Goal 2: Reduce Human Disease

Immune response to myocardial infar

Identify the immune cell phenotype responsible for myocyte damage post infarction.

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 :

Developing targeted immune therapies to limit damage post-MI

Feasibility and challenges of addressing this CQ or CC :

Murine models prior to pathological studies in humans and primates

Name of idea submitter and other team members who worked on this idea : Randy Cron

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Goal 2: Reduce Human Disease

Pathogenesis and treatment of cardiovascular disease in survivors of critical illness.

Acute cardiovascular complications are frequent in critical illness and injury, occurring on a spectrum that includes troponin leak or demand ischemia to acute occlusive coronary events and lethal arrhythmias. They arise in the course of similar acute illnesses but they epidemiology, pathogenesis, treatment and long-term consequences are unknown. Are they the result of a generalized inflammatory state that persists ...more »

Submitted by (@greg.martin)

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

Details on the impact of addressing this CQ or CC :

Complications of critical illness are frequent and the most common are cardiovascular in nature but not well understood. Understanding the pathogenesis of these consequences will lead to improve treatments, acute survival of critical illness and injury, and improved long-term outcomes.

Feasibility and challenges of addressing this CQ or CC :

Patients receiving critical care services in the United States are among the most close monitored, including continuous monitoring of cardiorespiratory physiology. Integrating high dimensional data from ICU data streams and applying big data analytics, in combination with primetime genomic and metabolomic technologies, makes this question imminently feasible.

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

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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10 down votes
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Goal 2: Reduce Human Disease

Improving pre-hospital therapy of HLB disorders

There is compelling evidence that pre-hospital therapy of both stroke and MI can improve outcomes and yet, with the exception of aspirin for MI, almost no care is administered pre-hospital in the U.S. NHLBI has a major stake in improving pre-hospital care because there already are sufficient data to show that currently available interventions would improve outcomes if they could be administered in the prehospital setting. ...more »

Submitted by (@collerb)

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 mortality and disability from stroke could be substantially reduced. The early mortality of STEMI and late disability from heart failure could be substantially reduced.

Feasibility and challenges of addressing this CQ or CC :

There are numerous challenges including:

• Obtaining informed consent for pre-hospital clinical trials

• Fragmentation of EMS services by locale

• Need to train EMS personnel

• CMS rules on reimbursement for ambulance services and novel drugs

 

NHLBI could use its convening power in partnership with other groups to integrate this effort.

Name of idea submitter and other team members who worked on this idea : Barry Coller

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Goal 2: Reduce Human Disease

Fundamental stress-response mechanisms in the heart.

What are the primary molecules and cellular signals associated with prolonged hypertensive stress that cause adverse myocardial tissue remodeling, and what strategies that prevent or reverse adverse remodeling can be developed and tested?

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 :

Could potentially contribute to the development of new therapies for heart disease and cardiomyopathies.

Feasibility and challenges of addressing this CQ or CC :

Yes, addressing this CQ may be feasible. Since it is likely that a multitude of signaling mechanisms are involved, an unbiased, global approach may be necessary to identify the key molecular pathways. However, experimental challenges remain and even developing appropriate animal models has been challenging.

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

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

Technologies for Ex-Vivo Cardiac Repair

What is needed to develop the technologies that will allow reparative interventions to be performed on excised natural hearts that have been overhauled ex vivo and replanted?

 

This will involve keeping the myocardium alive and sterile for extended periods that are long enough to complete the interventions while being able to also perform the necessary reparative interventions.

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 :

The long-term impact would be to alleviate the need for permanent circulatory support devices or transplants by providing a means for hearts to be repaired while patients are temporarily supported using total artificial hearts. The immediate impact of developing the technologies to do this would be that the necessary interventions for ex-vivo cardiac repair could be developed and tested leading to a new therapy.

Feasibility and challenges of addressing this CQ or CC :

A very basic foundation for this already exists. That foundation is an "Organ Care System" currently used in the UK to keep hearts functioning, not simply preserved, until the time of transplant for up to 12 hours. A timeframe of 5-10 years to extend the duration and the function of such a system for the stated purposes would seem feasible.

