Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease

Do SCD patients with hemodynamics consistent with pulmonary arterial hypertension (PAH) respond to medications designed to treat PAH?

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 :

What is known about this topic:

1) Case series have demonstrated potential therapeutic benefits for endothelin receptor antagonists, phosphodiesterase 5 inhibitors and prostacyclins in PH of SCD patients

2) Three attempted randomized placebo controlled trials of these agents in SCD patients have not gone to completion and, as a result, were under-powered to demonstrate efficacy.

3) Sildenafil produced an increase in hospitalization for pain crises in this population.

4) Anecdotally, select SCD patients with PAH have hemodynamic and clinical benefits from PAH medications.

5) Approximately ½ of PH in SCD patients have some degree of pulmonary venous hypertension and these medications may not be helpful here.

Feasibility and challenges of addressing this CQ or CC :

Areas of controversy:

1) Only one of the three randomized controlled trials required a PAH diagnosis prior to randomization, so the actual question hasn’t been properly addressed.

2) SCD patients with PAH are different than idiopathic PAH patients in terms of their underlying disease, so possibly the treatment response is different.

3) What are the right clinical trial endpoints for this population?

4) What is the role of SCD specific therapy (hydroxyurea, transfusions) in treating PAH of SCD?

5) How can investigators design a clinical trial which allows for enough patient accrual to achieve its endpoints?

6) What novel therapies can be developed to treat this population?

7) What unrecognized medication toxicities are SCD patients at increased risk for?

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

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Goal 2: Reduce Human Disease

Hypertension in the Pediatric Population

We also wish to draw attention to the rise in the prevalence of hypertension in the pediatric population, mostly as a consequence of the childhood obesity epidemic.

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 :

Additionally, hospitalizations related to pediatric hypertension have doubled over the past decade. These phenomena have clear and profound implications for the future cardiovascular health of the American population. The NHLBI has been instrumental in supporting studies in pediatric hypertension in the past, and we encourage a continued focus on pediatric populations for future hypertension research.

Name of idea submitter and other team members who worked on this idea : American Society of Pediatric Nephrology (ASPN)

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Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease

Does screening for pulmonary hypertension (PH) of sickle cell disease (SCD) alter disease outcomes?

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 :

What is known about this topic:

1) An elevated tricuspid regurgitant jet velocity (TRV) by echocardiography occurs in 1/3 of HbSS adults, 10-25% of HbSC adults and 10-20% of HbSS adolescents.

 

2) An elevated TRV is associated with mortality risk in adults, but not children/adolescents

 

3) Epidemiologically, associations of an elevated TRV with markers of hemolysis and other disease complications (leg ulcers, priapism, proteinuria, etc.) exist.

 

4) Some patients with an elevated TRV have pulmonary hypertension but there is a high false positive rate.

Feasibility and challenges of addressing this CQ or CC :

Areas of controversy:

1) Does screening change outcomes? Currently, there is no established treatment for an elevated TRV. Are there either SCD related therapies (such as hydroxyurea) or treatments for disease associations (such as treatment for proteinuria) that change outcomes?

 

2) Does an elevated TRV predict an increased risk of venous thromboembolic disease, obstructive sleep apnea, asthma or other pulmonary diseases with established treatment?

 

3) What are the implications of an elevated TRV in the pediatric/adolescent population?

 

4) If screening is beneficial, what is the optimal frequency?

 

5) What is the best method of screening and what role does newer technologies such as genomics and proteomics play in identifying a higher risk group for whom screening would be more advantageous?

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

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Goal 2: Reduce Human Disease

Risk factors and treatment options for pulmonary hypertension in Sickle Cell Disease

What are the risk factors and treatment options for pulmonary hypertension related to diastolic dysfunction in Sickle Cell Disease (SCD)?

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 :

What is known about this topic:

 

1) Pulmonary venous hypertension (PVH) related primarily to left ventricular diastolic dysfunction accounts for at least 50% of cases of PH in SCD patients.

