Goal 3: Advance Translational Research

Human Heart Systems Biology

In the human failing heart, it is the systems biology that ultimately fails: electrical, mechanical, and chemical perturbations in their function do not manifest in isolation, but critically impact on each other in health and disease. Investigation of human myocardium, unlike inbred rodent models, is challenging since no two humans are identical. There is a need for the collection and assessment of clinical patient data, ...more »

Submitted by (@janssen.10)

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

Details on the impact of addressing this CQ or CC :

Procured/stored tissue from these hearts could be made available NHLBI/NIH-wide, and studied by a large number of investigators on protein levels, RNA/DNA level, and/or histological assessments. This data could then be correlated to any other parameter assessed on these hearts, providing correlative guidance, through systems biology/neural network programming, for future mechanistic studies. For each additional parameter investigated, the number of correlation analysis (with any and all parameters, including clinical and biometric parameters) would mathematically double.

Feasibility and challenges of addressing this CQ or CC :

Supporting the basic collection of these in vivo and in vitro parameters and possibly the logistics for tissue distribution to collect correlative mechanical, proteomics, genomics, and histology data for correlation with the in vivo and in vitro data would allow for an NIH/NHLBI-wide translational approach to human heart failure that could encompass everyone’s “favorite” molecule, protein, pathway, and disease etiology. A logistical challenge is that such a project would likely exceed the funding of a single standard grant, but more importantly would surely exceed the standard 4-5 year duration, requiring long-term vision, planning, and buy in from NIH/NHBLI and investigators.

Name of idea submitter and other team members who worked on this idea : Paul Janssen

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6 net votes
13 up votes
7 down votes
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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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8 net votes
14 up votes
6 down votes
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Goal 2: Reduce Human Disease

Critical Challenge

• One of the most important public health issues the Nation faces is the rising incidence of heart failure. HF incidence rates have risen faster than predicted. The prevalence will increase as better and more therapy becomes available. While heart failure is the biggest ticket item in the Medicare budget, the cost to society will increase more than it has already. But much HF can be prevented or onset prolonged. Investing ...more »

Submitted by (@tsansone)

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

Details on the impact of addressing this CQ or CC :

See attached file

Feasibility and challenges of addressing this CQ or CC :

Critical Challenge

Name of idea submitter and other team members who worked on this idea : ASH Officers, Committee Members

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

Stem Cell Immunology

We now can create critical cell types like cardiomyocytes etc. from stem cells. Additionally, we are learning the rules of using these cells to rebuild tissues. A major gap in our knowledge relates to the immunobiology of these cells. Lessons from transplantation medicine are only partially applicable, because solid organs are more complex and likely more immunogenic than defined cell populations. How does the immune ...more »

Submitted by (@murry0)

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

Details on the impact of addressing this CQ or CC :

We now can generate large quantities of critical cell types whose deficiencies underlie many chronic diseases like heart failure. This breakthrough brings us to the next-level impediment: the immune system. While induced pluripotent stem cells have the potential to obviate rejection, in practical terms this is cost-prohibitive: It will cost huge amounts of money to produce and qualify a single patient's cell dose. Moreover, human cardiomyocytes are potent when given to infarcted hearts in the acute or sub-acute phase of infarction, but they have no benefit with chronic heart failure. The 6 months required to produce iPSC-cardiomyocytes precludes their autologous use for myocardial infarction.

 

We need an off the shelf cell therapy product for myocardial infarction that can be mass produced and qualified for large numbers of patients. This means an allogeneic product is necessary. Identifying the immune response to cardiomyocytes or other cell products will teach us how to precisely immunosuppress the patient, thereby minimizing complications, or alternatively, how to engineer the cells so as to avoid immunogenicity in the first place.

 

Lessons from the study of cardiomyocyte transplantation could extend to dopamine neurons, pancreatic beta-cells, retinal cells, myelinating cells and many other areas that cause common chronic disease.

