Upgrading the level of evidence that recommendations are based on in clinical guidelines, will potentially improve outcomes, reduce unnecessary risk and reduce cost of all aspects of cardiovascular care.

There are three phases:

1. Review the current published clinical guidelines (and Appropriate Use Criteria) for recommendations relying on level of evidence of C- Very feasible.
2. Ranking impact of clinical recommendations that only have level of evidence C- Quite feasible, but will need to set up a protocol and review committee.
3. Designing and funding high priority studies: Feasible- especially if done under the umbrella of the NHLBI. The challenges will be to set up good studies that supply enough data to be useful in making recommendations based on Level of evidence A in the Guidelines.

This innovative and transformative proposal could improve tolerance to many different types of transplants.

In 2002, Hochedlinger and Jaenisch (Nature 415:1035-1038) created a mouse by nuclear transplantation from a mature B-cell. This was proof of principle that the immune system can be reprogrammed entirely. Since then there has been little work in this area, but Reprogramming Immune System Cells (RISC) is risky but promising.
A second approach involves mechanisms that cancer cells use to evade immune detection. While most cancer research works to restore immune competence for therapy, the basic biology of evading immune detection could be exploited to improve tolerance. These approaches could be tested in an animal model in 5 years.

There is no doubt that insufficient sleep and circadian disruption are very common in our society. There are also compelling epidemiological data that they are associated with multiple adverse consequences, including increased cardiovascular disease, increase in metabolic abnormalities such as insulin resistance and for shift work an increased incidence of specific concern. Animal studies based on microarrays are showing that inadequate sleep and circadian rhythm alter gene expression not only in brain but also in peripheral tissues. These studies are hypothesis-generating and there are many opportunities for hypothesis-driven research in this area to assess mechanisms. Identifying mechanisms will allow investigators to begin to assess mechanisms of individual differences and to identify new pathways for intervention.

Sleep and circadian research is in a very strong position. Sleep and clock function has now been identified in all the major model systems—C. elegans, Aphysia, Drosophila, zebra-fish, mice, etc. Thus, there is a strong platform to assess conserved pathways for effect of sleep loss and circadian disruption. Moreover, microarray studies have identified likely pathways thereby setting up hypothesis-driven research. There are major opportunities in this area.

Although there are some recent successes in the West, there are more smokers nowadays than ever before in human history, causing far too many premature death and disability. We strongly believe that research drives all health advocacy, and that the final solution to the tobacco problem will be thought legislation.

Imagine a world with no tobacco, and later, perhaps only one generation after, a no tobacco-related disease world…

Over the past two years, it has become extremely clear that impaired processing of triglyceride-rich lipoproteins has an enormous impact on the frequency of coronary heart disease. For example, large genetic studies have shown that loss-of-function mutations in the gene for apolipoprotein CIII protect from atherosclerotic heart disease. Equally important is the observation that mutations in the gene for apolipoprotein AV are nearly as important as the LDL receptor as a cause of coronary heart disease.

The fact that plasma triglyceride metabolism is so important for atherosclerotic heart disease has caught the field by surprise. For many years, there was considerable doubt about the importance of plasma triglycerides for atherosclerotic heart disease. These doubts have vanished.

Now, in terms of basic research, the triglyceride metabolism field needs to play "catch up" ball. At this time, we have little understanding of intravascular lipolysis. We don't really know the molecular basis for the effects of apo-CIII, apo-CII, and apo-AV on intravascular lipolysis. The effects of these proteins on the LPL–GPIHBP1 complex are unknown. We don't understand how the lipid products of lipolysis move across capillary endothelial cells. We don't even understand why heparin releases LPL from GPIHBP1, and that observation is more than 60 years old! We don't understand the factors that explain differences in the efficiency of plasma triglyceride metabolism.

I believe that the field is now poised to understand intravascular lipolysis at the molecular level, and to investigate why some individuals have inefficient lipolysis and higher plasma triglyceride levels. Within the past few years, the "cast" of molecules that affect (or regulate) plasma triglyceride metabolism have come into focus. The field is poised for progress.

In part because of long-held doubts about the importance of plasma triglyceride metabolism, reagents for key proteins in intravascular metabolism are not in hand simply not in hand (recombinant proteins, specific antibodies). Developing and distributing these reagents is quite feasible, but it has not yet been accomplished.

Similarly, imaging tools are now available to understand the movement of the fatty acid products of lipolysis to myocytes and adipocytes, but there have been few attempts to use those tools.

We need to understand intravascular metabolism. At this time, no one understands the basics. No one knows how app-CII, app-CIII, and app-AV work. We need to understand how ANGPTL4 and ANGPTL3 regulate lipolysis. We need to understand the biochemistry of the LPL–GPIHBP1 complex. These tasks are feasible but will require hard work from many interested investigators.

In the end, once intravascular lipolysis is better understood, it is highly likely that there will be many new strategies for lowering plasma triglyceride levels and reducing the frequency of coronary heart disease.

It is expected that incorporating Oral Bacterial ailments such as Gingivitis for cardiac care will more than pay for itself. It will significantly improve the cardiac event prognoses and CUT THE COST OF CARDIAC CARE.

It is quite feasible and practically possible to incorporate Gingivitis or other serious bacterial oral health problems as integral part of the work of a Cardiologist.
CHALLENGES: Researching the contribution of Oral bacterial issues such as Gingivitis as compared to smoking, obesity and cholesterol levels.
My hypothesis is that Chronoc Oral Bactrial diseases are significant contributors to cardiac problems.

