Diabetes mellitus has long been recognized as a major risk factor for cardiovascular disease and stroke. One of the major risk factors is diabetic autonomic neuropathy (loss of small nerve fibers). Patients with diabetic mellitus and autonomic neuropathy show impaired short-term cardiovascular regulation. During orthostatic stress testing such as postural change from sitting to standing and head-up tilt, arterial and cardiopulmonary baroreflexes play an important role in maintaining blood pressure by regulation of heart rate. During such orthostatic stress tests, blood is pooled in the legs due to the effect of gravity resulting in a drop in systemic arterial pressure and widening of the blood flow velocity. This can be modeled by increasing the blood pressure in the compartments representing the lower body. To restore blood pressure and blood flow velocity a number of regulatory mechanisms are activated. The most important mechanisms are autonomic reflexes mediated by the sympathetic nervous system and cerebral autoregulation mediated by changes in concentrations of oxygen and carbon dioxide. The response to standing is an increase in nervous activity, which results in increased heart rate and cardiac contractility, vasoconstriction of the systemic arterioles, and changes in unstressed volume and venous compliance. The response by the cerebral autoregulation is to dilate arterioles in the cerebral vascular bed. It is not clear how the autonomic and autoregulation interacts; one theory suggests that vasoconstriction, resulting from increased sympathetic activity, has an effect throughout the body, but that cerebral vasoconstriction gets overridden (possibly with a significant delay) by autoregulation resulting in a net vasodilatation of the cerebral vascular bed. In this work we demonstrate how mathematical modeling can be used to predict the interaction between autonomic and autoregulation, and how nonlinear optimization methods can be used to identify model parameters to make the model patient specific. |
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