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 1: Promote Human Health

Role of the lymphatic system in heart, lung, blood, sleep health and diseases

What is the role of lymphatic system in normal function of the heart? Do dysfunctional lymphatics contribute to heart failure? Do lymphatics have a role in recovery after MI? It has been reported that lymphatic vasculature transport HDL during reverse cholesterol transfer. Do lymphatics have a role in atherosclerosis? What is the contribution of lymphatic system to asthma or COPD? Does the lymphatic system contribute ...more »

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 :

Understanding how lymphatic system contributes to normal physiology of heart, lung, blood, sleep systems will help also lead to new approaches for treatment of heart, lung, blood, sleep diseases.

Feasibility and challenges of addressing this CQ or CC :

Basic understanding of the development and hemodynamics of the lymphatic system and reagents to study the lymphatic function are available.

Lymphatic vasculature is essential for fluid hemostasis in the body, collects and returns the protein- and lipid-rich interstitial fluid to blood circulation, and also involved in immune cell trafficking and inflammation. Given these important physiological roles, function of the lymphatic system is expected to contribute to normal physiology of organs and its dysfunction to major diseases. There is very little or no information how the lymphatic system contribute to health and diseases of the cardiovascular, pulmonary and blood systems, and there are many unanswered questions. Answers to these questions may lead to new approaches for treatment of major HLB diseases. Main challenge is to get heart, lung, blood, sleep investigators interested in studying the contribution of the lymphatic system to heart, lung, blood, sleep health and diseases.

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

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77 up votes
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Goal 2: Reduce Human Disease

Risk scores for valvular heart disease

What is an appropriate risk score for intervention in valvular heart disease?

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 :

More accurate risk estimates would provide clinicians with clearer guidance in selecting how and when to intervene in valvular heart disease.

Feasibility and challenges of addressing this CQ or CC :

The advent and rapid advance of transcatheter therapy for valvular heart disease makes this an opportune time to develop metrics to determine whether transcatheter or surgical intervention is most appropriate and when.

The decision to intervene, as well as the type of intervention, is based on individual risk scores such as the STS risk estimate or the Euroscore. However, these scores are derived only from surgical patients and do not take into account procedure-specific impediments, major organ system compromise, comorbidities, or the frailty of the patient.

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

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

Current State of Regenerative Medicine: Moving Stem Cell Research from Animals into Humans for Clinical Trials

Realizing the developmental and therapeutic potential of pluripotent human embryonic stem cell (hESC) derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation.

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 :

Realizing the developmental and therapeutic potential of pluripotent human embryonic stem cell (hESC) derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient, incomplete, and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity. In addition, undefined foreign or animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic.

Feasibility and challenges of addressing this CQ or CC :

Opportunity: Recent technology breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for derivation and maintenance of clinical-grade pluripotent hESC and lineage-specific differentiation of pluripotent hESC by small molecule induction. Such milestone advances and medical innovations in hESC research enable direct conversion of pluripotent hESC into a large supply of homogeneous populations of clinical-grade hESC neuronal and heart cell therapy products for developing safe and effective stem cell therapies. Currently, these hESC neuronal and cardiomyocyte therapy derivatives are the only available human cell sources with adequate capacity to regenerate neurons and contractile heart muscles, vital for CNS and 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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13 up votes
34 down votes
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Goal 2: Reduce Human Disease

Congenital heart disease effects on neurodevelopment

What factors drive neurodevelopment impairment in children with congenital heart disease?

Submitted by (@nhlbiforumadministrator1)

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

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

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-9 net votes
13 up votes
22 down votes
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Goal 2: Reduce Human Disease

Antibiotic prophylaxis of infective endocarditis

What is the optimal use of antibiotics for prophylaxis of infective endocarditis?

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 :

Answering this question would provide an evidence base for the use of antibiotics for prophylaxis of infective endocarditis (IE). Clinicians in the US remain skeptical of the 2007 AHA guidelines reducing the use of antibiotics, and the guidelines, themselves, cited the need for additional prospective studies. In addition, a recent study by Dayer et al reports an increase in the incidence of IE in the UK following adoption of similar guidelines.

Feasibility and challenges of addressing this CQ or CC :

The question is actually overdue to be addressed following adoption of the 2007 guidelines.

Challenge: Considering the severe consequences of infective endocarditis, it may be difficult to design a definitive placebo-controlled clinical trial.

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

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-6 net votes
3 up votes
9 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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Goal 3: Advance Translational Research

Safety and effectiveness of new direct oral anticoagulants

What is the optimal use of new direct oral anticoagulants?

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 :

Vitamin K antagonist, warfarin, has traditionally been the mainstay of anticoagulation therapy. It requires frequent monitoring to maintain safe and effective dose and is associated with many food and drug interactions. A new generation of direct oral anticoagulants has been developed to overcome such shortcomings.

