Goal 3: Advance Translational Research

Exploring Future Cardiovascular Medicine: Heart Precursors Directed from Human Embryonic Stem Cells for Myocardium Regeneration

Cardiovascular disease (CVD) is a major health problem and the leading cause of death in the Western world. Currently, there is no treatment option or compound drug of molecular entity that can change the prognosis of CVD.

Submitted by (@xuejunparsons)

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 human stem cell is emerging as a new type of pharmacologic agent of cellular entity that is much more complex in structure, function, and activity than the conventional drug of molecular entity, which is usually comprised of simple chemicals or compounds. Since the etiologies of most diseases that involve both molecular and cellular processes are much more complex than simple chemicals or molecules, conventional chemical drugs are often severely limited by the molecular entity of the compound that usually targets or blocks certain pathological molecular pathways, which would otherwise be harmful to common molecular pathways shared in normal cellular processes of vital tissues and organs, thus, cause severe toxic side effects that may outweigh the benefits. For instance, a drug for weight loss may cause severe damage to the heart. In addition, the therapeutic effects of conventional drugs of molecular entity provide only temporary or short-term symptomatic relief but cannot change the prognosis of disease. As a result, millions of molecular leads generated in mainstream of biomedical research from animal studies and studies of other lower organisms have vanished before even reach clinical trials, or for a few lucky ones, in clinical trials. In the last few decades, despite of many animal leads, no drug of molecular entity has ever been approved by FDA as a new treatment for heart disease and failure for humans.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: In contrast, the human stem cell has the potential for human tissue and function restoration that the conventional drug of molecular entity lacks. The ability of a human stem cell, by definition, to both self-renew and differentiation makes it a practically inexhaustible source of replacement cells for many devastating or fatal diseases that have been considered as incurable, such as neurodegenerative diseases and heart diseases. The pharmacologic activity of human stem cells is measured by their extraordinary cellular ability to regenerate the tissue or organ that has been damaged or lost, such as the heart in the case of human cardiac stem cells. Therefore, the pharmacologic utility of human stem cells cannot be satisfied only by their chaperone activity, if any, to produce trophic or protective molecules to rescue existing endogenous host cells that can simply be accomplished by a drug of molecular entity. The embryo-originated human embryonic stem cells (hESC) are not only pluripotent, but also incredibly stable and positive, proffering unique revenue to generate a large supply of cardiac lineage-committed stem/precursor/progenitor cells as well as functional cardiomyocytes as adequate human myocardial grafts for cell-based therapy. Currently, the hESC cardiomyocyte therapy derivatives provide the only available human cell sources with adequate capacity to regenerate the contractile heart muscles, vital for heart repair in the clinical setting.

Name of idea submitter and other team members who worked on this idea : Xuejun Parsons

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Goal 2: Reduce Human Disease

Improving understanding of heart attack mechanisms in women and targeting of treatment

There remain many differences between women and men in the risk of myocardial infarction (MI or “heart attack”), manifestations of MI and outcomes after MI. The time in which the facts about differences between the sexes were unknown or ignored has passed. However, there are many basic answers women and their physicians need, such as: a) Why are younger women with MI at such high risk of death as compared to their male ...more »

Submitted by (@harmony.reynolds)

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 of sex differences is the most fundamental aspect of personalized medicine. When considering MI, some sex differences, such as lower risk of MI and a lesser extent of coronary artery disease (CAD, plaque buildup), favor women. Others, such as the 2-fold higher risk of death in younger women with MI and sex differences in the association between diabetes and MI, favor men. Insights into these and other sex differences should provide the foundation for optimal treatment for the prevention of MI and its complications.

Feasibility and challenges of addressing this CQ or CC :

Mechanistic and descriptive studies may be needed before clinical trials can be undertaken.

Name of idea submitter and other team members who worked on this idea : Harmony Reynolds

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Goal 3: Advance Translational Research

Neglect of Valuable Heart Health Data

Routine bypass surgery generates left ventricle pressure and volumetric flow data which can be modeled by estimated parameters capable of determining a heart health index. This capability is also available online for the surgeon's

guidance and is applicable to any heart chamber.

