Strategic Goal: 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)

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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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Strategic Goal: 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)

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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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Strategic Goal: Goal 2: Reduce Human Disease

Blood Pressure Recommendation

What should be the systolic blood pressure goal for pharmacological treatment, and should it vary by age or by cardiovascular disease (CVD) risk category?

Submitted by (@nhlbiforumadministrator)

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

Feasibility and challenges of addressing this CQ or CC :

Despite fifty years of clinical trial research and forty years of national guideline activity, important clinical questions remain under intense scientific debate. The importance of these questions are underline by the scientific consensus that hypertension is most important cardiovascular risk factor globally, in fact, more important than even tobacco use.

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

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Strategic Goal: Goal 2: Reduce Human Disease

Would patients with pulmonary arterial hypertension (PAH) benefit from background anticoagulation in addition to their PAH-targe

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. For several decades, oral anticoagulation has been recommended by some societies for patients with a specific form of PH called pulmonary arterial hypertension. However, the evidence currently supporting this recommendation is very limited. To date, no prospective randomized clinical trial has been completed ...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 :

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

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Strategic Goal: Goal 2: Reduce Human Disease

A Program of Research in the Prevention of Chronic Heart Failure

There is a need to improve identification and surveillance of persons at risk for heart failure and pathological ventricular remodeling prior to development of clinically overt heart failure.

Submitted by (@nhlbiforumadministrator)

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Substantially reduce the age-adjusted incidence and population burden of chronic heart failure.

Feasibility and challenges of addressing this CQ or CC :

The big data and omics revolutions have made it feasible to collect and analyze a variety of data in large numbers of persons within a relatively short time. A very large sample size provides excellent statistical power. Also, the public health and economic magnitude of the problem create the urgency needed to address the critical challenge expeditiously.

Chronic heart failure (HF) is easily the most common and growing cardiovascular cause of hospitalization and impaired functional status and quality of life in the U.S. and much of the world. This is the case despite improved pharmacologic and lifestyle treatment of HF, as well as improved control of blood pressure in the general population. While some HF in the very elderly may reflect the aging process, the epidemiology suggests that most incident cases could be prevented or postponed for years. Also, there are major ethnic and socioeconomic disparities in the incidence of HF.

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

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Strategic Goal: Goal 2: Reduce Human Disease

How can we non-invasively, but still accurately, measure blood pressure in the pulmonary arteries?

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. The gold standard for measuring pressures in the pulmonary arteries is a right heart catheterization, where a special catheter is guided through the right side of the heart and into the pulmonary artery, the main vessel carrying blood to the lungs. This measurement is essential, as it allows physicians and ...more »

Submitted by (@katherinek)

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

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i. In patients with pulmonary hypertension, the use of multiple tests to characterize the type and severity has long been recommended by global experts; one commonly used diagnostic algorithm recommends more than ten different tests to accurately define this complex, heterogeneous disease. Despite the algorithm used, to confirm a diagnosis of one specific type of PH, pulmonary arterial hypertension (PAH), one must always directly measure the pressures in the heart and pulmonary artery through a right heart catheterization (RHC). Complications for this procedure are rare, but not non-existent with potentially 1 in every 100 patients having a right heart catheterization experiencing a serious adverse event (Hoeper MM 2006). Patients would significantly benefit from a non-invasive method of quantifying their pulmonary artery pressures and/or disease progression, but to date this has not been possible with echocardiography due to measurement errors (Laver 2014), CT scan due in part to measurement inconsistencies (Alhamad 2011), and cardiac MRI due to lack of standardization and multicenter trials (Peacock 2013). Not only would wider utilization of a non-invasive method of measuring pulmonary artery pressures and disease progression potentially reduce the risk from RHC, depending on the modality it could lead to earlier diagnosis of this progressive disease and/or application in countries where RHC is less common.

Feasibility and challenges of addressing this CQ or CC :

Addressing a non-invasive method of measuring pulmonary artery pressures requires investment in both technology and multicenter clinical trials to validate these measures.

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

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Strategic Goal: 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)

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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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Strategic Goal: 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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Strategic Goal: Goal 2: Reduce Human Disease

Hypertension Treatment Metrics

What goal and what should be the threshold to initiate hypertension treatment?

Is a risk based approach most relevant?

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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Strategic Goal: Goal 2: Reduce Human Disease

Optimization of Existing Therapies for Sickle Cell Disease

How can the safety, dosing and benefits of existing therapies for sickle cell disease such as hydroxyurea, be optimized in order to increase its efficacy and improve patient adherence?

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

Details on the impact of addressing this CQ or CC :

Hydroxyurea is a widely available disease-modifying therapy for sickle cell disease (SCD), but its effectiveness is currently limited by inadequate utilization, and less than optimal response. Research is needed to improve adherence to this evidence-based therapy and emphasis needs to be placed on determining whether therapy with hydroxyurea can prevent or even reverse organ dysfunction. In addition, research identifying new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease, and pulmonary hypertension will be valuable in the management and treatment of SCD.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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Strategic Goal: Goal 2: Reduce Human Disease

What is the optimal treatment goal for hypertension?

In adults without diastolic hypertension (DBP ≥ 90 mm Hg), what is the best way to determine at what systolic blood pressure should treatment be initiated?

Submitted by (@nhlbiforumadministrator)

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

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The failure to resolve the debate about what is the appropriate goal for treatment of systolic hypertension could adversely effect the progress we have made in reducing the level of systolic blood pressure among the one third of adults with hypertension. At the heart of this debate is what is the optimal balance between lowering systolic blood pressure versus causing adverse consequences in those who are being treated for hypertension.

Feasibility and challenges of addressing this CQ or CC :

Because the existence of large clinical research networks with electronic medical records and use of generic drugs, all mean that a large pragmatic trial is definitely feasible.

Despite fifty years of clinical trial research and forty years of national guideline activity, important clinical questions remain under intense scientific debate. The importance of these questions is underlined by the scientific consensus that hypertension is the most important cardiovascular risk factor globally, in fact, more important than even tobacco use. Further hypertension research could be important because of the role of hypertension not only in CVD, but also in chronic kidney disease, stroke, and possibly in dementia and age related cognitive decline.

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

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Strategic Goal: Goal 2: Reduce Human Disease

Anti-angiogentics in pulmonary hypertension

Would anti-angiogenic therapeutics prevent patients with pulmonary hypertension from worsening?

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

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