 

2) PVH is an independent risk factor for mortality

 

3) Etiology of diastolic dysfunction in this population is unknown as well as the contribution of relative systemic hypertension

 

4) No specific therapies exist for this condition although traditional diastolic dysfunction CHF are at times eomployed. No standard of care exists.

Feasibility and challenges of addressing this CQ or CC :

Areas of Controversy:

 

1) What role, if any, does iron chelation play in disease prevention?

 

2) What role does treatment of systemic hypertension play in prevention and treatment?

 

3) Is obstructive sleep apnea a risk factor for diastolic dysfunction in this population?

 

4) Is there increased risk of VTE in this population?

 

5) Are SCD specific therapies (hydroxyurea, transfusions) beneficial in improving outcomes?

 

6) What is the best means of diagnosing PVH of SCD? Are there ways non-invasively to predict PAH vs PVH in this population?

 

7) Is cardiac MRI superior to echocardiography in evaluating diastolic function in this patient population?

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

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Goal 2: Reduce Human Disease

Molecular mechanism for hypertension and the diverse co-morbidities

What molecular mechanism causes hypertension as well as the diverse co-morbidities in hypertension? We discovered a fundamental mechanism that causes chronic and acute tissue injury due to the action of the powerful digestive enzymes, the same used for daily digestion. In various acute and chronic cardiovascular conditions the compartmentalization of these enzymes fails and they escape into the intestine and systemic ...more »

Submitted by (@gwss00)

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

Details on the impact of addressing this CQ or CC :

- There is a need to identify with genomic, proteomic and zymographic tools the full extend of unchecked digestive and proteolytic enzyme activities in hypertensives. Since unchecked protease activity is transient and depends on daily and monthly cycles, continuous in-vivo measurement techniques need to be developed with next generation sensitivity and specificity. The enzymatic profile of individuals needs to be determined.

- Knowledge of specific enzyme activities in patients will open the opportunity for individualized pharmacological treatment of the fundamental cause of hypertension and its co-morbidities as compared to treatment of multiple symptoms, a strategy, which leads to a significant reduction of costs.

- Identification of the unchecked degrading enzyme activity opens the door to determine the root cause of its activity in the cardiovascular systems, especially its connection to the digestive system. It will be possible to link digestion (including specific digestive enzymes and the protection mechanisms against their escape into the cardiovascular system, the macronutrients and specific food contents) with cell and organ dysfunctions on an omic scale.

- The role of digestive enzymes provides a rational opportunity to establish a link to the protective effect of “calorie restriction” identified in aging research. It will be possible to determine the relationship between aging in hypertension and autodigestion as basis for new interventions.

Feasibility and challenges of addressing this CQ or CC :

The investigation of "autodigestion" as a fundamental mechanisms of various diseases requires the development of new techniques and will profoundly guide thinking about inflammatory diseases (e.g. non-infectious) and their treatment.

 

Study of autodigestion will shed light on cell/tissue molecular degrading mechanisms and in particular on proteolytic destruction of membrane receptors and their impact on loss of cell functions and associated co-morbidities.

 

There is a need to develop omic approaches that identify the degrading process and the breakdown products generated and the role of digestive and other degrading enzymes in the context of specific food consumption.

 

The work fits into all three strategic goals:

 

Promote health, reduce disease and provide translational approaches.

Name of idea submitter and other team members who worked on this idea : Geert Schmid-Schoenbein

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Goal 3: Advance Translational Research

Calcium channels in cardiovascular functions and diseases

Fifty years ago Prof. Harald Reuter of the University of Bern, Switzerland obtained the first experimentally supported evidence that the calcium channel is a physiologically distinct entity. Further stimulated by the synthesis of the dihydropyridine calcium channel blocker nifedipine, the field of calcium channel research rapidly encompassed cardiovascular and other powerful biomedical directions.