Submitted by (@woneill)

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 comprehensive heart health state would be established

Feasibility and challenges of addressing this CQ or CC :

The theory has been proven multiple times, intellectual and political inertia are the roadblocks.

Name of idea submitter and other team members who worked on this idea : William ONeill, Jeffery Shuhiaber

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Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

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

Details on the impact of addressing this CQ or CC :

Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

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

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Goal 1: Promote Human Health

Investigating Co-Morbidities in Women's Cardiovascular Health

There are important questions related to the cardiovascular health of women, and particularly to diagnostic and therapeutic challenges arising from the common existence of co-morbid conditions. The latter consideration, as well as the limitations of the budgets of individual institutes and centers at the NIH, suggest that it may be reasonable for the NHLBI to consider cross-NIH collaborations with I/Cs that have related ...more »

Submitted by (@rosemarie.robertson)

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

Details on the impact of addressing this CQ or CC :

Collaboration across I/Cs could encourage investigators or teams to explore new concepts underlying the etiology of common or rare cardiovascular diseases (CVD), including stroke, particularly those with gender-related differences. In addition, clinical research on these disorders would benefit from active consideration of the common co-morbidities seen in patients with CVD, especially as patients with these co-morbidities are often specifically excluded from clinical trials. Since the patients who will ultimately benefit from treatments developed will often suffer from multiple other disorders, the societal benefit would be substantial. While any single I/C could support such studies, collaborative funding would be likely to bring together new teams of investigators with novel ideas.

Feasibility and challenges of addressing this CQ or CC :

We believe that there is likely to be a good response from investigators, both basic and clinical, to collaborative, multi-I/C RFAs. It might be of additional benefit to provide some funds specifically for teams that are newly collaborative in response to the RFAs, to encourage increased cross-field collaboration.

Name of idea submitter and other team members who worked on this idea : Rose Marie Robertson for American Heart Association

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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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Goal 3: Advance Translational Research

Risk Mitigation of Implantable Cardiovascular Devices

There is a serious need to improve implantable cardiovascular devices to eliminate, or at least substantially reduce, the risk of serious adverse events from occurring to more effectively treat patients.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Cardiovascular devices would be more widely used to treat such cardiovascular diseases as heart failure, coronary artery disease, valvular disease and, therefore, have a greater public health benefit. Furthermore, costs associated with treating the serious adverse events (e.g. hospitalizations, therapeutics, etc.) would decrease.

Feasibility and challenges of addressing this CQ or CC :

Technologies such as surface coatings and topographies as well as evolved design tools are under development already or are being used to mitigate the risks of devices currently being used or under development. A more concerted effort to do this would almost certainly help to substantially reduce the risks further, especially over the next 5-10 years.

Despite the widespread and growing use of implantable cardiovascular devices such as ventricular assist devices, stents, and prosthetic heart valves, substantial serious adverse events such as infections, neurological events, and bleeding limits the efficacy and use of the devices. Scientific and technological breakthroughs in such areas as biomaterials, design tools, coatings, and concomitant pharmacologic therapy are needed to address this challenge.

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

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Goal 2: Reduce Human Disease

10. What biological variables are most influential in the development and clinical outcomes of heart disease and what can be don

Given that approximately 64 percent of women who died suddenly of CHD had no previous symptoms4 and that traditional risk factors and scores underestimate CHD risk in women, there is a need to identify unique markers for women at risk for CHD60.

 

( from 10 Report)

Submitted by (@scampbell)

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

Details on the impact of addressing this CQ or CC :

Early detection and correction of such variables as elevated cholesterol, hypertension, diabetes and cigarette smoking, can reduce atherosclerosis (the main cause of CHD) and improve outcomes. These are modifiable to some extent with changes in lifestyle, improved diet, exercise and smoking cessation. Psychosocial risk factors, such as low socioeconomic status, anxiety, and depression have also been linked to CHD and should be evaluated.

