanhorn)

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

Details on the impact of addressing this CQ or CC :

AHA/ACC guidelines subsequent to the NHLBI ATPIII all provide diet-related recommendations for improving public health that, if followed, could offer tremendous benefits in reduced disability, death and health care costs. However, imperative to the implementation of these life-saving recommendations, is an informed and educated provider base that is skilled in: assessment of patients’ diets and eating behaviors, evaluation of possible risk factor contributors and initiation of diet counseling or referral to a qualified nutritionist.

 

Nowhere is the opportunity greater to assess, evaluate and offer guidance towards improvement of key diet behaviors than in primary care. Patients perceive physicians as credible, respected sources of nutrition counseling. Physician endorsement of diet and lifestyle change favorably influences patient adherence. Research to evaluate patient-centered medical education and training programs is needed to evaluate and compare patient perception, health impact and health outcomes of these translational nutrition efforts. Ultimately, the goal is to further calculate and quantify the economic and personal benefits that accompany these strategies in order to implement transformed medical education aimed at preventive strategies.

Feasibility and challenges of addressing this CQ or CC :

This is a major challenge due to current medical training focused on diagnosis and treatment rather than prevention. Research is needed to demonstrate cost/benefit of transformative education and training that shifts the focus from treatment to prevention. Successful outcomes can provide preliminary evidence needed to promote a paradigm shift across -medical schools and allied health professions with the ultimate goal of - improving medical practice and quality of life. Evidence is needed that documents patient-centered impact resulting from this training and actual practice. Proposed is a comprehensive, team science approach to testing the results of nutrition and lifestyle medicine in primary care and the biomedical, behavioral and economic impact derived from it.

This represents an ambitious task requiring an academic medical center environment that not only has the educational aspect in place but also the capacity to provide the translational effort at the bedside and in outpatient settings to allow measurement of results. It requires leadership in multiple arenas and coordination between education and clinical application that are crucial to successful implementation. It further requires leadership and expertise in big data, economics, biostatistics and the accompanying technology required to

assess, analyze and report all of the aspects and components inherent in a project of this magnitude.

Name of idea submitter and other team members who worked on this idea : Linda Van Horn, PhD, RD

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3 net votes
7 up votes
4 down votes
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Goal 1: Promote Human Health

How do Circulating Precursor Endothelial Cells contribute to newly formed vessels

Endothelial cells derive from cells in the bone marrow. Circulating precursor endothelial cells contribute to newly forming vessels.

Do Alk 1 and/or Endogln mutations affect the functions of these cells once they incorporate into growing vessels. These vessels then go on to form arteriovenous malformations

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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2 net votes
2 up votes
0 down votes
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Goal 2: Reduce Human Disease

Why does loss of endoglin in adult blood cells lead to cardiac hypertrophy in HHT patients

Liver arteriovenous venous malformations creates a high flow shunt that over time creates high output cardiac failure with no effective treatments.

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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1 net vote
1 up votes
0 down votes
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Goal 2: Reduce Human Disease

Seeking the secret behind “resilience” to a variety of HLBS diseases

What is the secret behind the “resilience” some people have to heart, lung, blood, and sleep (HLBS) diseases?

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 :

Results of such research should reveal physiological mechanisms of resilience that could be used to develop interventions that would prevent or cure a variety of heart, lung, blood, and sleep diseases.

Feasibility and challenges of addressing this CQ or CC :

Advances in omics, clinical testing

, accumulation of large sets of clinical data and samples

, big data tools

, and increased interest from public (normal volunteers) and patients to participate in large scientific experiments make it feasible.

For instance, these may be healthy people carrying genetic mutations strongly associated with HLBS diseases (or causing rare/familial genetic diseases – these might easier to focus on first), but also people who are not hypertensive, hypercholesterolemic, or diabetic in spite of consistently making bad dietary choices, people who did not develop lung conditions in spite of high pollutant exposure, or are otherwise “protected” from other heart, lung, blood and sleep diseases. This reasoning is not very different from that used to identify ApoA Milano, or even PCSK9 or the “longevity genes”. Such information should reveal physiological mechanisms that could be leveraged to develop interventions to prevent or cure HLBS diseases.