Submitted by (@soldatovn.humgenex)

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 coming Theme Issue of Current Molecular Pharmacology "50th Anniversary of Calcium Channel Research: Biomedical Perspectives" brings together leading experts in calcium channel research with the aim of discussing new ideas and recent developments in research of voltage gated calcium channels and calcium signaling with specific focus on biomedical perspectives. This CMP Theme issue may be particularly interesting for those who are involved in molecular cardiovascular research. Please see further: http://benthamscience.com/journal/upcoming-articles.php?journalID=cmp

Feasibility and challenges of addressing this CQ or CC :

In 2010, heart diseases cost the United States $316.4 billion in health care services, medications, and lost productivity (Circulation 2010, 121, e1). Search for new therapeutical targets associated with the family of calcium channels becomes an increasingly powerful future direction.

Name of idea submitter and other team members who worked on this idea : Nikolai M. Soldatov, Ph.D., Guest Editor, and authors of 23 papers of the CMP Theme Issue

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Goal 2: Reduce Human Disease

Identification and validation of surrogate endpoints for long-term morbidity in Sickle Cell Disease

Research in sickle cell disease (SCD) has mostly focused on preventing or treating acute medical events, such as vaso-occlusive pain, acute chest syndrome, and, in pediatric patients, acute strokes. Chronic SCD complications such as chronic kidney disease or pulmonary hypertension, develop over decades, thus are poor choices for clinical trial endpoints. There is a great need to develop surrogate endpoints that predict ...more »

Submitted by (@hulbertm)

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

Details on the impact of addressing this CQ or CC :

Longitudinal cohorts of SCD patients, spanning childhood and adulthood, with biobanking DNA, plasma, and serum, and standardized clinical and imaging assessments will allow identification predictors of negative clinical outcomes. An NHLBI-funded national SCD clinical registry with biobanking will be necessary to validate any surrogate endpoints.

Name of idea submitter and other team members who worked on this idea : Monica Hulbert

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Goal 3: Advance Translational Research

Guideline effectiveness in treating COPD patients with comorbidities vs. those without

What is the effectiveness of guideline recommendations for chronic obstructive pulmonary disease (COPD) care in patients with multimorbidity, including angina, heart failure, atrial fibrillation, diabetes mellitus, hypertension, and osteoporosis, vs. patients without these conditions?

Submitted by (@spencer)

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

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Goal 2: Reduce Human Disease

Development of right ventricular-targeted therapies in pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. A great increase in the treatment armamentarium has been noted for this rare disease in the past 20 years, with 12 new PAH-targeted therapies. Though these therapies do improve cardiac performance, this is most likely due to their primary ...more »

Submitted by (@katherinek)

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

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Goal 3: Advance Translational Research

Increasing Regenerative Medical Strategies in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Current PAH therapies mainly act of the vasoconstrictive component of the disease; however there is a widely accepted view that another contributor to the disease is an abnormal overgrowth of cells that line the pulmonary arteries, which ...more »

Submitted by (@michaelg)

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

Details on the impact of addressing this CQ or CC :

In the past twenty years, 12 PAH targeted-therapies have been approved by the FDA. This increase in disease state awareness and in the treatment armamentarium have contributed to an increase in average survival from 2.8 years to an estimated 8-10 years. However, current treatments primarily address the vasoconstrictive component of the disease and do not address the now accepted theory of post-apoptotic overgrowth of hyperproliferative cells of the pulmonary vessels. A number of circulating stem and progenitor cells, derived from the bone marrow, have been identified that could have roles in repair of the pulmonary vascular system when interacting with the quickly, abnormally growing cells in the lung vessels. Work in this area has been named as a future research opportunity in the NHLBI-ORDR Strategic Plan for Lung Vascular Research (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

Basic and translational research support is needed—including high-throughput approaches such as phage display and large-scale proteomic analysis—to better understand the relationship between circulating bone marrow-derived cells, lung-resident stem and progenitor cells, and endothelial cells of the pulmonary arterial system.