There are also biomarkers, biomediators, neurohormones, and surrogate markers which can signal CHD. Some of these can be modified, including

 

• neurohormones which are part of the renin-angiotensin-aldosterone system that directly impact angiotensin II and arginine vasopressin1, 61, 62

• markers of the inflammatory processes such as C-reactive protein which may be a useful predictor of CVD and correlates significantly with future risk of developing hypertension63, 64

• markers of heart failure such as B-type natriuretic peptide

Surrogate markers of atherosclerosis and CHD risk include left ventricular hypertrophy, intima-media arterial wall thickness, proteinuria and microalbuminuria, endothelial dysfunction, coronary calcification and anemia1, 62.

Feasibility and challenges of addressing this CQ or CC :

Research shows that a variety of treatments – from lifestyle/behavioral changes, medications, and interventional treatments – can interrupt the progression of CHD. Further research is needed to demonstrate whether lifestyle and behavioral changes in women with known or suspected CHD can improve prognosis. Innovative approaches to care management that encourage changes in lifestyle should be considered. These include customized care management and the use of multidisciplinary teams of health practitioners who coordinate care for women at risk. Further research is needed to determine whether reducing or minimizing the novel biomarkers associated with CHD will result in lower mortality rates.

Name of idea submitter and other team members who worked on this idea : Susan M. Campbell, WomenHeart Scientific Advisory Council

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Goal 2: Reduce Human Disease

Exercise in congenital heart disease and arrhythmia syndromes

What are the true risks of physical activity and competitive sports for children/young adults with congenital heart disease and arrhythmia syndromes?

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 :

Improve the quality of life of patients with congenital heart disease or arrhythmia syndromes who are currently restricted from competitive sports.

Feasibility and challenges of addressing this CQ or CC :

While we previously restricted many of these patients, the pendulum seems to be swinging back in terms of our thinking about this. While some preliminary data has suggested safety, more data is needed.

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

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Goal 2: Reduce Human Disease

How to organize artificial pulsatile propelling of blood maintaining the balanced circulation?

Venous pressure, being very low, distends (deforms) the ventricle - but due to elastic or viscous law of deformation? Elastic deformation depends on stress (pressure) only and the viscous one - on stress and time. When pressures are low you can't get large distention due to stress only (time-independent) unlike the case when you apply low stress and long time interval. If we want to use venous pressure as one of regulators ...more »

Submitted by (@yuri.astrakhan)

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 impact (in case of constructive solution of the problem) can be expected as a breakthrough in the field of engineering of extracorporal circulatory devices and artificial heart. More exactly: the impact will concern the dosage of blood while filling of the ventricle - without intrusion into the essential levels of venous pressure (the levels play the role of regulators together with levels of diastolic arterial pressure).

Feasibility and challenges of addressing this CQ or CC :

The feasibility of implementation (engineering of a device) of the above idea depends on preliminary supercomputer modeling of blood circulation based on simulation of viscous relaxation of ventricle combined with the controlling of circulation according to the deduced equation (see the reference).

Name of idea submitter and other team members who worked on this idea : Kamnev Yuri

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Goal 2: Reduce Human Disease

A Program of Research in the Prevention of Chronic Heart Failure

There is a need to address chronic heart failure (HF) through improved identification of patients at risk for HF and of patients with pathological ventricular remodeling who have minimal evidence of clinical HF, and more focused and individualized pharmacologic and lifestyle treatments and monitoring of patients with HF risk. Approaches would include big data collection, omics, statistical modeling, and focused clinical ...more »

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Substantially reduce the age-adjusted incidence and population burden of chronic heart failure.

Feasibility and challenges of addressing this CQ or CC :

The big data and omics revolutions have made it feasible to collect and analyze a variety of data in large numbers of persons within a relatively short time. A very large sample size provides excellent statistical power. Also, the public health and economic magnitude of the problem create the urgency needed to address the critical challenge expeditiously.

Chronic heart failure (HF) is easily the most common and growing cardiovascular cause of hospitalization and impaired functional status and quality of life in the U.S. and much of the world. This is the case despite improved pharmacologic and lifestyle treatment of HF, as well as improved control of blood pressure in the general population. While some HF in the very elderly may reflect the aging process, the epidemiology suggests that most incident cases could be prevented or postponed for years. Also, there are major ethnic and socioeconomic disparities in the incidence of HF.

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

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