Luca Antiga

An image-based modeling framework for patient-specific computational hemodynamics

We present a modeling framework designed for patient-specific computational hemodynamics to be performed in the context of large-scale studies. The framework takes advantage of the integration of image processing, geometric analysis and mesh generation techniques, with an accent on full automation and high-level interaction. Image segmentation is performed using implicit deformable models taking advantage of a novel approach for selective initialization of vascular branches, as well as of a strategy for the segmentation of small vessels. A robust definition of centerlines provides objective geometric criteria for the automation of surface editing and mesh generation. The framework is available as part of an open-source effort, the Vascular Modeling Toolkit, a first step towards the sharing of tools and data which will be necessary for computational hemodynamics to play a role in evidence-based medicine.

Geometry of the Carotid Bifurcation Predicts Its Exposure to Disturbed Flow

Background and Purpose— That certain vessels might be at so-called geometric risk of atherosclerosis rests on assumptions of wide interindividual variations in disturbed flow and of a direct relationship between disturbed flow and lumen geometry. In testing these often-implicit assumptions, the present study aimed to determine whether investigations of local risk factors in atherosclerosis can indeed rely on surrogate geometric markers of disturbed flow. Methods— Computational fluid dynamics simulations were performed on carotid bifurcation geometries derived from MRI of 25 young adults. Disturbed flow was quantified as the surface area exposed to low and oscillatory shear beyond objectively-defined thresholds. Interindividual variations in disturbed flow were contextualized with respect to effects of uncertainties in imaging and geometric reconstruction. Relationships between disturbed flow and various geometric factors were tested via multiple regression. Results— Relatively wide variations in disturbed flow were observed among the 50 vessels. Multiple regression revealed a significant (P<0.002) relationship between disturbed flow and both proximal area ratio (&bgr;≈0.5) and bifurcation tortuosity (&bgr;≈−0.4), but not bifurcation angle, planarity, or distal area ratio. These findings were shown to be insensitive to assumptions about the flow conditions and to the choice of disturbed flow indicator and threshold. Conclusions— Certain geometric features of the young adult carotid bifurcation are robust surrogate markers of its exposure to disturbed flow. It may therefore be reasonable to consider large-scale retrospective or prospective imaging studies of local risk factors for atherosclerosis without the need for time-consuming and expensive flow imaging or CFD studies.

Robust and objective decomposition and mapping of bifurcating vessels

Computational modeling of human arteries has been broadly employed to investigate the relationships between geometry, hemodynamics and vascular disease. Recent developments in modeling techniques have made it possible to perform such analyses on realistic geometries acquired noninvasively and, thus, have opened up the possibility to extend the investigation to populations of subjects. However, for this to be feasible, novel methods for the comparison of the data obtained from large numbers of realistic models in the presence of anatomic variability must be developed. In this paper, we present an automatic technique for the objective comparison of distributions of geometric and hemodynamic quantities over the surface of bifurcating vessels. The method is based on centerlines and consists of robustly decomposing the surface into its constituent branches and mapping each branch onto a template parametric plane. The application of the technique to realistic data demonstrates how similar results are obtained over similar geometries, allowing for proper model-to-model comparison. Thanks to the computational and differential geometry criteria adopted, the method does not depend on user-defined parameters or user interaction, it is flexible with respect to the bifurcation geometry and it is readily extendible to more complex configurations of interconnecting vessels.

A Framework for Geometric Analysis of Vascular Structures: Application to Cerebral Aneurysms

There is well-documented evidence that vascular geometry has a major impact in blood flow dynamics and consequently in the development of vascular diseases, like atherosclerosis and cerebral aneurysmal disease. The study of vascular geometry and the identification of geometric features associated with a specific pathological condition can therefore shed light into the mechanisms involved in the pathogenesis and progression of the disease. Although the development of medical imaging technologies is providing increasing amounts of data on the three-dimensional morphology of the in vivo vasculature, robust and objective tools for quantitative analysis of vascular geometry are still lacking. In this paper, we present a framework for the geometric analysis of vascular structures, in particular for the quantification of the geometric relationships between the elements of a vascular network based on the definition of centerlines. The framework is founded upon solid computational geometry criteria, which confer robustness of the analysis with respect to the high variability of in vivo vascular geometry. The techniques presented are readily available as part of the VMTK, an open source framework for image segmentation, geometric characterization, mesh generation and computational hemodynamics specifically developed for the analysis of vascular structures. As part of the Aneurisk project, we present the application of the present framework to the characterization of the geometric relationships between cerebral aneurysms and their parent vasculature.

Variation in the Carotid Bifurcation Geometry of Young Versus Older Adults Implications for Geometric Risk of Atherosclerosis

