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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 : AHA Staff & Volunteers

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 mechanisms leading to the structural and functional defects of common COPD have not been sufficiently clarified for rational new drug development, and disease-modifying pharmacotherapy for common COPD currently is not available. In contrast to common COPD, both CF and AATD are monogenetic conditions associated with protein misfolding and gain or loss of function, and several of the mechanisms underlying their clinical manifestations have been identified. Recent research has pointed to links between CF and AATD on the one hand and common COPD on the other.

"Do AATD and CF inform COPD?" was recently asked at conference that brought together investigators with interest in either CF, AATD or common COPD and provided a forum for scientific discourse among them. The proceedings of the conference will be published in the Annals of the ATS Supplements.

The content highlighted not only phenotypic commonalities among the three conditions but also identified key pathogenic similarities, notably CFTR dysfunction, ER stress and lung cell apoptosis. Preliminary data presented at the conference suggest that agents currently reserved for the treatment of either CF or AATD could have a broader therapeutic spectrum. For example, drugs designed to restore CFTR function in CF could benefit COPD patients with or without AATD. Conversely, alpha-1 antitrypsin, which is administered for the treatment of AATD-related COPD, could benefit CF patients and COPD patients without AATD.

Feasibility and challenges of addressing this CQ or CC :

As Andre Cantin, a scientific committee member and speaker at the conference put it “All participants recognized the value of comparing these uncommon genetic diseases with the more common environmental disease COPD and felt that the research communities should enhance their dialogue. All also recognized that it is a challenging exercise to think of one’s data in the broader context of other diseases outside of one’s usual area – something we do not do enough”.

This, however, is not an insurmountable challenge. The NHLBI has the resources to solicit and sponsor such research that is likely to lead to new therapeutic solutions for common COPD, a condition for which disease modifying treatment currently is lacking.

This compelling questions lends specifically to the strategic goal of promoting basic and translational research that links CF and AATD to common COPD. Importantly though, this platform could apply to additional uncommon genetic conditions and the opportunity to inform common disease.

Name of idea submitter and other team members who worked on this idea : K. Erickson, A. Wanner, MD

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

Name of idea submitter and other team members who worked on this idea : American Thoracic Society member

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

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)? : Critical Challenge (CC)

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 existing data shows that sleep apnea may be moderate risk factor for poor outcomes and complications from surgery but the magnitude of the risk and the degree to which sleep apnea therapy modifies this risk is not known and won’t be determined without larger scale trials. This field desperately needs some randomized trials to answer some of these questions. Trials which randomize patients undergoing some major surgery to a sleep apnea treatment with CPAP if OSA is diagnosed before surgery  vs. treating with CPAP after surgery in the post operative period is one such study that could be performed.

Name of idea submitter and other team members who worked on this idea : ATS Member

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

Details on the impact of addressing this CQ or CC :

Improve targeting of statins to high-risk patients without prior CV disease.

Feasibility and challenges of addressing this CQ or CC :

New guidelines issued last year. Statin and recently ezetimibe are proven to be safe and efficacious.

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 :

Protein cysteine thiols are recognized to be important for multiple signaling and cell biology functions due to unique properties of oxidation/reduction resulting in a 'thiol switch'. However, oxidative modifications of thiols are highly complex involving nitrosation, sulfhydration, sulfenylation, and glutathiolyation among many others. It has become increasingly clear that these posttranslational modifications are associated with cardiovascular and pulmonary pathophysiology. Yet, many important questions remain such as: how these thiol modifications occur during disease and differ from health? How do these thiol switches impact protein function involved in cellular pathophysiology? And can thiol switch manipulation be exploited for therapeutic purposes to maintain cellular and organ health or treat disease? In order to begin to answer these questions, careful and comprehensive investigations are required to understand thiol-switching principals employing a host of molecular, biochemical and pathophysiological approaches.

Feasibility and challenges of addressing this CQ or CC :

Given the significant advances in quantitative analytical chemical and molecular techniques, molecular redox mediators and pathways, non-invasive imagine modalities and comprehensive translational study designs; multiple fields are uniquely poised that could provide significant insight into this critical challenge. Primary objectives would be to establish consensus analytical methodologies, chemical and molecular biology approaches, and cellular and animal models in conjunction with rigorous clinical investigations. Results from efforts at understanding the importance of ‘thiol switches’ will make significant clinical impact on cardiovascular and lung pathogenesis and would feasibly be accomplished in 5-10 years.