Repair and recovery of the heart is the currently limited to in vivo therapies. With the availability of artificial hearts and with the proper technologies available, the excised natural hearts from these patients could be overhauled ex vivo and re-implanted. Ideally, the overhaul would allow a way for various reparative interventions to be performed on the excised heart that would help to return it to a healthy functioning state before re-implantation. Such reparative interventions might include, but would not be limited to, surgical repair, adjunctive cell therapy, and stimulated exercise of the myocardium to influence reverse remodeling.

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

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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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29 up votes
7 down votes
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Goal 2: Reduce Human Disease

Combination Cardioprotective Therapy for AMI

Which therapy or combination of therapies to reduce injury from acute myocardial infarction (AMI) will be most efficacious for future clinical trials?

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 :

AMI and heart failure continues to be a major cause of morbidity and mortality in the Western world.

Feasibility and challenges of addressing this CQ or CC :

Promising cardioprotective candidates are emerging. Additional pre-clinical and clinical research is needed to further investigate these new strategies, alone and in combination, to improve outcomes following AMI.

Numerous studies have implicated various pharmacological and interventional techniques (e.g., adenosine, cyclosporine, postconditioning, and remote ischemic per-conditioning) have been explored.

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

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6 up votes
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Goal 2: Reduce Human Disease

Ischemia-independent mechanisms contributing to infarct size

What are the mechanisms of ischemia-independent mechanisms contributing to the infarct size in patients with acute myocardial infarction? Infarct size is the single most important prognostic factor for short- and long-term outcomes. The success in reperfusion strategies have shown that prompt reperfusion leads to a reduction in infarct size, and to improved outcomes. Despite effective reperfusion, however, a secondary ...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 compelling question may lead to:

1) Improved therapy and outcomes for acute myocardial infarction

2) Reduction of acute morbidity/mortality following reperfusion

3) Prevention of heart failure

Feasibility and challenges of addressing this CQ or CC :

The progresses in basic science/signaling, preclinical models, imaging techniques, and invasive monitoring now provide the ideal setting to complete this research in a preclinical model or pilot exploratory clinical trials.

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

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6 up votes
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Goal 3: Advance Translational Research

Validating surrogate/intermediate clinical outcome endpoints for ST segment elevated myocardial infarction (STEMI)

The introduction of troponin assays has changed the criteria for myocardial infarction (MI), with much smaller myocardial damage now classified as an MI. Since to date, the FDA has not approved new agents based on their decreasing size of an MI, regulatory approval has required endpoints like death or heart failure that require large numbers of patients and long periods of time. Thus, it is difficult to attract industry ...more »

Submitted by (@collerb)

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

Details on the impact of addressing this CQ or CC :

Identifying a validated surrogate endpoint FDA approval of novel intervention for STEMI would potentially attract broad industry support to address this crucial health need.

Feasibility and challenges of addressing this CQ or CC :

NHLBI could potentially bring together all of the data in NHLBI-sponsored trials along with those sponsored by industry to assess the validity of infarct size measured by different methods as a surrogate indicator of death and clinical MI complications, including heart failure. By working with the FDA on this project, the impact on regulatory review would be immediate. The major challenges will be integrating data from multiple studies and choosing statistical methodology that is acceptable to the FDA for validating a surrogate endpoint.

Name of idea submitter and other team members who worked on this idea : Barry Coller

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Goal 2: Reduce Human Disease

Early cardioprotection for acute MI through cooling

What is an appropriate mechanism and study design to evaluate the beneficial effects of hypothermia following acute myocardial infarction?

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 :

Acute myocardial infarction remains a major cause of morbidity and mortality. Additional therapies beyond reperfusion are required to improve outcome.

Feasibility and challenges of addressing this CQ or CC :

Proof of concept has been established to support the acute effects of cooling in experimental models as well as humans.

Induction of hypothermia has proven dramatically effective in reducing myocardial infarct size in experimental models. Most studies in humans for STEMI have also shown a reduction in infarct size for subjects with anterior MIs cooled to below 35 degrees prior to reperfusion. However, long-term outcomes, including survival rates, LV remodeling, and prevention of heart failure, are unknown. Early treatment during transport to a hospital with a cardiac catheterization laboratory may be the most critical application for such a method. Ensuring trained first responders, community consent, appropriate study design, and financial support to assess long-term effects are a challenge. Simple methods of quickly and adequately ensuring consistent cooling are emerging.

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

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4 up votes
20 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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22 down votes
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