Goal 3: Advance Translational Research

Arrhythmia Therapies Based on Understanding Mechanisms

There is a need to translate these new insights of genetic, molecular, cellular, and tissue arrhythmia mechanisms into the development of novel, safe, and new therapeutic interventions for the treatment and prevention of cardiac arrhythmias.

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 :

Reduced socioeconomic burden of cardiac arrhythmias. Development of new technologies and recognition of new arrhythmia mechanisms.

Feasibility and challenges of addressing this CQ or CC :

Several studies have already recognized the unexpected antiarrhythmic effects of some therapies intended for other cardiovascular disease. For example statins, aldosterone blockers, and possibly some essential fatty acids may reduce arrhythmia burden in patients receiving these interventions. Clinical trials should be developed to demonstrate the efficacy of these interventions, and arrhythmia endpoints, including those for atrial fibrillation and sudden cardiac death, should be incorporated into other large clinical trials. Research into novel antiarrhythmic might focus on (a) drug development; (b) cell/gene-based therapy and tissue engineering; and (c) improvements in development and use of devices and ablation to prevent or inhibit arrhythmic electrical activity. Continued research might also focus on targeting of upstream regulatory cascades of ion channel expression and function. Continued antiarrhythmic strategies might include the exploration of novel delivery systems (e.g., utilizing advances in nanotechnology and microelectronics), biological pacemakers, AV node repair/bypass, and treatment and/or reversal of disease-induced myocardial remodeling and tachyarrhythmias. Evaluation of new therapies should include a cost analysis. Studies in both children and adults with congenital heart are needed. New interventions might include new pharmacologic approaches as well as advances in electrophysiologic imaging and improved approaches to ablation.

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

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51 net votes
86 up votes
35 down votes
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Goal 2: Reduce Human Disease

Understanding Cardiothoracic Surgery in Elderly Populations

There is a vital need for evidence-based clinical evaluation tools to assess operative risk and post-operative recovery in the elderly, including biomarkers of physiologic age and a simple/reliable clinical evaluation scheme to determine frailty as a risk factor for poor surgical outcomes.

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 :

Development of tools to assess operative risk and post-operative recover in the elderly would improve surgical outcomes in this growing patient population.

Feasibility and challenges of addressing this CQ or CC :

This at risk population is growing rapidly.

Older patients represent an important, different, and under-studied subgroup of those undergoing cardiothoracic surgery according to the Joint NHLBI-AATS Working Group (http://aats.org/CME/2011-AATS-NHLBI-Symposium.cgi). Due to the aging of the US population and the increased severity of coronary and valve disease in older individuals, the use of cardiothoracic surgery in older patients in relative terms is growing rapidly. Between 1990 and 2008, the percentage of those aged 80 years or older has gone from 8% to 16% of total for bypass surgery and 14% to 30% of total for valve surgery.

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

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39 net votes
56 up votes
17 down votes
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Goal 2: Reduce Human Disease

How should platelet (PLT) transfusions be used to treat active bleeding?

Multiple randomized controlled trials have been performed to evaluate the use of prophylactic PLT transfusions in non-bleeding, thrombocytopenic hematology-oncology patients. However no high-quality data exist to guide PLT transfusions in actively bleeding patients inclduing pediatric and adult medical and surgical patients. After hematology-oncology patients, cardiac surgery patients are the next largest group of PLT ...more »

Submitted by (@bldbuddy)

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

Details on the impact of addressing this CQ or CC :

PLT count is almost always the only laboratory result considered in deciding to transfuse PLTs. But PLT counts provide no information about PLT hemostatic function and its contribution to bleeding. A variety of in vitro coagulation tests have been developed: viscoelastography, whole blood PLT aggregometry, etc. But while testing-based transfusion algorithms may reduce blood product utilization, it has not been established that any in vitro test can either predict or help reduce bleeding. There is a gold standard method to assess clinical efficacy of transfused PLTs: incidence of grade 2 or higher bleeding in clinical trials of thrombocytopenic hematology-oncology patients receiving prophylactic PLT transfusions. No analogous gold standard of PLT hemostatic efficacy exists for therapeutic PLT transfusions to treat active bleeding. There is a pressing need to develop such a standard. Establishing reliable methods for evaluating the effects of PLT transfusion in actively bleeding patients will improve our understanding of how different factors (storage conditions, pathogen reduction etc.) affect the functional performance of PLTs.

