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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 high prevalence of chronic cardiovascular and lung diseases has created burden in increasing healthcare costs and high mortality rates in the US compared to other developed countries. Even so, they remain among the most preventable health problems. A national surveillance system for chronic cardiovascular and lung diseases would enable data-driven decision-making about public health strategies for prevention, management, and cost containment.

Feasibility and challenges of addressing this CQ or CC :

A 2011 Institute of Medicine (IOM) report concluded that a coordinated surveillance system is needed. It proposed a framework for such a system that would integrate existing information through collective efforts of multiple stakeholders. The time is right to gain from and build upon numerous ongoing broad initiatives in biomedical Big Data, including growing health IT adoption mandated by the HITECH Act, ONCHIT efforts to achieve health IT interoperability, the NIH BD2K initiative, and the multiorganizational network participating in FDA Mini-Sentinel, HCS Collaboratory, and PCORnet, among others. The NHLBI is well-positioned to lead, develop and implement the IOM’s recommended framework and system. (IOM report - http://www.iom.edu/Reports/2011/A-Nationwide-Framework-for-Surveillance-of-Cardiovascular-and-Chronic-Lung-Diseases.aspx)

Existing data sources (i.e., population surveys, registries, cohort studies, administrative data, and vital statistics) do not individually provide nationally representative data, cannot be linked, and are not currently readily accessible to all levels of users. One potential way to build such a system is to integrate and expand existing data sources.

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

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 tools for studying sex differences. It is envisioned that the development of new tools will improve the comparison of males and females used in research and uncover sex-biased facts that protect from disease, such as if being of the male sex protects from pulmonary arterial hypertension. Additionally, improved tools and training will better enable the researcher to ask important clinical questions, such as whether acute estrogen therapy improves clinical outcomes in post-MI males. Further, unmet clinical needs where sex differences may predominate and influence disease outcome, such early menopause or microchimerism, may be more readily undertaken and tracked. By creating more reliable and user-friendly databases, the quality and quantity of evidence-based medicine should increase and thereby improve, clinical decision-making for health professionals.

Feasibility and challenges of addressing this CQ or CC :

The NIH is in the process of developing new policies for inclusion of both sexes in experimental studies.

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

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

Details on the impact of addressing this CQ or CC :

Extracorporeal membrane oxygenation (ECMO) is being used earlier in adult and pediatric patients disease course to support them through reversible causes of heart and/or lung failure. Therefore, it's use has increased and, I speculate, will continue to increase.

Hemostatic complications, such as thrombosis and intracranial hemorrhages, limit the duration and intensity of ECMO support. Not surprisingly then, multiple studies show that ECMO patients who suffered a hemostatic complication have worse outcomes.

Every ECMO center builds their circuit a little different and has their own anticoagulation protocol, but yet, no one center treats enough patients on ECMO to power any robust study. To date, anticoagulation in ECMO is driven by some case series, retrospective single-center studies, and experience. We need multi-institutional studies to study this so that we can harness this technology to its fullest so that we can save lives and minimize morbidity.

Feasibility and challenges of addressing this CQ or CC :

This CC is feasible in that the community of ECMO providers is small and cooperative and anticoagulation is a top concern amongst ECMO physicians. Multi-center study proposals have been submitted but, to date, not funded.

Obstacles include:

- The urgency: ECMO is usually initiated emergently so accruing and consenting patients (or their power of attorney) under the duress of ECMO is difficult, but as we have proven, is possible

- Vulnerable population: Many (if not most) patients who go on ECMO are neonates.

- Patient sample size. A huge ECMO center does 40-60 ECMO cases/year so many centers would need to be involved to accrue an adequate sample size

- Patient heterogeneity: Patients who are initiated on ECMO are very different. Differences in age, degree of heart failure versus lung failure, mechanism of lung and/or heart failure, whether they are post-operative and even who their surgeon is can all affect rates of hemostatic complications

- Variable clinical practice: Every ECMO center runs their ECMO different than the next so we would need to standardize some procedures before we could do a multi-center study.

Name of idea submitter and other team members who worked on this idea : Trish Wong

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 creation of one or more Research Consortia devoted to research in Apheresis Medicine would allow for the establishment and support of a core group of investigators and institutions representing key specialty areas across the spectrum of Apheresis Medicine. An initial focus would be translational research priorities. In addition, we believe that a strong U.S. based consortium would facilitate participation of international investigators and societies, which would improve patient accrual on studies, especially those patients with rare disorders or who have rare indications for apheresis therapy. Such a group would significantly enhance the likelihood of completing high quality studies.

There is increasing national interest in developing new registries, bio-repositories and data-repositories. Very often such efforts do not include information regarding apheresis nor do they consider apheresis information as being important data points. A centralized, well organized and sustainable registry, either established and/or new for Apheresis Medicine, would be of great value to study the outcomes of therapeutic apheresis for different disease conditions. This need is particularly relevant for rare disorders and rare indications, for which a pilot effort is already being undertaken and sponsored by ASFA- the American Society for Apheresis.

Feasibility and challenges of addressing this CQ or CC :

Feasibility: There are hundreds of thousands apheresis procedures performed each year in the US. Many of these procedures are performed in tertiary and quaternary academic medical centers. These centers have experience in education, basic science, translational research and clinical trials. Despite the low frequency of some diseases there is a real possibility of performing clinical trials in the context of multicenter consortium. Such consortium could also assist in development of new projects related to Apheresis Medicine (both basic science and clinical) which then can proceed to clinical trials quickly as the appropriate infrastructure will be created within the consortium. This infrastructure would also serve education of the new investigators.

