Search

Graphical abstract:

Abstract

Many materials systems comprise complex structures where multiple materials are integrated to achieve a desired performance. Often in these systems, it is a combination of both the materials and their structure that dictate performance. Here the authors layout an integrated computational–statistical–experimental methodology for hierarchical materials systems that takes a holistic design approach to both the material and structure. The authors used computational modeling of the physical system combined with statistical design of experiments to explore an activated carbon adsorption bed. The large parameter space makes experimental optimization impractical. Instead, a computational–statistical approach is coupled with physical experiments to validate the optimization results.

Introduction:Systemic inflammation may play a central role in development of pulmonary hypertension (PH). We examined the association of eicosanoid metabolites (upstream regulators of pro- and anti-inflammatory activity) with PH. We hypothesized that multi-site sampling would reveal transpulmonary release or uptake of specific PH-associated eicosanoids.Methods:We studied 482 patients with preserved LVEF who underwent right heart catheterization. PH was defined as mean pulmonary artery pressure >20mmHg. Eicosanoid metabolites (n=888) were assessed using a mass spectrometry-based platform. We examined the association of eicosanoids with PH status using multivariable logistic regression. Multi-site sampling from radial and pulmonary arteries was conducted and differences assessed using paired t-tests. Analyses were deemed significant at FDR q<0.05.Results:Among 482 patients (56±16 years, 62% women), 200 (41%) had PH. Of 888 eicosanoids, 59 were associated with PH (FDR q<0.05; p<0.004 for all). Of these, 38 were known eicosanoid metabolites/classes and the rest were novel eicosanoids. Known metabolites including linoleic acid (12,13 EpOME) and eicosapentaenoic acid derivatives (11[12]-EpETE) were associated with lower odds of PH; by contrast leukotriene (LTB4) and arachidonic acid derivatives (11,12 diHETrE) were associated with higher odds of PH. Eighteen of 59 observed eicosanoids had concomitant transpulmonary gradients (Figure; FDR q<0.05; p<0.003 for all). Most metabolites associated with higher odds of PH displayed transpulmonary uptake, and those with lower odds of PH displayed transpulmonary release.Conclusions:We found specific eicosanoid metabolites including linoleic acid derivatives, thromboxanes, and leukotrienes were associated with PH. Further, transpulmonary gradients indicated potential physiologic relevance. Further studies are needed to elucidate the role of specific eicosanoids in the pathogenesis of PH.