God-Science-Universe: Business

Systems medicine is the application of systems biology approaches to medical research and medical practice. Its objective is to integrate a variety of biological and medical data at all relevant levels of cellular organization using the power of computational and mathematical modeling, to enable understanding of the pathophysiological mechanisms, prognosis, diagnosis and treatment of disease.

The clinical needs should be the driver for the applications of systems biology methods in medicine and for the evolution of the essential new technologies. The possible actions required are, systems biology approaches could guide clinical trial design, shortening times and costs. Re-defining clinical phenotypes based on molecular and dynamic parameters, discovering effective biomarkers of multiple nature for disease progression; clinically useful for risk, prognosis, diagnosis. Combinatorial therapy approach would be useful to find out a combination and lower doses of effective drugs, in particular in the case of co-morbidity, where more than one disease is affecting the patient, upgrading of drug development; optimizing drug efficacy, safety and delivery, timing and dosage of therapy. Finally, healthy individual are to be addressed in the long term.

Scientific areas for partnership in Systems Medicine includes understanding the pathophysiology of chronic diseases, multifactorial diseases like cancer, diabetes, obesity, metabolic disorders, aging through network analysis of disease processes, and the recognition of biomarkers for early diagnosis and prognosis and personalized treatment, combinatorial therapies and combinatorial drug screening and mixing of personalized genomics with personalized metabolomics, endocrinomics, proteomics and clinical phenotyping.

The major confrontation is for systems biology to furnish a change in the medical model in order to build the foundation for a prospective medicine that will be predictive, personalized, preventive and participatory. In order for systems medicine to become a reality, one needs coordinated vision of all relevant stakeholders and a field guide at the same level of ambition as the Human Genome project. In addition, the creation of a strong networking effort among funded systems biology projects is essential, in order to share information and resources on successful methodological approaches and tools with the broader systems biology and clinical community.

Recent years have seen the rapid emergence of systems biology as a new discipline. In the biomedical sciences, this trend is very apparent as research moves from a reductionist approach to a systems understanding model that attempts to understand biology and pathophysiology in an integrative manner, making use of the rapidly increasing amounts of novel (-omics) data and other relevant quantitative biological and medical data that are becoming available.

However, despite the spectacular advances in the post-genomic era, there exists a hiatus between experimental data and medical knowledge, and even a greater gap exists when we evaluate new knowledge in terms of clinical utility and benefit to patients. As a result, despite major technological advances, there are still obstacles that separate systems biology from medical applications. Systems medicine, a newly emerging area should aim the bridging of this gap.

Experts in a wide range of relevant disciplines from clinical, diagnostics and pharmaceutical areas, to high throughput –omics technologies, and computational and systems biology, including representatives from academia, industry, and funding agencies should get together to explore opportunities and challenges for the development of systems medicine. The aims are to analyze the state-of-the-art of systems biology for medical applications, identify key opportunities and bottlenecks for the translation of systems biology to medicine and the clinic, and identifying key research and policy areas for joint research in the short, medium and long term in order to make systems medicine a reality.

The key feature defining transcatheter cardiovascular interventions is that access to the vessels and heart is achieved by arterial puncture with a needle, rather than surgical incision with a scalpel. However, arteriotomy and vessel closure are performed without direct visualization of the arterial wall, which risks vessel damage and bleeding. Vascular closure devices offer the potential for enhanced control of access-site haemostasis and reduced complications in comparison with manual compression. However, although randomized clinical trials have shown reductions in time to haemostasis and ambulation, the data do not demonstrate consistent reductions in access-site complications or improvements in clinical outcomes. Another approach to increase the safety of percutaneous procedures is to use radial, rather than femoral, arterial access, a strategy that has polarized opinions among cardiologists. Clinical trial data show a clear reduction in access-site bleeding and complications with radial access, at the expense of a marginal increase in markers of procedural efficiency. However, randomized trials have not demonstrated improved clinical outcomes with radial access. The lack of impact on prognostically relevant bleeding events could explain this null finding, although the setting of primary percutaneous coronary intervention could be an exception. Ongoing, iterative improvement in catheter technologies, as well as in adjuvant antiplatelet and antithrombotic therapies, are likely to underlie the difficulty in demonstrating clear outcome benefits with different vascular access and closure strategies.

