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)

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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

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)?

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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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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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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)

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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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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)

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- 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 2: Reduce Human Disease

Biomarkers of Pulmonary Hypertension

What are informative and clinically relevant biomarkers of pulmonary hypertension (PH)?

Submitted by (@nhlbiforumadministrator)

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This research emphasis would help identify novel pulmonary hypertension biomarkers of disease risk and progression that can be used for early detection or as outcome measures in prevention trials or treatment of PH, which is a disease currently still not curable with high mortality rate.

Feasibility and challenges of addressing this CQ or CC :

NHLBI Division of Lung Diseases just launched the multi-center PVDOMICS research program last September that will enroll ~1,500 patients in the next 5 years for deep phenotyping PH. PVDOMICS will provide a perfect foundation and platform for this proposed featured study about informative and clinically relevant biomarkers of PH, and make answering this proposed question more feasible in the next 5-10 years.

Although significant advances in the treatment of pulmonary hypertension have been made in the past two decades, currently pulmonary hypertension remains a devastating disease without many clinically relevant and specific biomarkers available. Novel new informative and clinically relevant pulmonary hypertension biomarkers would greatly help advance the subtype-specific early diagnosis and precision treatment of this disease that could potentially decrease the mortality of PH.

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

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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?

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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

Critical Challenge

• One of the most important public health issues the Nation faces is the rising incidence of heart failure. HF incidence rates have risen faster than predicted. The prevalence will increase as better and more therapy becomes available. While heart failure is the biggest ticket item in the Medicare budget, the cost to society will increase more than it has already. But much HF can be prevented or onset prolonged. Investing ...more »

Submitted by (@tsansone)

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See attached file

Feasibility and challenges of addressing this CQ or CC :

Critical Challenge

Name of idea submitter and other team members who worked on this idea : ASH Officers, Committee Members

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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)

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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)

Details on the impact of addressing this CQ or CC :

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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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

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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