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

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26 up votes
7 down votes
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Goal 3: Advance Translational Research

Direct thrombin inhibitors and anti-Xa (Ten A) inhibitors in trauma patients - physiologic effects and impact on outcomes

Direct thrombin inhibitors and anti-Xa (Ten A) inhibitors are new, undetectable and irreversible. We have no data on how well these drugs correlate with current measures of coagulopathy such as thromboelastography, or whether antifibrinolytics should be used in patients who are on these drugs. These drugs may increase incidence of traumatic brain injury after minor injury. They are also going to be used increasingly in ...more »

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 :

Understanding pathophysiology of coagulopathy in trauma patients due to these drugs may lead to innovations in management of coagulopathy and help increase our ability to predict/prognostic poor clinical outcomes in patients on these new anticoagulants, detect these drugs in a timely manner and develop antidotes/reversal agents. 

Feasibility and challenges of addressing this CQ or CC :

These are eminently feasible with adequate support from the NHLBI. Challenges will be finding collaborations or institutions that have enough clinical volume and adequate basic science/translational research infrastructure to look at these questions seriously.

Name of idea submitter and other team members who worked on this idea : Sudha Jayaraman

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-7 net votes
6 up votes
13 down votes
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Goal 3: Advance Translational Research

Implementation of Evidence-based Guidelines in LMICs

How can implementation strategies be tested in low and middle income countries for contextually and culturally adapted evidence-based clinical care guidelines with a focus on prevalent non-communicable diseases with large burdens such as sickle cell disease, hypertension, heart disease, stroke, asthma, and COPD?

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 :

Evidence-based guidelines for heart, lung, and blood diseases, developed within high income countries are challenging to implement within low and middle income countries because delivery capacity and health care infrastructure is often limited. Contextually, culturally and language adapted guidelines implementable within low and middle income countries can impart substantial benefit while distributing more evenly global knowledge of proven effective interventions while improving health equity. Proven effective interventions would get delivered in an effective manner across low and middle income countries which will improve heart, lung, and blood health outcomes.

Feasibility and challenges of addressing this CQ or CC :

The NHLBI Global Health Think Tank recommended research on implementation of contextually, culturally and language-adapted clinical care guidelines in low and middle income countries and encouraged addressing this issue in the near future.

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

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-10 net votes
8 up votes
18 down votes
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Goal 2: Reduce Human Disease

PUFA Toxicity

Our diets contain 20 times more omega-6 fatty acids than the diets of humans before agriculture, industrial solvent extraction of seed oils and hydrogenation. These acids including linoleic and arachidonic acids are precursors to eicosanoids that mediate inflammation and blood clotting and the amount in our diet has been shown to correlate with negative health outcomes. Should NHLBI fund more research into the effects ...more »

Submitted by (@shoemajd)

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

Details on the impact of addressing this CQ or CC :

Federal regulations could limit the amount of omega-6 fatty acids in foods and significantly reduce the incidence of atherosclerosis, strokes, heart attacks, asthma and autoimmune disease.

Feasibility and challenges of addressing this CQ or CC :

Evidence already exists but should be confirmed in large scale studies

Name of idea submitter and other team members who worked on this idea : James Shoemaker MD PhD

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-4 net votes
9 up votes
13 down votes
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Goal 2: Reduce Human Disease

Role of epigenetic mechanisms in cardiovascular disease

Are epigenetic changes the cause or the consequence of changes in cell function that contribute to cardiovascular disease? If they are the cause, what are the mechanisms that lead to changes and how do they impact disease pathogenesis? If the consequence, do they play any role in disease pathogenesis? What methods can be used to test if epigenetic changes play a causal role in disease pathogenesis? Thus far studies ...more »

Submitted by (@gko000)

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

Details on the impact of addressing this CQ or CC :

Although it is widely speculated that epigenetic control mechanisms play a critical role in disease pathogenesis, few if any studies, particularly in the CV field, have actually determined if and how epigenetic mechanisms result in functional changes in the plethora of cells that contribute to CV disease pathology. Moreover, there is a general lack of methods available to determine how specific epigenetic modifications, including histone modifications or DNA methylation of a given gene locus impacts gene expression and function of that cell. Rather, most studies have been limited to studying the effects of global alterations in chromatin structure, and/or studying global changes in epigenetic modifications average over the tens or hundreds of cell types and phenotypes within a complex tissue.

