Effects of arterial wall models and measurement uncertainties on cardiovascular model predictions

We developed a methodology to assess and compare the prediction quality of cardiovascular models for patient-specific simulations calibrated with uncertainty-hampered measurements. The methodology was applied in a one-dimensional blood flow model to estimate the impact of measurement uncertainty in wall model parameters on the predictions of pressure and flow in an arterial network. We assessed the prediction quality of three wall models that have been widely used in one-dimensional blood flow simulations. A 37-artery network, previously used in one experimental and several simulation studies, was adapted to patient-specific conditions with a set of three clinically measurable inputs: carotid–femoral wave speed, mean arterial pressure and area in the brachial artery. We quantified the uncertainty of the predicted pressure and flow waves in eight locations in the network and assessed the sensitivity of the model prediction with respect to the measurements of wave speed, pressure and cross-sectional area. Furthermore, we developed novel time-averaged sensitivity indices to assess the contribution of model parameters to the uncertainty of time-varying quantities (e.g., pressure and flow). The results from our patient-specific network model demonstrated that our novel indices allowed for a more accurate sensitivity analysis of time-varying quantities compared to conventional Sobol sensitivity indices.     

In-vitro investigation of a potential wave pumping effect in human aorta

An impedance pump – also known as Liebau pump – is a simple valveless pump that operates based on the principles of wave propagation and reflection. It has been shown in embryonic zebrafish that a similar mechanism is responsible for the pumping action in the embryonic heart during the early stages before valve formation. Recent studies suggest that the cardiovascular system is designed to take advantage of wave propagation and reflection phenomena in the arterial network. In this study we report the results of an in-vitro study that examines the hypothesis that the adult human aorta acts as a passive pump based on Liebau effect. A hydraulic model with different compliant models of an artificial aorta was used for a series of in-vitro experiments. Our result indicates that wave propagation and reflection can result in a pumping mechanism in a compliant aorta.     

Targeted proteomics in biomarker validation: detection and quantification of proteins using a multi-dimensional peptide separation strategy

Authentic biomarkers, distilling the essence of a complex, functionally significant process in a mammalian system into a precise, physicochemical measurement have been implicated as a tool of increasing importance for drug discovery and development. However, even in spite of recent technological advances, validating a new biomarker candidate, where generation of suitable antibodies is required, is still a long-lasting task. Methods to accelerate initial validation by MS approaches have been suggested, but all methods described so far are associated with serious drawbacks, finally leading to non-generic methods of detection and quantification. Moreover, when complex body fluids are used as samples, efficient debulking strategies are crucial to open a window of analytical sensitivity in the ng/mL range, where many diagnostically relevant analytes are present. Here we report the proof-of-principle of a multi-dimensional strategy for accelerated initial validation of biomarker candidates by MS, which promises to be generally applicable, sensitive and quantitative. The method presented employs a combination of electrophoretic and chromatographic steps on the peptide level, followed by MS quantification using isotopically labeled synthetic peptides as internal standards. Our proposed workflow includes up to four dimensions, finally resulting in a desired LOD sufficient to detect and quantify diagnostically relevant analytes from complex samples. Although the current state of the method only represents a starting point for further validation and development, it reveals great potential in biomarker validation.     

Neutron activation analysis of biological samples with a preirradiation chemical separation

A preirradiation separation procedure has been developed to separate Al, Cu, Mn, and V from biological materials. Chelex-100 resin is used as the separation medium, and the resin is irradiated directly. Three NIST biological Standard Reference Materials and five samples of human blood serum, obtained under carefully controlled conditions, have been analyzed by NAA following this separation.