Showing 10 ideas for tag "dysfunction"

Goal 3: Advance Translational Research

TREATMENT OF SEPSIS-MULTIPLE ORGAN DYSFUNCTION SYNDROME (MODS) UTILIZING APHERESIS BASED STRATEGIES

Sepsis, a systemic inflammatory response to infection, is the most common cause of death in non-cardiac intensive care units. The incidence and severity of sepsis have increased over the last two decades. With advances in supportive care, sepsis carries a mortality that averages 17%, however, this figure increases to 50 - 80% in Multiple Organ Dysfunction Syndrome (MODS), defined as failure of 3 or more organ systems.... more »

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

Details on the impact of addressing this CQ or CC

Despite many attempts, therapeutic trials using pharmacologic agents to interrupt specific pathways of inflammation and coagulation have been unsuccessful. The failed targeted therapies include the administration of corticosteroids, monoclonal antibodies to TNF, soluble TNF receptor, antithrombin (AT), activated protein C, and tissue factor pathway inhibitor. Because it is non-selective, plasma exchange has the potential to remove deleterious mediators and restore anti-inflammatory/anticoagulant factors consumed in sepsis/MODS. There is evidence that some of the implicated mediators of sepsis can be effectively removed by plasma exchange, eg, TNF alpha and endotoxin. In addition, the normal regulatory molecules consumed during the systemic inflammatory process, such as AT, proteins C and S, and ADAMTS-13 would be replaced, which may influence the pathophysiology of MODS/sepsis. However, the mechanism of action of plasma exchange, whether removal of inflammatory mediators of sepsis or modulation of the later consequences of MODS such as sustained endothelial activation, remains unclear at the present time. Other apheresis based strategies also have been attempted but their results also require confirmation by well-designed clinical trials to answer the question of their value in treatment of sepsis.
Development of apheresis strategies which address the pathophysiology of sepsis and identify responsive patient populations would have a great societal value

Feasibility and challenges of addressing this CQ or CC

Feasibility: the large number of patients who develop sepsis provides for significant number of potential patients who can be enrolled. More sophisticated methods of enrollment may help as many patients are not capable of providing informed consent. Establishing an apheresis consortium and collaboration with intensive care physicians will be an important step in assuring appropriate accrual of patients. The availability of apheresis devices is likely to be high in the tertiary/quaternary care medical centers where these studies can be performed. Animal models of sepsis are being investigated and are necessary for studies evaluating pathophysiology; though some apheresis strategies can be moved to clinical studies without additional preclinical developments.

Challenges: Identification of the patient population which responds optimally to apheresis based strategies is critical to the development of a randomized clinical trial. One study has indicated that it would be the critically ill pediatric population; however, the critically ill adult population is the largest affected group). Given the equipoise of using apheresis based strategies in the treatment of sepsis/MODS, finding patients to randomize is unlikely to be difficult. Other potential challenges include the cost of developing randomized clinical trials using apheresis, competition with other pharmacology based strategies, center bias, and the timing for initiation of the apheresis.

Name of idea submitter and other team members who worked on this idea Zbigniew M. Szczepiorkowski; Joseph Kiss, Ed Wong on behalf of ASFA

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115 up votes
18 down votes
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Goal 2: Reduce Human Disease

Fundamental stress-response mechanisms in the heart.

What are the primary molecules and cellular signals associated with prolonged hypertensive stress that cause adverse myocardial tissue remodeling, and what strategies that prevent or reverse adverse remodeling can be developed and tested?

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

Details on the impact of addressing this CQ or CC

Could potentially contribute to the development of new therapies for heart disease and cardiomyopathies.

Feasibility and challenges of addressing this CQ or CC

Yes, addressing this CQ may be feasible. Since it is likely that a multitude of signaling mechanisms are involved, an unbiased, global approach may be necessary to identify the key molecular pathways. However, experimental challenges remain and even developing appropriate animal models has been challenging.

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

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21 up votes
7 down votes
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Goal 1: Promote Human Health

New Approaches to study interactions of blood cells with components of the vascular wall

To eventually modulate pathologic communication processes employing new therapeutics, there is a need to better understand the transcellular communication between blood cells and components of the vascular layer in vivo.

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

Details on the impact of addressing this CQ or CC

A better understanding of this largely unrecognized and underappreciated form of transcellular communication would allow us to use the information to not only detect disease at its very earliest stages, but perhaps also modulate pathologic communication processes employing new therapeutics.

Feasibility and challenges of addressing this CQ or CC

It is now feasible to address this CQ because of the availability of techniques such as atomic force microscopy, multi-photon intravital microscopy, computational and experimental approaches.

