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)

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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

Congential heart defects in diabetic pregnancies: a devastating reality

There is an urgent need to understand the mechanisms underlying diabetes-induced congenital heart defects (CHDs) through basic science research and biomarker identification in human maternal circulation. Majority of the current research in CHDs is related to genetic analyses; however, environmental factors contribute to the majority of human CHDs, but the underlying mechanism is unknown. There is 60 million worldwide ...more »

Submitted by (@pyang0)

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

Details on the impact of addressing this CQ or CC :

More than 32,000 infants are born with heart defects each year in the United States, and about 1 in 150 adults are expected to have some form of congenital heart defect. Approximately, 25% of infants born with heart defects (2.4 per 1,000 live births) require invasive treatment in the first year of life, and in 2009 heart defects were the most common cause of infant death. Therefore, understanding the underlying causes of abnormal heart formation is an essential step towards developing effective new therapeutic treatments or preventions for heart defects. Using diabetes-induced CHDs as research models will reveal critical molecular pathways that contributes to heart cell proliferation and apoptosis.

Feasibility and challenges of addressing this CQ or CC :

The same types of heart defects seen in human diabetic pregnancies can be recapitulated in diabetic animal models, making rodents ideal models to investigate how maternal hyperglycemia may induce congenital heart defects. Dietary supplements of natural compounds may be effective against CHDs in diabetic pregnancies. Clinically, new imaging techniques needs be developed for the early diagnosis of CHDs in diabetic pregnancies. Biomarkers in human blood samples needs be detailed analyzed so that we can use small molecules such as microRNA for reliable and early diagnosis.

Name of idea submitter and other team members who worked on this idea : Peixin Yang

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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)

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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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Goal 1: Promote Human Health

Improving longterm outcomes after surgery for congenital heart disease

Survival has improved but neurobehavioral disabilty remains a common complication with adverse impacts on quality of life, educational and occupational attainments, and resource utilization. There is increasing evidence that brain development is abnormal, and leads to a rrisk of peri-operative brain injury. Studies are needed to; 1. Further define the prevalence and spectrum of neurobehavioral disability. 2, Understand ...more »

Submitted by (@gaynor)

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

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Survival has improved following surgery for complex congenital heart disease. There is an ever increasing population of adolescents and adults with repaired congenital heart defects. Neurobehvaioral disability can be identified in over 50% of survivors, including ADHD, autism spectrum disorders, learning disabilities and impaired motor skills. These deficits adversly affect their schools and job performance, as well as interactions with their peers and families. The need for special education and other rehabilitative services leads to significant resurce utilization and costs to society. Development of novel neuroprotective therapies will significantly improve the long-term outcomes for these fragile children.

Feasibility and challenges of addressing this CQ or CC :

Because of the small numbers of patients treated at single instituions, this project will require multi-institutional collaboration with long-term follow-up assessments. There is need for collabortaive databases, standardized neurodevelopment evaluations, and acquistion of genomic data. In particular, there is a need to development methodolgy to track outcomes from fetal life to adulthood.

Name of idea submitter and other team members who worked on this idea : J William Gaynor

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Goal 3: Advance Translational Research

The Designation of Human Cardiac Stem Cell therapy Products for Human Trials or First-in-Human Studies

For successful pharmaceutical development of cardiac stem cell therapy, the human cardiac stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials.

Submitted by (@xuejunparsons)

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

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For successful pharmaceutical development of cardiac stem cell therapy, the human cardiac stem cell therapy product must meet certain commercial criteria in plasticity, specificity, and stability before entry into clinical trials. Moving stem cell research from current studies in animals into human trials must address such practical issues for commercial and therapeutic uses: 1) such human stem cells or their cardiac derivatives must be able to be manufactured in a commercial scale; 2) such human stem cells and their cardiac derivatives must be able to retain their normality or stability for a long term; and 3) such human stem cells must be able to differentiate or generate a sufficient number of functional or contractile cardiomyocytes for repair. Those practical issues are essential for designating any human cardiac stem cells as a human cardiac stem cell therapy product for investigational new drug (IND)-filing and entry into clinical trials. So far, the therapeutic effects, if any, of human cardiac stem cells in the existing market, including those derived from patients’ heart tissues, were mediated by protective or tropic mechanism to rescue dying host cardiomyocytes, but not related to myocardium regeneration.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent breakthrough stem cell technologies have demonstrated the direct pharmacologic utility and capacity of pluripotent human embryonic stem cell (hESC) therapy derivatives for human CNS and myocardium regeneration and, thus, have presented the hESC cell therapy derivatives as a powerful pharmacologic agent of cellular entity for a wide range of CNS and heart diseases. The hESC cardiomyocyte cell therapy derivatives by novel small molecule induction provide a large scale of high quality human cardiomyocyte source for myocardium regeneration and, thus, meet the designation of human stem cell therapy products in plasticity, specificity, and stability for commercial development and human trials or first-in-human studies in cardiovascular diseases.