The feasibility and success of transcatheter therapeutics are heavily dependent on the related issues of vascular access and arteriotomy closure. Manual compression remains the most frequently used modality for closure of vascular access after diagnostic catheterization or percutaneous intervention; however, a range of vascular closure devices are available. Randomized trial data show that the use of vascular closure devices results in reduced time to haemostasis, ambulation, and hospital discharge. Rates of access-site bleeding and complications, as well as overall clinical outcomes, are not improved by use of vascular closure devices. Worldwide, the femoral artery approach is the most-common vascular access modality for coronary angiography and intervention; however, uptake of radial access has increased rapidly in the past 10 years. Radial artery access reduces access-site bleeding and complications at the expense of a slight increase in metrics of procedural efficiency when compared with femoral access; overall clinical outcomes are not different.

Over the past 35 years, transcatheter coronary intervention has revolutionized the treatment of patients with obstructive coronary artery disease. In the past decade, transcatheter valve replacement has broadened the treatment options available for patients with valvular heart disease. The hallmark of transcatheter cardiovascular therapeutics, and the feature that distinguishes these procedures from conventional surgical treatment, is that access to the vessels and heart is achieved by arterial puncture with needle arteriotomy. Avoiding surgical incision reduces the need for analgesia and sedation, almost completely eliminates the necessity for circulatory support and assisted ventilation, and shortens the time to patient mobilization and hospital discharge. These benefits enable transcatheter therapeutics to be used in patients for whom disease-modifying interventions would otherwise be precluded owing to operative risk, comorbidity, or both.

Integral to the feasibility and success of transcatheter therapeutics are the related issues of vascular access at the beginning of the procedure and arteriotomy closure at the end of the intervention. By virtue of high system pressures, as compared with the venous circulation, arterial access is associated with a small but important risk of access-site bleeding. This problematic issue increases patient morbidity and mortality, and can erode some of the clinical advantages inherent to a nonsurgical approach. Accordingly, considerable effort has been focused on techniques to minimize access-site bleeding, recognising that amelioration of this complication would improve the benefit-risk ratio of transcatheter cardiovascular therapy and the clinical outcomes of patients. Two strategies in particular have been the subject of considerable investigation; first, the use of vascular closure devices; which are primarily designed to reduce femoral access-site-related bleeding complications and second, the use of the radial artery, rather than the femoral artery, for procedural vascular access.

In the past 20 years, a number of studies of patients undergoing percutaneous coronary intervention have highlighted the important association between major bleeding events and increased morbidity and mortality. Accordingly, strategies that reduce bleeding are expected to improve clinical outcomes. Vascular access might well be considered a 'Trojan horse', in that the route to managing coronary disease syndromes becomes a focus for events that lead to adverse outcomes. However, the relevance of access-site bleeding to clinical outcomes remains somewhat unclear. Although, the use of a vascular closure device reduces time to haemostasis and ambulation compared with manual compression, existing data from randomized controlled trials does not suggest that these devices have a significant impact on bleeding events or clinical outcomes. Moreover, meaningful reductions in access-site bleeding with radial artery access compared with the femoral approach have not translated into improvements in clinical outcomes, even in large-scale randomized controlled trials. The specific setting of primary percutaneous coronary intervention might be an exception, with emerging data supporting better outcomes with trans-radial intervention. However, even in this clinical scenario, the impact of modern antithrombotic therapies on the efficacy of these two strategies remains unknown.

The available evidence on vascular closure devices therapy and choice of vascular access indicates that tailored approaches based on analysis of benefit-risk according to individual patients and procedural settings should be the strategy of choice. As catheter technology and individualized antiplatelet and antithrombotic treatment continue to improve, I believe that the outcomes of patients undergoing percutaneous cardiovascular procedures will become increasingly independent of the strategies used for vascular access and closure.