Feasibility and challenges of addressing this CQ or CC :

We know a great deal of transplant immunology from hematopoietic stem cell transplantation (graft versus host) and from solid organ transplantation (host versus graft). There are good mouse and large animal (including non-human primate) models of stem cell differentiation and organ transplantation. This offers low hanging fruit where, in perhaps 5 years, we could discern the critical similarities and differences between transplanting stem cell derivatives and organ or marrow transplantation. These studies will inform clinical trials of allogeneic human stem cell derivatives that will be underway by then.

 

Success in this area will require bringing together researchers interested in stem cell biology and transplant immunology. A properly resourced RFA from NIH could be just the thing needed to promote this interaction.

Name of idea submitter and other team members who worked on this idea : Charles Murry, MD, PhD

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23 net votes
45 up votes
22 down votes
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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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13 net votes
15 up votes
2 down votes
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Goal 2: Reduce Human Disease

Is heart failure reversible by diet and lifestyle changes?

Once heart failure has developed, can diet and exercise measures work to reverse it?

 

Well-designed clinical trials are needed to answer this question.

Submitted by (@nhlbiforumadministrator1)

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 no known therapy that can reverse heart failure. Drug and device treatments may slow progress but not a cure. If diet and lifestyle changes could reverse heart failure, even if just in segments of the heart failure population, it would be a tremendous impact in saving lives and would have a great fiscal impact as well.

Feasibility and challenges of addressing this CQ or CC :

Innovative dietary and lifestyle intervention studies could be done cheaply and efficiently.

There is low impact, mostly anecdotal evidence that heart failure (HF) is reversible through diet and exercise, but no higher level research has investigated this question. It is an accepted notion that healthy diet and exercise can prevent cardiovascular diseases. Obesity, diabetes and coronary artery disease are strong risk factors for HF. Accordingly, a high portion of HF patients has ischemic etiology, is obese and/or diabetic. Diet and lifestyle interventions could beneficially influence these comorbidities and might reverse HF.

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

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6 net votes
34 up votes
28 down votes
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Goal 3: Advance Translational Research

New Targets for the Treatment of Heart Failure

Heart failure (HF) is one of the major health challenges in the 21st Century. Its prevalence is due a growing number of patients who survive heart attacks, who later develop heart failure; and the high incidence of diabetes leading to diabetic cardiomyopathy. Current treatments for HF only slow the progression of the disease; no treatment stops or reverses this adverse sequence. These limitations provoke the question ...more »

Submitted by (@wchilian)

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 current treatment regimens for patients with heart failure (HF) focus on strategies to reduce cardiac work (by reducing heart rate, beta-blockers), afterload reduction (ACE inhibitors), and decrease in preload/blood volume (ACE inhibitors, aldosterone antagonists, diuretics). None of these treatments stop or reverse the progression of the disease. A recent gene therapy trial designed to improve cardiac contractility and calcium handling in HF has failed in clinical trials. Perhaps the reason that the current and experimental treatments have not produced an outcome of stopping or reversing the progression of the disease relates to the "cell" they are targeting. In this regard, the current treatments principally target cardiac myocytes, but there is evidence that vascular perfusion abnormalities may also be involved in the disease. One such piece of evidence relates to the diffuse fibrosis occurring in the failing hearts. Such fibrosis is often referred to as replacement fibrosis in that the fibrotic tissue has replaced cardiac myocytes which died. This death could be the result of a perfusion abnormalities caused by inadequate dilation of the coronary resistance vessels. Thus, is heart failure a pathology involving both the coronary circulation and cardiac muscle? In this regard, future investigations of heart failure consider cardiac-coronary interactions leading to perfusion abnormalities as a key factor in the progression of heart failure.

Feasibility and challenges of addressing this CQ or CC :

The challenge of addressing a coronary vascular contribution to heart failure would involve an interdisciplinary approach using genetic models with cardiac and/or vascular (smooth muscle and endothelium) expression or knock-out of key genes involved in cardiac function and vascular control. Sophisticated measurements of cardiac function and metabolic status of the heart using echocardiography, MRI, PET and a L-Band EPR would provide insight into flow-function-metabolism-oxygenation relations in the normal and failing heart.