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

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25 up votes
10 down votes
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Goal 2: Reduce Human Disease

Triggers of pulmonary dysfunction in Duchenne

Pulmonary function generally remains stable in Duchenne until loss of ambulation. What is the trigger that occurs at loss of ambulation that initiates the cascade of pulmonary dysfunction?

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

Details on the impact of addressing this CQ or CC

: recommendations guiding care indicate that pulmonary function remains normal, requiring little or no monitoring prior to loss of ambulation. This finding has remained consistent both prior to, and with the advent of, corticosteroid therapy. It has been difficult to identify what triggers the cascade toward pulmonary dysfunction that, presumably, begins with nocturnal hypoventilation.

Feasibility and challenges of addressing this CQ or CC

gathering natural history data and the identification of biomarkers consistent with the onset and severity of pulmonary dysfunction in Duchenne, would allow an accurate delineation of pulmonary function and identify the need for respiratory assistance. A challenge to address is that there is controversy around which measures of pulmonary function most accurately identify the degree of pulmonary dysfunction present and respiratory assistance required. Discussions are needed around which guidelines for obtaining and evaluating spirometery are most appropriate and beneficial for this population. Given the sophistication of ongoing efforts in the natural history of Duchenne, by making the commitment of resources to longitudinal evaluation of pulmonary status, in parallel with other measures, it should be feasible to address this question

Name of idea submitter and other team members who worked on this idea Parent Project Muscular Dystrophy

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18 up votes
5 down votes
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Goal 2: Reduce Human Disease

Mechanism of Cardiopulmonary dysfunction in Duchenne

What is the exact mechanism affecting the cardiopulmonary cascade of events that occurs in Duchenne?

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

Details on the impact of addressing this CQ or CC

Very little is truly known about the cardiopulmonary cascade in Duchenne. While patients are tested (pulmonary function testing, sleep studies) and encouraged to use assistive devices (cough assist, non –invasive and invasive assisted ventilation), we have no insight into exactly what is happening to the diaphragm, accessory muscles, effects on the heart, etc. that results in sudden death. The investigation of this area is vital to the well being of this patient population, and represents a gap in both research and care.

Feasibility and challenges of addressing this CQ or CC

identifying the exact mechanisms of the cardiopulmonary decline in Duchenne would allow the development and implementation of appropriate interventions, delaying, and possibly, preventing this cascade of events that lead to sudden death in this disease. The implications for Duchenne are tremendous. Likewise, the implications for other muscular dystrophies resulting in cardiopulmonary deaths, as well as other diagnoses resulting in cardiomyopathy, cardiac and pulmonary failure, would benefit as well.

Name of idea submitter and other team members who worked on this idea Parent Project Muscular Dystrophy

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2 net votes
7 up votes
5 down votes
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Goal 2: Reduce Human Disease

Targeting Preclinical Diastolic Dysfunction to Prevent Heart Failure

Heart failure (HF) affects over 5 million American adults, and projected estimates show growth of this epidemic by 25% over the next 15 years as the population of the United States continues to age. Heart failure with preserved EF (HFpEF) encompasses 50% of all heart failure cases. Preclinical diastolic dysfunction (PDD) is defined as normal systolic function, moderate or severe diastolic dysfunction determined by Doppler... more »

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 currently no FDA approved therapy for HFpEF and yet HFpEF makes up 50% of all HF population. The prevalence of PDD (ACC/AHA Stage B HF) is abt 28% of the general population and these patients do not have symptoms of HF. Understanding the pathophysiology of PDD may leady to the development of therapeutic strategies to prevent the development of HFpEF. This would decrease the burden of HF impact public health and be cost-effective, similar to the use of vaccine to prevent infectious diseases.

Feasibility and challenges of addressing this CQ or CC

With echocardiography, we are able to identify PDD patients before they develop symptomatic HF. Hence with research funding, we can better characterize preclinical diastolic dysfunction, and to discover further targets for this entity to prevent development of HFpEF

Name of idea submitter and other team members who worked on this idea Horng H Chen

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2 up votes
1 down votes
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Goal 2: Reduce Human Disease

Cardiovascular dysfunction in geriatric trauma patients

There is too little research funding addressing cardiovascular dysfunction in geriatric trauma patients. There have been little interest in funding this work. Yet, the geriatric population is growing.



Geriatric trauma patients are predominantly women.



Historically, the trauma societies provide guidance for diagnosis and treatment of severe trauma. However, "trauma guidance" historically was the same for children,... more »

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

Details on the impact of addressing this CQ or CC

Document and understand the role of cardiac dysfunction in contributing to morbidity and mortality of geriatric trauma patients.

Reduce mortality rates in geriatric trauma patients.