Collaboration across I/Cs could encourage investigators or teams to explore new concepts underlying the etiology of common or rare cardiovascular diseases (CVD), including stroke, particularly those with gender-related differences. In addition, clinical research on these disorders would benefit from active consideration of the common co-morbidities seen in patients with CVD, especially as patients with these co-morbidities are often specifically excluded from clinical trials. Since the patients who will ultimately benefit from treatments developed will often suffer from multiple other disorders, the societal benefit would be substantial. While any single I/C could support such studies, collaborative funding would be likely to bring together new teams of investigators with novel ideas.

We believe that there is likely to be a good response from investigators, both basic and clinical, to collaborative, multi-I/C RFAs. It might be of additional benefit to provide some funds specifically for teams that are newly collaborative in response to the RFAs, to encourage increased cross-field collaboration.

the impact is obvious in the sense that predicton based on theory can lead to new discovery

Understanding how lymphatic system contributes to normal physiology of heart, lung, blood, sleep systems will help also lead to new approaches for treatment of heart, lung, blood, sleep diseases.

Basic understanding of the development and hemodynamics of the lymphatic system and reagents to study the lymphatic function are available.
Lymphatic vasculature is essential for fluid hemostasis in the body, collects and returns the protein- and lipid-rich interstitial fluid to blood circulation, and also involved in immune cell trafficking and inflammation. Given these important physiological roles, function of the lymphatic system is expected to contribute to normal physiology of organs and its dysfunction to major diseases. There is very little or no information how the lymphatic system contribute to health and diseases of the cardiovascular, pulmonary and blood systems, and there are many unanswered questions. Answers to these questions may lead to new approaches for treatment of major HLB diseases. Main challenge is to get heart, lung, blood, sleep investigators interested in studying the contribution of the lymphatic system to heart, lung, blood, sleep health and diseases.

Blood donation is generally safe and well tolerated by most individuals, but some people will experience syncopal reactions after donating blood, such as dizziness, lightheadedness, or loss of consciousness. Injuries which occur as a result of loss of consciousness after blood donation can rarely cause significant morbidity or disability. Although uncommon, such donation-related injuries are likely underreported because they often occur after the donor leaves the blood center. Published studies on interventions that reduce the risk of reactions have not shown an effect on preventing injuries, although some incidents might still be preventable. Physiologists have successfully treated syncope in patients with dysautonomia, in trained athletes, in astronauts, in pilots and others, using physical maneuvers with muscle tensing, to almost instantly increase venous return, cardiac output and cerebral perfusion. But studies on the use of physical maneuvers during blood donation have yielded conflicting results. Further efforts are needed to design, implement and monitor strategies to reduce injuries after blood donation and optimize donor health.

Injuries are most commonly associated with syncopal reactions which occur after the blood donor leaves the collection site and resumes normal daily activities. Reducing injuries will require identifying susceptible donors, providing them with postdonation instructions, and improving their ability to recognize prodromal symptoms and respond to orthostatic changes in blood pressure. Technology for personalized medicine platforms, such as mobile phone apps, could be developed to capture information about post-donation reactions and facilitate real-time interactions with blood donors. Such a system would also enable blood centers to design and deliver intervention and continuously monitor the effectiveness of the approach to prevent postdonation injuries.

There are major individual differences in response to sleep loss (both acute and chronic) and to circadian disruption. This has major impact both in terms of health consequences and in safety. Some individuals are particularly vulnerable to sleep loss and hence are more likely to have adverse consequences of losing sleep—increased risk of crashes, errors by physicians, etc. They are also more likely to be affected by metabolic and other consequences if they have chronic insufficient sleep.

Identifying the basis of these individual differences will have several impacts:

1. It will provide likely targets for development of biomarkers to assess effect of sleep loss and circadian disruption.
2. It will provide tools to risk stratify individuals and to employ preventative strategies to reduce risk of major adverse consequences.
3. It will identify novel pathways that could be the target for future intervention studies.

These studies are highly feasible. Phenotyping and recruitment strategies to study this question have been established in many laboratories. Moreover, more laboratories are utilizing genetic, -omic approaches and epigenetic approaches that could be applied to this question. There is also a developing repertoire of neuroimaging studies that can be applied to address this question.

I think if this question were answered and that industry understood the impact of COPD on the potential workforce going forward, there would be significant interest from business and industry to do several things:
prevent COPD; develop accommodations that would allow people with COPD to continue to work; reduce the burden to both industry and individuals with COPD by allowing them to continue to work and produce until planned retirement.

This would not be a difficult question to answer. More difficult would be the education of both individuals and business and industry in how to accommodate people with COPD so they can continue to work until their planned retirement. Techniques and strategies could be developed, however, benefiting both business and the individual.

Neonatal and early life events can be essential elements for risk of development of chronic lung disease developing after age 40. Prevention of late life chronic lung disease may require that action takes place during the neonatal and childhood periods.

Early life and late life events can be readily studied; however, integrating cause and effect relationships between the two is challenging due to the multiple decades of time separating these events.

­Conduct community level and scale studies in higher risk populations, identify effective tools to achieve healthy lifestyle and prevent or retard the progression of vascular disease. Determine which interventions work.