Statistical techniques for predicting rupture risk in abdominal aortic aneurysms: A contribution based on bootstrap

The morphometry of abdominal aortic aneurysms (AAA) has been recognized as one of the main factors that may predispose them to rupture. The need to quantify the morphometry of AAA on a patient-specific basis constitutes a valuable tool for assisting in rupture risk prediction. Previous results of this research group have determined the correlations between hemodynamic stresses and aneurysm morphometry by means of the Pearson coefficient. The present work aims to find how the AAA morphology correlates with the hemodynamic stresses acting on the arterial wall. To do so, the potential of the bootstrap technique has been explored. Bootstrap works appropriately in applications where few data are available (13 patient-specific AAA models were simulated). The methodology developed can be considered a contribution to predicting the hemodynamic stresses from the size and shape indices. The present work explores the use of a specific statistical technique (the bootstrap technique) to predict, based on morphological correlations, the patient-specific aneurysm rupture risk, provide greater understanding of this complex phenomenon that can bring about improvements in the clinical management of aneurysmatic patients. The results obtained using the bootstrap technique have greater reliability and robustness than those obtained by regression analysis using the Pearson coefficient, thus allowing to obtain more reliable results from the characteristics of the samples used, such as their small size and high variability. Additionally, it could be an indicator that other indices, such as AAA length, deformation rate, saccular index, and asymmetry, are important.

Glucose transporter 4-deficient hearts develop maladaptive hypertrophy in response to physiological or pathological stresses

Pathological cardiac hypertrophy may be associated with reduced expression of glucose transporter 4 (GLUT4) in contrast to exercise-induced cardiac hypertrophy, where GLUT4 levels are increased. However, mice with cardiac-specific deletion of GLUT4 (G4H−/−) have normal cardiac function in the unstressed state. This study tested the hypothesis that cardiac GLUT4 is required for myocardial adaptations to hemodynamic demands. G4H−/− and control littermates were subjected to either a pathological model of left ventricular pressure overload [transverse aortic constriction (TAC)] or a physiological model of endurance exercise (swim training). As predicted after TAC, G4H−/− mice developed significantly greater hypertrophy and more severe contractile dysfunction. Somewhat surprisingly, after exercise training, G4H−/− mice developed increased fibrosis and apoptosis that was associated with dephosphorylation of the prosurvival kinase Akt in concert with an increase in protein levels of the upstream phosphatase protein phosphatase 2A (PP2A). Exercise has been shown to decrease levels of ceramide; G4H−/− hearts failed to decrease myocardial ceramide in response to exercise. Furthermore, G4H−/− hearts have reduced levels of the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1, lower carnitine palmitoyl-transferase activity, and reduced hydroxyacyl-CoA dehydrogenase activity. These basal changes may also contribute to the impaired ability of G4H−/− hearts to adapt to hemodynamic stresses. In conclusion, GLUT4 is required for the maintenance of cardiac structure and function in response to physiological or pathological processes that increase energy demands, in part through secondary changes in mitochondrial metabolism and cellular stress survival pathways such as Akt. NEW & NOTEWORTHY Glucose transporter 4 (GLUT4) is required for myocardial adaptations to exercise, and its absence accelerates heart dysfunction after pressure overload. The requirement for GLUT4 may extend beyond glucose uptake to include defects in mitochondrial metabolism and survival signaling pathways that develop in its absence. Therefore, GLUT4 is critical for responses to hemodynamic stresses.

Visualization of three pathways for macromolecule transport across cultured endothelium and their modification by flow

Transport of macromolecules across vascular endothelium and its modification by fluid mechanical forces are important for normal tissue function and in the development of atherosclerosis. However, the routes by which macromolecules cross endothelium, the hemodynamic stresses that maintain endothelial physiology or trigger disease, and the dependence of transendothelial transport on hemodynamic stresses are controversial. We visualized pathways for macromolecule transport and determined the effect on these pathways of different types of flow. Endothelial monolayers were cultured under static conditions or on an orbital shaker producing different flow profiles in different parts of the wells. Fluorescent tracers that bound to the substrate after crossing the endothelium were used to identify transport pathways. Maps of tracer distribution were compared with numerical simulations of flow to determine effects of different shear stress metrics on permeability. Albumin-sized tracers dominantly crossed the cultured endothelium via junctions between neighboring cells, high-density lipoprotein-sized tracers crossed at tricellular junctions, and low-density lipoprotein-sized tracers crossed through cells. Cells aligned close to the angle that minimized shear stresses across their long axis. The rate of paracellular transport under flow correlated with the magnitude of these minimized transverse stresses, whereas transport across cells was uniformly reduced by all types of flow. These results contradict the long-standing two-pore theory of solute transport across microvessel walls and the consensus view that endothelial cells align with the mean shear vector. They suggest that endothelial cells minimize transverse shear, supporting its postulated proatherogenic role. Preliminary data show that similar tracer techniques are practicable in vivo. NEW & NOTEWORTHY Solutes of increasing size crossed cultured endothelium through intercellular junctions, through tricellular junctions, or transcellularly. Cells aligned to minimize the shear stress acting across their long axis. Paracellular transport correlated with the level of this minimized shear, but transcellular transport was reduced uniformly by flow regardless of the shear profile.

STATISTICAL ANALYSIS FOR RUPTURE RISK PREDICTION OF ABDOMINAL AORTIC ANEURYSMS (AAA) BASED ON ITS MORPHOMETRY

The morphometry of the abdominal aortic aneurysms (AAA) has been recognized as one of the main factors that may predispose its rupture. The variation of the AAA morphometry, over time, induces modifications in hemodynamic behavior which, in turn, alters the spatial and temporal distribution of hemodynamic stress on the aneurismatic wall, establishing a bidirectional process that can influence the rupture phenomenon. In order to evaluate potential correlations between the main geometric parameters characterizing the AAA and hemodynamic stresses, 13 unrupture AAA patient-specific models were created. To AAA geometric characterization, 12 indices based on lumen center line were defined and determined. The computing of temporal and spatial distributions of hemodynamic stresses was conducted through Computational Fluid Dynamics. Statistical techniques were used to assess the relationships between the hemodynamic parameters and the different geometrical indices of the AAA. Regression analyses were conducted to obtain linear predictor models for hemodynamic stresses using the different indices defined in this paper as predictor variables. The statistical analysis confirmed that the length L, the asymmetry and the saccular index significantly influenced the hemodynamic stresses. The results obtained show the potential of the use of statistical techniques in predicting the rupture risk of patient-specific AAA.