Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure.

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.

An analytical framework for group simulation model building.

This paper presents a framework for understanding and improving the process of simulation model building involving a group of domain experts, classifying the different roles the model may play at various stages of its development. The framework consists of four different "object roles", defined along two dimensions: a functional dimension (boundary object vs. representational object) and a knowledge dimension (epistemic object vs. technical object). A model can take different roles during the development process, e.g. for facilitating communication, for gaining insight into the real-world system, or for experimentation and policy evaluation. The use of the framework is illustrated by two case studies in healthcare. Its relevance and applicability are examined through a survey on model use. The survey was conducted among a group of modelling consultants with experience of using both discrete-event simulation and system dynamics within the NHS, and indicated the potential usefulness of the framework.