Challenges: Standardization of approaches between different medical centers might be initially difficult, but as it has been shown many centers follow in their clinical practice ASFA designated indications. Setting up research priorities for the consortium might be challenging as well as accrual patients to clinical trials within the consortium. Though standardization of the apheresis devices is not feasible, this could be mitigated by appropriate study designs. The number of investigators in apheresis medicine is limited but the consortium may serve as a great platform to expand its numbers through collaborative efforts of involved centers.

Name of idea submitter and other team members who worked on this idea : Zbigniew M. Szczepiorkowski, Yanyun Wu on behalf of ASFA

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 the role of chronic inflammation in chronic lung and vascular diseases will impact both the HIV population and our growing U.S. aging population. Approaches to the question could include:

1.. Causes of chronic inflammation

- Antiretroviral drugs, persistent HIV, persistence of other viruses, exogenous retroviral elements, exosomes, other epidemiologic exposures

2. Downstream mechanistic effects of chronic inflammation

- Alterations in gene regulation, alterations in oxidative stress, direct tissue damage

3. Clinical outcomes of chronic inflammation

- Lung – COPD, pulmonary HTN, cancer, interstitial lung disease, asthma.

- Vascular compartment - premature coronary and vascular disease

- Does HIV-infection itself require alterations in treatment modalities for lung disease

- Does HIV infection itself alter the outcome of chronic lung disease?

4. Therapeutic options

- Directed against the cause – i.e. antivirals.

- Immune specific targets against inflammatory mediators

Feasibility and challenges of addressing this CQ or CC :

The critical challenge for this question lies in the fact that complications caused by chronic inflammation such as COPD and coronary disease will by definition take years to develop. Intervention trials will take even longer. This is not like the early HIV epidemic, where complications were primarily infectious and could be seen and addressed quickly. Because of this chronic nature, it will necessary to try and establish cohorts with long term follow-up. Furthermore, it will be critical to have well defined appropriate HIV-uninfected cohorts to compare the HIV-infected population to.

Name of idea submitter and other team members who worked on this idea : Homer L. Twigg III on behalf of the INHALD Consortium

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

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

Details on the impact of addressing this CQ or CC :

If short terms outcomes are improved but not long term outcomes, we are only adding costs and not improving population health

Feasibility and challenges of addressing this CQ or CC :

Will require a large prehospital clinical trials network and ideally also a current national registry of OHCA to address secular changes in other confounding variables

Name of idea submitter and other team members who worked on this idea : Mohamud Daya

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

Details on the impact of addressing this CQ or CC :

Understanding the pathophysiology and risk factors of right heart failure in the context of LVAD use might lead to preventative and therapeutic options for these patients.

Feasibility and challenges of addressing this CQ or CC :

Current resources in terms of a National Registry for VADS (INTERMACS) exists and can be leveraged.

While we have a substantial understanding of the risk factors associated with poor outcomes of patients with heart failure and left ventricular dysfunction, much less is known about the syndrome of heart failure and right ventricular (RV) dysfunction. Right-sided heart failure occurs in approximately 20% of patients receiving LVAD support. Investigation into the pathophysiology of right ventricular failure and its consequences following LVAD support, including identification of risk factors and treatment strategies, remains a high priority according to the Joint NHLBI-American Association for Thoracic Surgery (AATS) Working Group convened in 2011 (http://aats.org/CME/2011-AATS-NHLBI-Symposium.cgi). Development of new devices designed to optimally support the RV are warranted.

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

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

Details on the impact of addressing this CQ or CC :

Opening the program to all FDA approved drugs would benefit development of the most useful repurposed therapeutics. The goal should not be focused upon drugs that large corporations still hold license to, but opened to therapeutic development that helps people, regardless of the size of the corp. Another advantage is that the program could then help small companies, startups, and generic companies develop new uses for drugs proven safe.

Feasibility and challenges of addressing this CQ or CC :

Of course, large corporations can claim that they have the best chances of marketing a repurposed drug, therefore investment should be in areas and drugs they control. The reality is, no matter which entity does the work for repurposing, a successful project will likely be bought and marketed by big Pharma anyway. So the focus should be on repurposing drugs for disease that have few therapeutic options, with exemplary benefit efficacy and low rosk, ect., The focus should not be on a list of drugs submitted by

Name of idea submitter and other team members who worked on this idea : K. Jones

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

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 : Desai

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

Details on the impact of addressing this CQ or CC :

Since 2006, 12 medical therapies for PAH have been approved by the FDA, which have increased survival of this rare disease from around 2.8 years to approximately 9 years; these therapies primarily act by dilating the pulmonary arteries in order to reduce pulmonary vascular resistance to blood flow. However, patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle (RV). Despite patients ultimately dying from RV failure, little is known about the effect of the currently available PAH-targeted therapies on RV functional support. Prostacyclins, PDE5i, and sGC agonists are thought to enhance RV contractility—though the long-term effects remain unknown—while ERAs are thought to reduce it. The direct RV effect of some potential therapies targeting the pseudo-malignancy theory of PAH is a concern, as these therapies seek to reduce the hypertrophy and angiogenesis that may actually be supporting the adapting RV. Further, therapies targeting the ventricle directly have historically been centered on the LV—for example β-adrenergic receptor blockers and RAS inhibition—and either remain controversial or without data in the RV. There remains no identified RV-specific therapy to either provide support through increase contractility or molecularly prevent the progression from RV hypertrophy to ultimate failure.

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CC on the lack of RV-targeted therapies for the treatment of PAH is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle, and subsequently responds differently to autocrine, paracrine, neuroendocrine, pressure, and pharmaceutical changes to name only a few. However, when identified, these RV biologic distinctions can be translated and tested clinically to more comprehensively and appropriately treat the RV-arterial uncoupling ultimately leading to right heart failure: through both reduction in afterload and an increase in contractility.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA