Sleep deficiency and untreated sleep disorders threaten the health of 20-30 percent of US adults through an increased risk of stroke, hypertension, diabetes, inflammatory disease, and all-cause mortality. Developing the scientific evidence-base of validated interventions will enhance the management of cardiometabolic and pulmonary risks to health, present new opportunities for secondary prevention, and reduce associated burden on health care systems.

Improving sleep health through informed public recognition of decision-relevant science, and relatively low cost therapies for management of sleep disorders are available for immediate assessment of impact in appropriate clinical trials to demonstrate efficacy and effectiveness.
Discovery research advances implicate an array of cellular sleep and circadian mechanisms in pathophysiological pathways leading to cardiometabolic and pulmonary disease.

Irregular and disturbed sleep impairs cellular biological rhythm in all tissues and organs leading to oxidative stress, unfolded protein responses, and impaired cell function. The pathophysiological findings juxtaposed with epidemiological evidence of disease risk indicate that sleep deficiency contributes to an erosion of health across the lifespan over and above the effects of aging.

This question will have considerable impact. Sleep apnea is an independent risk factor for insulin resistance. Moreover, observational studies show that treatment of OSA reduces the rate of future diabetes compared to that which occurs in untreated OSA. Therefore, identifying OSA and treating this could have a profound impact on reducing the rate of diabetes, i.e., a preventative strategy.

Both sleep loss and obstructive sleep apnea have also been shown to be risk factors for subsequent development of Alzheimer’s disease. This has been shown in mouse models and in epidemiological studies to address whether insufficient sleep and sleep apnea are independent risk factors for development of Alzheimer’s disease, in particular accelerating their onset. Determining whether this is so and whether interventions to treat these sleep disorders delay onset of diabetes and Alzheimer’s disease would have profound public health significance.

These disorders are extremely common so that recruitment of subjects is not challenging. Moreover, new technology reduces protocol burden to assess individuals. All studies can be done in the patients’ home. There are existing cohort studies focused on diabetes and the Alzheimer’s Center program that could be used for these studies. Thus, the studies are extremely feasible in the near term.

Successfully addressing this question would no double reveal novel mechanisms and ways of monitoring treatment responses of cardiovascular disease, ultimately leading to novel drug targets, valuable biomarkers and extended new directions of basic research as well.

Tools of studying these cells are mostly available. Both adult cardiomyocytes and endothelial cells from the heart can be isolated and cultured, although cardiomyotyes need to used within 24 hrs and cannot be passaged. However successful preparation of these cells from WT and transgenic animals would permit co-culture experiments and mechanistic studies. These cells can also be studied using in-situ techniques either detecting molecular changes/events or dynamic interactions. Potential challenges would side in selective targeting of these cells, for example, either ECs or cardiomyocytes, once a potential therapeutic is in the testing. Nonetheless, PECAM-ab conjugated techniques have been employed to specifically deliver proteins to endothelial cells, so I am confident most of the challenges can be worked out, particularly within a RFA awardees group with frequent exchanges of ideas.

Beyond helping with real-world problems (e.g., cancer drug cardiotoxicity), understanding of toxicity mechanisms in the CV system enables a different level of understanding. For example, acute toxicity testing is probably akin to crash testing of the CV system, permitting us to see where things break. Thus there is potential to lead to a fuller understanding and novel therapeutic ideas.

As the number of newer and more powerful therapeutics grow, their risk of adverse impact on the CV system grows. This is in part due to insufficient knowledge of toxicity mechanisms and lack of effective drug-screening tools during drug development. This field primarily lacks researchers.

Provide an evidence base for public policy on diet.

The Spaniards have shown that this kind of trial is possible. We have tools and interest in place for pragmatic trials.

The PREDIMED trial (done in Spain) randomized ~7000 adults and found that a diet supplemented with olive oil or nuts reduced cardiovascular events compared to a "low-fat" diet. However, in Spain the Mediterranean diet is arguably the norm.

Identify strategies to prevent or reduce recurrence of atrial fibrillation using available lifestyle and medical therapies.

There is a large population of patients with atrial fibrillation available to test this hypothesis along with strategies for treatment of modifiable risk factors. A challenge is to identify the good strategies to ensure adherence.

A substantial evidence base now exists showing that depression is associated with a two-fold increased risk of death and recurrent CV events in cardiac patients, leading to a recent AHA scientific statement recommending its elevation to the status of a risk factor for adverse medical outcomes in patients with acute coronary syndrome (Lichtman et al., 2014). Yet there is currently no clinical trial evidence that reducing depression improves cardiac morbidity and mortality. A clinical trial, using new, more effective depression treatment methods, such as collaborative care approaches that combine psychological counseling with medication in stepped-care fashion, is needed to determine whether effective treatment of depression can improve survival and reduce clinical cardiovascular events in cardiac patients.

Newer stepped-care treatments for depression, combining medication and psychotherapy, have recently been developed and found to more effectively reduce depression than earlier treatments. By using these newer treatment methods to substantially lower depression, we can better answer the question as to whether treating the newly acknowledged risk factor of depression in ACS patients can improve clinical outcomes in these patients.

Reduce the impact of autoimmune diseases on the heart and vascular system.

Generate RFAs dedicated to the field of autoimmune associated cardiovascular diseases.

Understanding how stress contributes to cardiovascular and metabolic disease could lead to additional therapies targeting stress reduction for their prevention. The long-term impact of studies to establish and reduce the negative impact of stress on health could include better outcomes for stress reduction programs at work and strategies to reduce stress at home.

Clinical trials to evaluate the efficacy of non-pharmacologic therapies targeting stress reduction are already feasible including such interventions as exercise, improved sleep, mindfulness, and social interaction. Some of these have been evaluated on a small scale, but future clinical trials should include long-term follow up and be sufficiently populated for their outcomes to influence patient care. Pharmacologic therapies targeting the stress system have not yet emerged as options for prevention and treatment, and pose a greater challenge. They will require investigation into the mechanisms of stress effects on chronic disease as well as intelligent drug design to minimize systemic side effects.

Phenotypical characterization of cardiovascular disease with computed tomography (CT) and magnetic resonance imaging (MR) to individualize targeted therapies for coronary artery and myocardial disease. Coronary artery disease is a major cause of patient death in the United States. Nonischemic myocardial disease includes entities with clinically heterogeneous presentations and is thus challenging to manage.

Currently CT and MR technology allows dynamic evaluation of the perfusion and contractility of the heart. Quantitative measures of disease burden, such as atherosclerotic plaque composition and myocardial texture imaging biomarkers (such as T1 mapping, activation mapping, flow pattern analysis, delayed myocardial enhancement), are possible. Positron emission tomography (PET)/MR, which combines metabolic with functional evaluation, is currently available and facilitates the development of targeted molecular-imaging techniques. Metrics derived from these techniques may serve to stratify patients noninvasively and direct appropriate therapies. Such imaging methods address noninvasive evaluation of cardiovascular disease, including ischemic heart disease but also myocardial diseases that include secondary and infiltrative cardiomyopathies, hypertrophic cardiomyopathy, and organ rejection in the scenario of transplantation.

The NHLBI could fund programs which enable vascular biologists to collaborate with neuroscientists and neurologists in order to understand whether the vasculature has a causal role in the progression of dementia.

Can interventions that improve vascular function prevent the progression of dementia? Instead of using broad interventions such as statins which affect numerous signaling pathways, vascular biologists could target selected aspects of vascular health such as improving vascular barrier function and vascular regeneration.

If these interventions that have been shown to be efficacious in other vascular beds outside of the brain are also effective in the brain, then important new therapies could be developed for dementia which is likely to become one of the leading cause of death in the next decades.

A key challenge for targeting the brain vasculature will be the blood-brain barrier. Understanding the role of the blood-brain barrier in dementia will be a prerequisite to developing novel vasculature-directed therapies.

Obesity and metabolic syndrome affect a large portion of the population and affects multiple organ systems. Identifying obesity phenotypes by imaging will impact the significant healthcare issue presented by MetS and could provide a reliable, non-invasive index of disease severity, guide prevention and intervention response.

Metabolic syndrome, abnormal metabolism, may be potentially linked to obesity and cardiopulmonary disease. Theories exist but are in need of clarification. The relationship between metabolic syndrome and multiple other diseases including chronic obstructive lung disease, coronary atherosclerosis, and obesity warrants further investigation and can be elucidated through imaging. Advances in computed tomography (CT) and magnetic resonance imaging (MR) enable assessment of the cardiopulmonary manifestations, with promising MR techniques to complement high-resolution imaging data achievable with chest CT and coronary CT angiography. Assessment of CT and MR techniques in combination with three-dimensional quantitative analysis of manifestations of metabolic syndrome such as fat deposits derived from different adipocytes (white fat versus brown fat) such as in the subcutaneous, visceral, epicardial, and perivascular regions is feasible with current technology and may enable differentiation of those with varying risks of cardiovascular and pulmonary disease. The association of imaging parameters, metabolic syndrome, and associated diseases are in need of investigation, and knowledge gained may prove crucial for identifying those at risk for metabolic syndrome and at higher risk for complications in the large population of our country affected by obesity.

Late gadolinium-enhancement cardiac magnetic resonance imaging (MR) plays a crucial role in the evaluation of patients with suspected myocardial scar tissue. Alternative methods to contrast-enhanced MR however are in need, given the number of patients who have concomitant compromised renal function and concern for nephrogenic systemic fibrosis. Noncontrast MR techniques such as diffusion-weighted imaging would complement and eventually replace gadolinium administration thus impacting the evaluation of those with suspected and confirmed infiltrative cardiac processes and systemic diseases.

Late gadolinium enhancement technique characterizes enhancement patterns of heart disease, identifies areas amenable to ablation, and aids in decisions pertaining to workup and therapy. The underlying mechanism of Brownian motion/diffusion in the expanded extracellular space makes diffusion weighted imaging a potential gadolinium-saving modality. Diffusion MR, applied primarily in the brain and abdominal imaging, is underutilized in the heart given respiratory and cardiac motion. A need exists to further develop and apply noncontrast MR techniques towards cardiovascular applications. Such methods are promising noncontrast alternatives to characterize patients with myocardial disease, determine those with differing prognoses, and direct appropriate therapies to subgroups.

Cardiovascular disease and cancer are frequently identified in the same patient. Both diseases are highly prevalent in the United States population, and cancer or its therapies can result in cardiovascular disease. Early diagnosis and prediction of cardiovascular disease in patients to undergo therapy will identify patients at higher risk for cardiac dysfunction and enable earlier diagnosis of subclinical cardiac dysfunction.

Cardiovascular magnetic resonance imaging (MR) is a powerful imaging modality for evaluating the heart function. Specifically, MR techniques allow for quantifying regional heart function, e.g. strain and strain rate, and may provide earlier markers of cardiovascular disease development than global measures of heart function, e.g. left ventricular ejection fraction, as estimated by echocardiography. Early identification of subclinical heart failure of post-chemotherapy cancer patients will allow for early and on-time chemotherapy change and personalized treatment.

By addressing this question, we will gain a greater understanding of hormone-based risk factors for ASCVD in women and men. Beyond expanding our fundamental knowledge of how hormones interact with cardiovascular systems, we could develop or improve therapeutic strategies for addressing risk factors for cardiovascular disease.

Addressing this question is feasible and could be most effectively addressed through strategic initiatives sponsored by the institute. It will require a systematic approach to investigating differences in hormonal status between pre and post-menopausal women, as well as comparing them to male hormonal status. At the level of basic research, progress in this area may be slowed because researchers are not currently required to balance the studies of males and females in preclinical research involving animal models.