Showing 8 ideas for tag "dysfunction"

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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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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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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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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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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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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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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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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