Name of idea submitter and other team members who worked on this idea : William M Chilian

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13 net votes
18 up votes
5 down votes
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Goal 2: Reduce Human Disease

National ARDS Registry

ARDS remains one of the most common and lethal forms of respiratory failure in critically ill patients. Improvements in understanding the pathogenesis has not led to effective treatments, and heterogeneity of the condition precludes major advances. A national registry would serve to improve understanding of epidemiology, disease characterization (for definitions) and can identify incidence, outcome, disparities, treatment ...more »

Submitted by (@greg.martin)

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

Feasibility and challenges of addressing this CQ or CC :

Can be modeled on the ARDS/PETAL Network, but more broadly implemented for epidemiology and pragmatic studies.

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

Therapy for Heart Failure with Preserved Ejection Fraction

Are existing neurohormonal antagonist drugs effective in HFPEF ?

Submitted by (@lars.lund)

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

Details on the impact of addressing this CQ or CC :

HFPEF is as serious as HFREF and as many forms of cancer. But there is no therapy. Generic neurohormonal antagonist drugs are effective in HFREF and have potential in HFPEF. They will not be studied by industry and trials need public funding.

Feasibility and challenges of addressing this CQ or CC :

The challenge is streamlined efficient trials. This can be addressed with the registry-randomized trial concept.

Name of idea submitter and other team members who worked on this idea : Lars H. Lund

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-6 net votes
7 up votes
13 down votes
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Goal 2: Reduce Human Disease

Predict the needs for inter and intra-hospital transfer for acute care surgery patients with respiratory failure

Density mapping of the need and flow of patients requiring acute care surgery vis-a-vis inter-facility transfer, care hand-off failures, post-acute care resource mismatch to articulate a funding plan resource allocation and development akin to what has been done for trauma care.

Submitted by (@greg.martin)

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 of Critical Care Medicine Executive Committee/Council

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

Heart Failure Therapies

We need much more support for critical basic research to understand and develop transformative therapies for this enormous health care burden. This is not simply a question of epidemiology and large multicenter population data bases. We really need hard core science. It is impossible to know where the next breakthrough will come, and setting aside funds for hot button things - stem cells, or iPS, or gene editing per ...more »

Submitted by (@dkass0)

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

Feasibility and challenges of addressing this CQ or CC :

NIH needs to stop trying to guess what the next big thing is and putting funds aside to support something that is popular at the moment. This has been done frankly with GWAS, with Stem cells, and perhaps ongoing now with "personalized medicine". All hot areas, but so are a ton of other things. IN my 30 years as a physician scientist, I cannot count on one hand the number of discoveries that were really transformative that came out of this type of ear-marked planning. Need more resources to support innovative individual scientists, particularly those with a track record of discovery, translation, and iinnovation We do not do that well enough at all.

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6 net votes
18 up votes
12 down votes
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Goal 1: Promote Human Health

A Systems Approach - Human Cardiac Electromechanical Activity

The challenge is to identify limitations in using data from non-human animal species for elucidation of human electromechanical function/activity and to identify what specific information and computational approaches need to be incorporated. To aid in achieving such a goal, it might be useful to convene a series of workshops to build consensus and improve communication among investigators working at the same horizontal ...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 :

This will provide an in silico computational platform to study human cardiac pathology. Note: by different horizontal levels, we mean for example measuring and modeling individual ion channels, transporters or myofilament properties in myocytes. By different vertical levels, we mean for example gogenomic/proteomic to cellular, and cellular to more integrative levels.

Feasibility and challenges of addressing this CQ or CC :

Advances in high-speed computation techniques and high-throughput measurement make the achievement of this challenge doable.

An integrated understanding of the eletromechanical activity of the human heart is needed to develop more effective approaches to cardiac disease diagnosis, treatment, and prevention. Robust computational models of human electromechanical activity that incorporate ion channel kinetics, calcium handling and dynamic changes in the intra-/extracellular milieu from human cardiac tissues are needed develop such an understanding and to provide an experimental platform to test interventions designed to maintain cardiac function. Computational models should be scalable and incorporate subcellular molecular mechanisms to whole system levels of integration to be most effective.

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

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7 net votes
20 up votes
13 down votes
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