 

We must develop approaches to dissect the causal role of specific epigenetic modifications in controlling cell function in health and disease.

Feasibility and challenges of addressing this CQ or CC :

There are approaches evolving that enable one to do epigenomic edting in single cells but thus far they have not been done in the CV system, nor in vivo. They are feasible but will take a major investment to be successful.

 

Keep in mind that epigenetic mechanisms presumably regulate overall change in cell function as a consequence of exposure to disease promoting stimuli. Importantly, this is in response not only to the environmental milieu to which the cell is currently exposed, but an integral of past signals it and its predecessors experienced. Unlocking these control mechanisms will likely greatly advance our understanding of all disease processes, but particularly CV diseases which typically develop over years or decades.

Name of idea submitter and other team members who worked on this idea : Gary K Owens

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21 net votes
28 up votes
7 down votes
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Goal 2: Reduce Human Disease

COPD and co-morbidities

Society is ageing and chronic degenerative diseases including COPD are increasingly occurring together. The critical question is whether certain diseases occur together by chance or are they occurring together because they share pathobiological commonalities and mechanisms? This leads to a series of practical consequences and questions 1. Which diseases are occurring concurrent with COPD more than chance alone would ...more »

Submitted by (@bcelli)

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

Details on the impact of addressing this CQ or CC :

It is entirely possible and actually likely that several diseases manifesting in different organ systems may have shared pathobiological mechanisms. This could be the case of systemic inflammation or abnormal repair, precipitated by interaction with external agents such as pollution or smoking. This would manifest as different diseases affecting different organ systems (as could be the case of COPD and Lung Cancer) using today's taxonomy.

As it stands (taking the COPD Lung Cancer example) each is treated differently and actually strategically and clinically, they are handled as separate entitites. In all reality, if we can identify the diseases that share common pathogenetic mechanism, it is likely that we can develop common biomarker profiles that will detect disease predisposition so that early intervention can be planned.

In addition and equally important, once common co-morbidities can be grouped by pathobiology, plans can be developed by the medical establishment including health authorities to develop common approaches rather than the disjointed separate specialties that today handle each of the different organ systems.

Finally, the potential of aggregation of diseases into common pathobiological fields can reduce health care cost by integrating fields and voiding dispersion of resources.

Feasibility and challenges of addressing this CQ or CC :

It is entirely possible to use large throughput data analysis such as system network analysis to determine in a hypothesis free environment, what is the relationship amongst diseases. This analysis, that can be facilitated by the availability of electronic medical records can provide a first glance evidence of commonality amongst certain diseases.

This can be validated in other cohorts and a plan for profiling a representative sample of those cohorts in order to determine their proteomic and metabolomics profile. This will provide insight into the mechanisms responsible for the expression of the diseases and can lead to translational research aimed at identifying the mechanisms for the generation of the syndrome and potential therapeutic targets.

Once proven correct, it will be possible to identify and treat several diseases simultaneously with targeted therapy once appropriate trials have been completed.

The project here presented is already feasible and likely to offer new roads leading to a better taxonomy, identification and treatment of what now represents a puzzle of different pieces poorly interlocked.

Given the magnitude of the population that is and will be even more affected by multiple chronic diseases, this is a field that is ready for prime research efforts.

Name of idea submitter and other team members who worked on this idea : COPD and co-morbidities: Chance or Fate?

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20 net votes
22 up votes
2 down votes
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