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 evolution of the anticoagulation recommendation in pulmonary arterial hypertension (PAH) is a relatively logical one at face value. Early in the modern era of PAH management, a “thrombosis” in the small pulmonary arteries was identified and described; studies since then have demonstrated hypercoagulability in patients with severe disease. Together, these observations led to a theory that in-situ thrombosis contributed to the PAH disease progression and a belief that anticoagulation should be beneficial. The empirical evidence currently supporting this recommendation comes mostly from a retrospective cohort study of the European COMPERA PH registry and a systematic review of 7 retrospective cohort studies that are at least 10 years old—2 of which did not suggest a survival benefit—and in a time where only 4 of the widely used PAH-targeted therapies were approved by the FDA. Purely based on observational evidence with a number of potential biases, warfarin (Coumadin) is widely used in PAH management to this day. Warfarin in this patient population is not without its risks, as some subgroups of PAH patients are at increased risk of bleeding complications based on their disease process alone. Assessing the true benefit of this widely used background therapy could allow clinicians and patients to more accurately weigh the risks and burden of anticoagulation with a true understanding of the survival benefit.

Feasibility and challenges of addressing this CQ or CC :

Addressing this compelling question is indeed feasible through an NIH-sponsored randomized, double-blind, placebo-controlled trial of anticoagulation in patients with certain types of pulmonary arterial hypertension.

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

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

Details on the impact of addressing this CQ or CC :

Enable leveraging existing resources and possible re-purposing of existing resources to address a wide variety of research questions.

This is a cross-study, cross-NHLBI, and even cross-NIH or beyond, need.

Feasibility and challenges of addressing this CQ or CC :

Digitized imaging data files are enormous. Advances in data storage, with corresponding decreases in cost, have enabled storage of these files. For some types of images, data format standards have also arisen.

Many studies have collected data using a wide variety of imaging technologies. While the extracted data have been utilized in analyses and incorporated into shared data resources, additional research could be done on the original images.

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)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The ability of allogeneic blood or marrow transplantation (BMT) to cure diverse non-malignant diseases is well-documented. However, widespread use in diseases such as sickle cell anemia that cause substantial morbidity and shorten life but are not immediately life-threatening, has been limited by transplant-related toxicity and mortality especially in the majority of these patients who lack HLA-matched donors. Several new therapeutic approaches now exist that are promising strategies, separately or in combination, for addressing issues of donor availability, graft rejection, organ toxicity and acute and chronic graft-versus-host disease more effectively. Evaluation and refinement of these therapeutic strategies in both preclinical and Phase I-III clinical trials now offers a real possibility that allogeneic BMT could be applied early in the course of these diseases, allowing normal growth, development, quality of life and lifespan. If successful, allogeneic BMT offers a major advantage over gene therapy approaches even if such approaches become possible in the future; i.e., allogeneic BMT can be done with low-dose, non-toxic conditioning while gene therapy requires high-dose myeloablative therapy which not only can be toxic/fatal to these patients who often have end-organ dysfunction but also universally induces infertility, a major concern of patient groups who usually survive beyond child-bearing years.

Feasibility and challenges of addressing this CQ or CC :

There are now single institution and registry (CIBMTR) data showing that related haploidentical allogeneic BMT using post-transplantation cyclophosphamide (PTCy) produces results similar to those seen with HLA-matched sibling donors. Accordingly, every patient in need of allogeneic BMT now can safely undergo the procedure, including those ethnic groups (such as African-Americans and Hispanics) who are unlikely to find a donor in unrelated registries. Combining PTCy with other approaches for preventing graft-versus-host disease (GVHD) can even eliminate GVHD and transplant-related mortality. Although recurrence of malignant diseases remains an issue, especially as GVHD is eliminated, relapse is not a concern for non-malignant diseases after successful allogeneic engraftment. Moreover, the average cost of allogeneic BMT, about $150K, is a cost-savings over the long-term management of many of these diseases. The NHLBI-funded BMT Clinical Trials Network (CTN) has developed the infrastructure to rapidly and efficiently carry out large multi-institutional BMT trials. Over the last 15 year, thousands of patients have been entered on BMT CTN trials. Of note, African-Americans and Hispanics remarkably represent 30% of the accruals on one such trial, CTN1101, studying unrelated umbilical cord and related haploidentical allogeneic BMT. However, funding for the infrastructure for continuing this work remains problematic, since BMT trials generally lack corporate funding.

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