Feasibility and challenges of addressing this CQ or CC :

PLT transfusions are administered routinely to support bleeding pediatric and adult medical and surgical patients. Opportunities to conduct clinical trials in various settings (cardiac surgery, neurosurgery, orthopedic surgery, trauma, etc.) are widely available. PLT transfusion is commonly used to support bleeding patients receiving perioperative supportive therapies such as extracorporeal membrane oxygenation (ECMO). These clinical situations represent critical opportunities to improve the care of bleeding patients. This approach will simultaneously facilitate comprehensive evaluation and validation of both current and novel in vitro tests of hemostasis. If a given in vitro test were reproducibly shown to correlate strongly with bleeding reduction caused by PLT transfusion, then by definition that would be a clinically meaningful test. Finally, this line of inquiry will allow assessment of the adverse effects of PLT transfusion in bleeding patients.

Name of idea submitter and other team members who worked on this idea : Terry Gernsheimer, University of Washington, for the 2015 NHLBI for the State of the Science in Transfusion Medicine

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30 net votes
44 up votes
14 down votes
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Goal 2: Reduce Human Disease

Improving Representation of the Elderly in Clinical Research

There is a need to optimize long-term cognitive and functional outcomes in the aging population during and after cardiothorasic surgery, including the development of simple, objective tools to enable risk stratification for vulnerability to neurocognitive deficit. First, cardiothoracic surgical trials and clinical studies should be more "age-representative" and reflect the increasing proportion of the aging population. ...more »

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 :

Many answers would result from including the elderly in ongoing and planned clinical research and trials.

Feasibility and challenges of addressing this CQ or CC :

This population is growing rapidly and available to be studied.

Elderly patients as a group face higher acute risks for complications and death following cardiothoracic surgery or coronary interventions, yet may also gain more long-term benefits from surgery due to their more severe disease. The balance between risks and benefits of surgery may be different in the older patient than in their younger counterparts. Major randomized trials that defined the “standard” for the field (e.g., CASS, VA cooperative, RITA, BARI, STICH) often failed to enroll many, if any, patients aged 75 years or older. The Joint NHLBI-AATS Working Group (http://aats.org/CME/2011-AATS-NHLBI-Symposium.cgi) identified several areas of high priority for cardiothoracic surgery research in the elderly.

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

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24 net votes
37 up votes
13 down votes
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Goal 2: Reduce Human Disease

Neurocardiology – A Challenge for Prevention of CV Disease

There is a need to recognize and study the interdependencies between the brain/peripheral nervous system and the heart/vascular systems in health and disease to develop interventions to detect, treat, and prevent cardiovascular disease.

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 :

Effective new therapies for treatment and prevention of cardiovascular disease

Feasibility and challenges of addressing this CQ or CC :

long recognition of interactions between neural and CV system provide a wealth of background knowledge, while new imaging and electronic designs provide means for administering novel interventions.

Presently it is recognized that the autonomic nervous system plays a major role in the pathophysiology of arrhythmias leading to sudden cardiac death (SCD), and NHLBI supports ongoing studies to determine if modulation of nerves may provide an effective means to reduce the occurrence of ventricular arrhythmias associated with SCD. Already, investigators have suggested that therapies such as right, left, or bilateral cerviocothoracic sympathectomy may provide a novel and cost effective intervention for the prevention of SCD. It is also well known that the sympathetic nervous system is activated during the onset and progression of heart failure. Currently investigators have proposed studies of specific central brain sites and the nerve supply to the heart during chronic heart failure progression to gain a better understanding of this pathway as a therapeutic target for the treatment of HF. This and the translation of results from similar studies is a challenge that should be encouraged.

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

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23 net votes
35 up votes
12 down votes
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Goal 3: Advance Translational Research

Cellular & molecular effects of diabetes on the heart

Diabetes increases cardiovascular disease risk factors. Evidence suggests that diabetes alters contractile and electrical function of the heart, but little is known about the cellular and molecular basis for these changes.

Submitted by (@catherine.proenza)

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

Details on the impact of addressing this CQ or CC :

Develop more effective treatments for cardiovascular disease in patients with diabetes and metabolic syndrome.

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21 net votes
36 up votes
15 down votes
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Goal 1: Promote Human Health

Mechanisms of cardiac aging

The electrical and mechanical function of cardiac myocytes is compromised with age, but little is known about the age-related changes that occur within individual myocytes.

Submitted by (@catherine.proenza)

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

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19 net votes
32 up votes
13 down 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

Voting

19 net votes
37 up votes
18 down votes
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Goal 2: Reduce Human Disease

Fibrosis Across Organs: Bringing Together Investigators of Fibrosis of the Heart, Lungs and Bone Marrow

Fibrosis can affect essentially any tissue or organ, including the heart, lungs and bone marrow. Effective anti-fibrotic therapy has long been elusive, and transplantation has been the only therapy capable of restoring patient function as fibrotic diseases progress to organ failure. Although these diseases present clinically with organ-specific manifestations, they are now thought to share many common pathogenetic mechanisms. ...more »

Submitted by (@amtager)

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

Details on the impact of addressing this CQ or CC :

In the aggregate, diseases characterized by fibrosis have been estimated to account for up to 45% of developed world deaths. Fibrotic diseases addressed by the NHLBI include heart failure with preserved ejection fraction (HFpEF), idiopathic pulmonary fibrosis (IPF), and myelofibrosis (MF), among many others. Each fibrotic disease represents an area of great unmet clinical need, as patients suffer and die with no or limited effective disease-modifying therapies. The impact of developing effective therapies for each of these diseases individually would be great; the impact of developing therapies effective for the entire class of fibrotic diseases across organs would truly be enormous. The clinical burden of HFpEF is staggering – more than 650,000 new patients are diagnosed with heart failure in the US each year, half with diastolic dysfunction. Although not as prevalent, IPF and MF are particularly lethal. IPF has a median survival of approximately three years. MF is arguably the most aggressive of the myeloproliferative disorders and is associated with significantly shortened survival. Although agents such as spironolactone have been unable to treat fibrosis in HFpEF as yet, two anti-fibrotic drugs, pirfenidone and nintedanib, have now been shown to slow progression of IPF, and the oral JAK1/2 inhibitor ruxolitinib has been shown to improve MF survival. These early successes underscore the great impact that developing effective anti-fibrotic therapies will have.

Feasibility and challenges of addressing this CQ or CC :

This challenge could be addressed by funding research efforts to identify and therapeutically target fundamental pathogenetic mechanisms shared by fibrotic diseases across organs. Although fibrotic diseases present clinically with organ-specific manifestations, there has been a growing appreciation of that these diseases share many aspects of their pathogenesis. Fibrosis In many of these diseases results from recurrent or non-resolving epithelial or endothelial injury, followed by over-exuberant or aberrant mesenchymal cell responses. Across all organs, these processes result in the pathologic accumulation of fibroblasts and extracellular matrix, with distortion of organ architecture and loss of organ function. Core pathways leading to epithelial and endothelial cell injury and senescence, to fibroblast accumulation and persistence, and to altered matrix biochemical and biomechanical properties, are now being identified. Therapeutics developed to target these core pathways could have broad clinical applicability. Funding initiatives aimed at better the characterization of core fibrotic pathways already identified, the identification of new core fibrotic pathways, and the development of therapies to target core fibrotic pathways, could allow the NHLBI to simultaneously and cost-effectively address the great unmet needs of the large patients with any of the many devastating fibrotic diseases that affect the heart, lungs and bone marrow.

Name of idea submitter and other team members who worked on this idea : Andrew M. Tager

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16 net votes
20 up votes
4 down votes
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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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14 net votes
21 up votes
7 down votes
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Goal 1: Promote Human Health

Paracrine Signaling in the Heart

We need to improve the understanding of the molecular and physiological bases of paracrine signaling of heart, and use the knowledge gained to develop improved, effective approaches to diagnose, treat, and prevent cardiac disorders.

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 :

Although myocytes comprise approximately three-fourths of the entire volume of mammalian ventricles, they account for only about one-third of all myocardial cells. Ninety percent of the remaining myocardial cells are cardiac fibroblasts which are located primarily in the interstitium. Understanding how complex paracrine signals interact at the molecular, cellular, and organ levels continues to be a challenge to investigators. Clearly, the cardiac fibroblast plays an important role in signaling by its ability to respond to a wide variety of chemical signals that are involved in the paracrine regulation of cardiac function. These and other cardiac paracrine signaling pathways need to be better elucidated before specific clinical interventions targeting them are developed.

Feasibility and challenges of addressing this CQ or CC :

This is presently an understudied area of research. Studies however suggest that paracrine factors released from fibroblasts are likely to play an important role in modulation of heart growth and function. This may be especially so in regulation of STEM cell differentiation and following insults to the adult heart.

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

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13 net votes
27 up votes
14 down votes
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Goal 2: Reduce Human Disease

Cardiac Arrhythmia Factors

What are the genetic and neurohormonal factors associated with cardiac arrthymias, and how might these factors be controlled to reduce arrhythmia incidence? How do we identify patients who are at imminent risk of arrhythmic death?

Submitted by (@nhlbiforumadministrator)

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

Voting

9 net votes
23 up votes
14 down votes
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