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

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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)

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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 3: Advance Translational Research

Advancing Translational Research

Ensuring that basic science is translated into clinical practice is essential. While there have been great strides in ensuring that babies born with congenital heart defects (CHD) are identified and repaired, we know that there are lifelong implications for those with CHDs that require continued follow-up and treatment. As the proportion of those with CHDs as adults continues to outpace the pediatric population, we urge ...more »

Submitted by (@dstephens)

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

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Extreme makeover: harnessing adaptation mechanisms for therapy

What extreme adaptive physiological mechanisms in heart, lung, and blood systems might have the greatest potential to be targeted or employed in therapeutic strategies? Human physiology, including the heart, lung and blood systems, is known to possess extreme adaptive mechanisms to counter extreme conditions or unusual situations. Although some studies are being done, many of these mechanisms have not been fully explored ...more »

Submitted by (@nhlbiforumadministrator)

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

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May lead to new therapeutic strategies for HLB diseases. May improve our understanding of HLB physiology and adaptation.

Feasibility and challenges of addressing this CQ or CC :

It is feasible to ask specific questions about adaptation mechanisms under extreme conditions and develop experiments to test them. This can be done in various experimental models as well as in humans.

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

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Deriving Cardiac Elements from Pluripotent Human embryonic Stem Cells for Heart Reconstitution

to date, the existing markets lack a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential, which has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged human heart in cardiovascular disease.

Submitted by (@xuejunparsons)

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

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Given the limited capacity of the heart for self-repair or renewal, cell-based therapy represents a promising therapeutic approach closest to provide a cure to restore normal heart tissue and function for CVD. There is no evidence that adult stem/precursor/progenitor cells derived from mature tissues, such as bone marrow, cord blood, umbilical cord, mesenchymal stem cells, patients’ heart tissue, placenta, or fat tissue, are able to give rise to the contractile heart muscle cells following transplantation into the heart. Despite numerous reports about cell populations expressing stem/precursor/progenitor cell markers identified in the adult hearts, the minuscule quantities and growing evidences indicating that they are not genuine heart cells and that they give rise predominantly to non-functional smooth muscle cells rather than functional contractile cardiomyocytes have caused skepticism if they can potentially be harnessed for cardiac repair. In recent years, reprogrammed or trans-differentiated adult cells, as a result of being backed by excess sum of government and private funding, have been rekindled as the adult alternates. However, major drawbacks such as abnormal gene expression, accelerated aging, immune rejection, not graftable, and extremely low efficiencies, have severely impaired the utility of reprogrammed or trans-differentiated somatic cells as viable therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Derivation of pluripotent human embryonic stem cells (hESCs) from the IVF leftover embryos has brought a new era of cellular medicine for the heart. The intrinsic ability of a hESC for both unlimited self-renewal and differentiation into clinically-relevant lineages makes it a practically inexhaustible source of replacement cells for human tissue and function restoration. Therefore, it has been regarded as an ideal source to provide a large supply of functional human cells to heal the damaged or lost tissues that have naturally limited capacity for renewal, such as the human heart and the human brain. Although a vast sum of NHLBI funding has been spent on looking for adult alternates, such as reprogramming and trans-differentiation of fibroblasts or mature tissues, so far, only human cardiac stem/precursor/progenitor cells derived from embryo-originated hESCs have shown such cellular pharmacologic utility and capacity adequate for myocardium regeneration in pharmaceutical development of stem cell therapy for the damaged human heart.

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

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Goal 2: Reduce Human Disease

Why is the heart resistant to cancer?

Cancer of the heart is almost unheard of, whereas most other organs can develop cancer. Why is this?

Submitted by (@nhlbiforumadministrator)

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If we could understand why cancer does not develop in the heart, this might help to develop strategies to protect other organs from doing so.

Feasibility and challenges of addressing this CQ or CC :

To my knowledge, no one has looked at this problem, because cardiologists and oncologists train in different fields. With molecular profiling, iPS technology, and animal models, this question can be addressed.

Name of idea submitter and other team members who worked on this idea : Henry Chang, M.D.

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Goal 1: Promote Human Health

Adult Cardiomyocytes in Culture

So much basic cardiovascular discovery relies on cell culture models. While cardiac cell lines exist (e.g. HL-1, H9c2), these often poorly model aspects of cardiomyocyte function in-situ (e.g. contractile function, metabolism). In contrast, primary cardiomyocytes isolated from adult animals (especially mice!) are not readily amenable to culture conditions. Even if cells can be kept alive, they are often refractory to ...more »

Submitted by (@paulbrookes)

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

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Addressing this challenge would provide tools for basic researchers to answer many key questions about basic cardiomyocyte function. Removing the "voodoo" element from these methodologies would be an enabling technology. In the neuron field, companies such as "brain bits" will ship tissue with specific protocols, to enable unskilled technicians to culture highly pure neuron subtypes in a matter of hours. Such methods have led to standardized methods in the field, which is good for reproducibility.

Feasibility and challenges of addressing this CQ or CC :

There have been several attempts at keeping adult myocytes alive in culture, using technologies such as electrical pacing, and inclusion of inhibitors in culture media. Likewise some AAV variants are known to transfect hearts in-vivo. However, no uniform widely-accepted methods are used between many different labs. Every lab has their own "trick" to get cells to behave. Many investigators can make a few cells on a dish survive, which is sufficient for single cell work (e.g. microscopy), but getting an entire culture of adult myocytes to survive beyond 24-48 hrs (the minimal time frame needed for genetic manipulations such as siRNA) would open up more common detection and assay measurements. Myocytes from larger animals (e.g. rabbits) are more stable and longer-lived in culture, but such methods do not appear to work for mouse CMs, which therefore precludes application of knockouts and other useful mouse resources.

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

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