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

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.

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.

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.

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.

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

Developing targeted immune therapies to limit damage post-MI

Murine models prior to pathological studies in humans and primates

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

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.

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.

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.

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

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.

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.

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.

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

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.

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

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.

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.

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.

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

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.