Feasibility and challenges of addressing this CQ or CC

Little research has been conducted to understand the role of cardiac dysfunction in elderly trauma patients. These patients may be intubated and treated with pain meds, so the normal symptoms of cardiac ischemia are silenced. Because 12 lead ECGs or cardiac enzymes are not routinely collected in these patients after admission, the question is what types of cardiac dysfunction occur and can they be prevented?

While evidence is scant, we conducted a structured chart review of WMD Shock Trauma patients' medical records in fiscal year 1999 data. Mean age was 76 and mean ISS of 24. In reviewing charts we found 71% of patients had one or more risk factors for ischemic heart disease (beyond age) and 30% had a history of ischemic heart disease. On admission 29% had ECG changes consistent with acute cardiac ischemia, but ischemic changes were noted equally between patients with and without a history of IHD. Cardiac enzymes were ordered for 45% of patients and 19% were positive. We found that patients with acute cardiac ischemia on admission (ECG or enzymes) had more adverse in-hospital cardiac events than those without ischemia on admission. Patients experiencing adverse events were significantly more likely to die.

We believe these findings suggest a substantial role of cardiac dysfunction in this population, but we were unable to generate interest in the topic.

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

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1 up votes
32 down votes
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Goal 2: Reduce Human Disease

Correlation of genetic modifiers and cardiopulmonary fibrosis/dysfunction in Duchenne

What are the protective genetic modifiers that may be associated with a Duchenne phenotype more resistant to the development of cardiac and pulmonary fibrosis and subsequent pulmonary/cardiac dysfunction? . Are there genetic modifiers that may ameliorate or enhance the onset of cardiac and/or pulmonary dysfunction?

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 two major causes of death in Duchenne are cardiac and pulmonary dysfunction. The onset of cardiac and pulmonary dysfunction in people living with Duchenne follows a heterogeneous path, not necessarily consistent with the underlying genotype or onset musculoskeletal dysfunction. This can often be seen in siblings/relatives with identical genetic mutations and very different disease progression.

Feasibility and challenges of addressing this CQ or CC

A number of studies have provided some degree of evidence for the presence of genetic modifiers in Duchenne, which may affect disease onset and musculoskeletal progression. Two of these modifiers, LTBP4 and SPP1 have been shown to have a profound effect on time to loss of ambulation, establishing the need for and feasibility of identification of genetic variants that impact the cardiorespiratory phenotype in Duchenne.
Several reports have alluded to the impact of genetic modifiers on pulmonary and/or cardiac disease progression in animal models. Further studies validating the presence and impact of these modifiers may have implications for the prevention, or postponement, of cardiac and pulmonary dysfunction in Duchenne, as well as other, muscular dystrophies, allowing enhancement of both quantity and quality of life.
In addition, drug development with pulmonary and/or cardiac primary or secondary outcomes, may be impacted by populations with genetic mutations that include genetic modifiers. At least one of the already identified genetic variants affects skeletal muscle responsiveness to corticosteroid treatment. The validation of the presence, and impact, of these modifiers, may impact the outcomes of these trials, and help delineate populations most likely to benefit from these new therapies.

Name of idea submitter and other team members who worked on this idea Parent Project Muscular Dystrophy

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4 up votes
6 down votes
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Goal 2: Reduce Human Disease

Correlation between abdominal/diaphragmatic fibrosis and cardiopulmonary dysfunction in Duchenne

Is there a correlation between the development of abdominal/diaphragmatic fibrosis and the development of cardio-pulmonary dysfunction? Are there mechanisms (i.e., pulmonary excursion therapy) that may prevent/postpone the development of diaphragmatic fibrosis and subsequent pulmonary dysfunction?

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

Details on the impact of addressing this CQ or CC

currently there is no adequate method of evaluating the development of fibrosis in the diaphragm. Mdx mouse models have provided insight into this progression, and to a possible correlation between abdominal fibrosis and cardiac dysfunction.

Feasibility and challenges of addressing this CQ or CC

: Maintaining cardiopulmonary function in Duchenne has been the mainstay of therapy, however little attention has been given to the accessory muscles of respiration. Supporting the muscles of respiration may prevent or postpone the ongoing process or cardiopulmonary dysfunction, resulting in an increased the lifespan, and quality of life, of people living with Duchenne. The current base of researchers addressing the cardiopulmonary issues in Duchenne, as well as the resources to identify and track patients with cardiopulmonary dysfunction, enhances the feasibility of answering this question.

Name of idea submitter and other team members who worked on this idea Parent Projct Muscular Dystrophy

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3 up votes
7 down votes
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Goal 2: Reduce Human Disease

Molecular basis for cardiac and neurological damage after cardiac arrest

What is the sequence and time course of molecular events that cause irreversible cardiovascular and neurologic dysfunction during and after cardiac arrest?

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

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5 down votes
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