Two main classes of new direct oral anticoagulants are available: factor Xa inhibitors and factor IIa (thrombin) inhibitors. Their mechanism of action involves direct inhibition of a single factor within the coagulation cascade to exert an anticoagulant effect. The industry is positioning them as monitoring-free universal warfarin replacement products. However, use of new direct oral anticoagulants introduces two major clinical issues: majority of new generation anticoagulants do not have developed dose-monitoring assay and do not have antidotes to rapidly restore blood coagulation properties in patients with trauma, emergent surgery, or anticoagulation overdose. Addressing these issues would positively impact cardiovascular, pulmonary, benign hematology, and orthopedic services worldwide.

While the idea of a universal, low-maintenance, “one dose fits all” anticoagulant is highly appealing to both patients and physicians, it may be feasible to consider more targeted approach, where each new anticoagulant would be assessed for most plausible effect in the specific patient population with consideration to genetic s, sex, race, age, thrombosis history, and obesity

Feasibility and challenges of addressing this CQ or CC :

Rapid advancement in the field of new generation direct oral anticoagulants and multiplicity of new drugs introduce opportunity to conduct comparative effectiveness research and assess how different characteristics of new products may be appropriate for different patients. Increased use of new direct oral anticoagulants requires expedited development of assays and antidotes for safe and efficient therapy of millions of Americans.

 

 

A challenge is that the majority of the clinical trials for new direct oral anticoagulants were conducted by the industry with the main goal of demonstrating superiority, or non-inferiority to warfarin. Secondary analyses of these trials’ data for efficacy in specific patient population may be difficult. Prospective clinical studies in this area may require large sample size and establishing collaboration between hematologists and other involved clinicians.

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

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31 up votes
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Goal 2: Reduce Human Disease

What is the Relationship Between CVD and Dementia in the Elderly?

The successes of preventing and treating CHD, CVD has resulted in a substantial increase in life expectancy, a very important success story, but unfortunately it has led to a growing population of elderly 80+ years of age.

Submitted by (@kullerl)

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

Details on the impact of addressing this CQ or CC :

Their high prevalence of congestive heart failure (CHF), atrial fibrillation (Afib), stroke, peripheral vascular disease, dementia, frailty, and disability is clearly going to lead to the public health tsunami of the 21st century and bankrupt the health systems. Further studies are badly needed to determine the interrelationship between CVD, dementia, disability, and whether prevention of CVD beginning early in life, middle ages, or even at older ages can impact on successful aging with reduced risks of dementia and disability.

Feasibility and challenges of addressing this CQ or CC :

Older individuals with 0 coronary artery calcium (CAC) have extremely low risk of subsequent clinical CHD, CVD, and total mortality even at older ages. Whether these individuals with low risk, e.g. very low CAC, have less extensive brain abnormalities associated with increased risk of dementia needs to be evaluated.

 

The NHLBI should establish a registry of individuals who have had very low CAC scores at older ages, determine the relationship between these very low CAC scores and risk factors, genetics, and then consider trials to prevent CVD, CHD among older individuals 80+ with relatively low levels of CAC, with dementia, stroke, CHF, Afib, as primary endpoints. The NHLBI should also consider trials in middle-aged individuals to prevent the development and progression of coronary atherosclerosis, e.g. maintenance of 0 CAC. The NHLBI, in collaboration with other institutes at NIH, should evaluate the interrelationship between coronary artery atherosclerosis, e.g. CAC, and other measures of atherosclerosis, other manifestations of CVD, such as CHF, Afib, and brain changes and the development of dementia and Alzheimer’s disease.

Name of idea submitter and other team members who worked on this idea : Lewis H. Kuller, MD, DrPH

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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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9 up votes
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Goal 3: Advance Translational Research

What is the optimal way to improve cardiac arrest resuscitation?

Sudden Death from cardiac arrest and gaps in knowledge of emergency cardiovascular care are the #1 killer of more than 400,000 Americans each year. This epidemic of death and disability is largely ignored and underfunded by NIH and all funding agencies and kills more than HIV, Cancer, Diabetes, and infectious diseases. There is no national registry of cardiac arrest, no mandatory reporting, and poor funding for both fundamental, ...more »

Submitted by (@nadkarni)

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

Details on the impact of addressing this CQ or CC :

Answering this question will save more lives and quality of life-years than all other infectious diseases in North America. The potential interventions are well developed and we need more fundamental, translational and implementation science to impact this most significant problem. An upcoming IOM report on needless deaths resulting from cardiac arrest is anticipated to be published in 2015.

Feasibility and challenges of addressing this CQ or CC :

Very feasible, just needs support and funding. A call to arms is being issued by the American Heart Association and Institute of Medicine. The roadmap is outlined, and all we need to do is follow the roadmap.

Name of idea submitter and other team members who worked on this idea : Vinay Nadkarni MD

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37 up votes
18 down votes
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