Name of idea submitter and other team members who worked on this idea : Pulmonary Hyeprtension Association, Michael Gray, Katie Kroner

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Goal 2: Reduce Human Disease

In pulmonary arterial hypertension (PAH), how can right ventricular function be improved in the setting of increased afterload

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Significant improvements have been made in medical management with through approved pulmonary vasodilator therapies. However, long-term right ventricular afterload reductions have still not yet been achieved. The process by which the ...more »

Submitted by (@katherinek)

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 of many components of the PAH disease state have evolved significantly in the past thirty years. When initially described by an NIH registry, in a time where pulmonary transplantation was the only treatment for PAH, the average life expectancy of PAH patients was estimated to be 2.8 years. Since then, 12 PAH-targeted therapies have been approved by the FDA; these therapies primarily act by dilating the pulmonary arteries in order to allow blood to flow easier through the pulmonary vascular system. Despite these advances and complex therapies, long-term afterload reduction is not achievable in most PAH patients. Patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle. Little is known about how and why the RV progresses from hypertrophy to full RV failure, the diagnostic signs indicating early RV failure, and how best to intervene to support the failing ventricle. Knowledge in this area is critical, however, as the RV is able to recover in many patients with severe PAH after lung transplantation. The relationship between the lung vasculature and cardiac function, and specifically a characterization of RV failure, was included as a research opportunity in the Strategic Plan for Lung Vascular Research in an NHLBI-ORDR Workshop Report (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CQ on how right ventricular function can be improved in the setting of increased afterload 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 (LV), and subsequently responds differently to changes in pressure, neurotransmitters, hormones, and pharmaceutical therapies to name only a few. However, when identified, these RV biologic distinctions can be further explored to develop a better understanding of RV failure and potential points of intervention.

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

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Goal 2: Reduce Human Disease

How can we increase the pharmaceutical clinical research of targeted therapies in pediatric PAH patients, including encouraging

Clinical research, especially randomized pharmaceutical clinical trials, poses many unique challenges compared to research in adult subjects. In pulmonary arterial hypertension, a disease characterized by high blood pressure of the lungs with increased pulmonary vascular resistance leading to right ventricular failure, there are 12 FDA-approved PAH-targeted therapies for adults. None of these medications are currently ...more »

Submitted by (@katherinek)

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

Details on the impact of addressing this CQ or CC :

Pulmonary arterial hypertension is a heterogeneous condition generally characterized by high blood pressure in the lungs and increased pulmonary vascular resistance that leads to right heart failure if left untreated. Though some causes of PAH are seen in both adult and pediatric populations, some etiologies are seen exclusively in pediatric populations, including persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, lung hypoplasia, and alveolar capillary dysplasia. Despite these differences in disease etiology, and known physiologic differences in pediatric populations, inhaled nitric oxide (iNO) in the acute setting is the only approved medication for PAH treatment in children. A number of issues have decreased pediatric PAH pharmaceutical research, including protection of the pediatric population as vulnerable subjects, principle of scientific necessity, balance of risk and potential benefit, parental consent/child assent, and feasibility of pediatric clinical trial design and implementation. Encouraging clinical trials of existing adult medications and potentially emerging, novel agents specifically for pediatrics—either through direct sponsorship or regulatory incentives—would not only lead to better outcomes for pediatric PAH patients, but potentially to a better and more comprehensive characterization of the developing pulmonary vascular system and right ventricle.

Feasibility and challenges of addressing this CQ or CC :

Several challenges exist for addressing this critical challenge. First, there are a number of differences between conducting clinical research in pediatric populations compared to adult populations. This not only includes the broad items referenced above, but items as noted by Rose and colleagues related to clinical trial design and analysis including (1) accepted age-matched normal ranges for laboratory values; (2) requirements for the validation of clinical endpoints for the assessment of efficacy and safety; and (3) standards for long-term safety monitoring and pharmacovigilance (Rose K, et al. NEJM 2005). Sponsorship of this type of clinical research is a second concern, which could either be mitigated by direct support from the National Institutes of Health of pediatric PAH clinical trials or in regulatory changes incentivizing pediatric clinical research in rare diseases.

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

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