Background and Purpose— Retrospective analysis of clinical data has demonstrated major variations in carotid bifurcation geometry, in support of the notion that an individual’s vascular anatomy or local hemodynamics may influence the development of atherosclerosis. On the other hand, anecdotal evidence suggests that vessel geometry is more homogenous in youth, which would tend to undermine this geometric risk hypothesis. The purpose of our study was to test whether the latter is indeed the case. Methods— Cross-sectional images of the carotid bifurcations of 25 young adults (24±4 years) and a control group of 25 older subjects (63±10 years) were acquired via MRI. Robust and objective techniques were developed to automatically characterize the 3D geometry of the bifurcation and the relative dimensions of the internal, external, and common carotid arteries (ICA, ECA, and CCA, respectively). Results— Young vessels exhibited significantly less interindividual variation in the following geometric parameters: bifurcation angle (48.5±6.3° versus 63.6±15.4°); ICA angle (21.6±6.7° versus 29.2±11.3°); CCA tortuosity (0.010±0.003 versus 0.014±0.011); ICA tortuosity (0.025±0.013 versus 0.086±0.105); ECA/CCA diameter ratio (0.81±0.06 versus 0.75±0.13), ICA/CCA (0.81±0.06 versus 0.77±0.12) diameter ratio, and bifurcation area ratio (1.32±0.15 versus 1.19±0.35). Conclusions— The finding of more modest interindividual variations in young adults suggests that, if there is a geometric risk for atherosclerosis, its early detection may prove challenging. Taken together with the major interindividual variations seen in older vessels, it suggests a more complex interrelationship between vascular geometry, local hemodynamics, vascular aging, and atherosclerosis, the elucidation of which now calls for prospective studies.

Computational geometry for patient-specific reconstruction and meshing of blood vessels from MR and CT angiography

Investigation of three-dimensional (3-D) geometry and fluid-dynamics in human arteries is an important issue in vascular disease characterization and assessment. Thanks to recent advances in magnetic resonance (MR) and computed tomography (CT), it is now possible to address the problem of patient-specific modeling of blood vessels, in order to take into account interindividual anatomic variability of vasculature. Generation of models suitable for computational fluid dynamics is still commonly performed by semiautomatic procedures, in general based on operator-dependent tasks, which cannot be easily extended to a significant number of clinical cases. In this paper, we overcome these limitations making use of computational geometry techniques. In particular, 3-D modeling was carried out by means of 3-D level sets approach. Model editing was also implemented ensuring harmonic mean curvature vectors distribution on the surface, and model geometric analysis was performed with a novel approach, based on solving Eikonal equation on Voronoi diagram. This approach provides calculation of central paths, maximum inscribed sphere estimation and geometric characterization of the surface. Generation of adaptive-thickness boundary layer finite elements is finally presented. The use of the techniques presented here makes it possible to introduce patient-specific modeling of blood vessels at clinical level.

Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial

BACKGROUND Autosomal dominant polycystic kidney disease slowly progresses to end-stage renal disease and has no effective therapy. A pilot study suggested that the somatostatin analogue octreotide longacting release (LAR) could be nephroprotective in this context. We aimed to assess the effect of 3 years of octreotide-LAR treatment on kidney and cyst growth and renal function decline in participants with this disorder. METHODS We did an academic, multicentre, randomised, single-blind, placebo-controlled, parallel-group trial in five hospitals in Italy. Adult (>18 years) patients with estimated glomerular filtration rate (GFR) of 40 mL/min per 1·73 m(2) or higher were randomly assigned (central allocation by phone with a computerised list, 1:1 ratio, stratified by centre, block size four and eight) to 3 year treatment with two 20 mg intramuscular injections of octreotide-LAR (n=40) or 0·9% sodium chloride solution (n=39) every 28 days. Study physicians and nurses were aware of the allocated group; participants and outcome assessors were masked to allocation. The primary endpoint was change in total kidney volume (TKV), measured by MRI, at 1 year and 3 year follow-up. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, NCT00309283. FINDINGS Recruitment was between April 27, 2006, and May 12, 2008. 38 patients in the octreotide-LAR group and 37 patients in the placebo group had evaluable MRI scans at 1 year follow-up, at this timepoint, mean TKV increased significantly less in the octreotide-LAR group (46·2 mL, SE 18·2) compared with the placebo group (143·7 mL, 26·0; p=0·032). 35 patients in each group had evaluable MRI scans at 3 year follow-up, at this timepoint, mean TKV increase in the octreotide-LAR group (220·1 mL, 49·1) was numerically smaller than in the placebo group (454·3 mL, 80·8), but the difference was not significant (p=0·25). 37 (92·5%) participants in the octreotide-LAR group and 32 (82·1%) in the placebo group had at least one adverse event (p=0·16). Participants with serious adverse events were similarly distributed in the two treatment groups. However, four cases of cholelithiasis or acute cholecystitis occurred in the octreotide-LAR group and were probably treatment-related. INTERPRETATION These findings provide the background for large randomised controlled trials to test the protective effect of somatostatin analogues against renal function loss and progression to end-stage kidney disease. FUNDING Polycystic Kidney Disease Foundation.

Correlations among indicators of disturbed flow at the normal carotid bifurcation.

A variety of hemodynamic wall parameters (HWP) has been proposed over the years to quantify hemodynamic disturbances as potential predictors or indicators of vascular wall dysfunction. The aim of this study was to determine whether some of these might, for practical purposes, be considered redundant. Image-based computational fluid dynamics simulations were carried out for N=50 normal carotid bifurcations reconstructed from magnetic resonance imaging. Pairwise Spearman correlation analysis was performed for HWP quantifying wall shear stress magnitudes, spatial and temporal gradients, and harmonic contents. These were based on the spatial distributions of each HWP and, separately, the amount of the surface exposed to each HWP beyond an objectively-defined threshold. Strong and significant correlations were found among the related trio of time-averaged wall shear stress magnitude (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). Wall shear stress spatial gradient (WSSG) was strongly and positively correlated with TAWSS. Correlations with Himburg and Friedmans dominant harmonic (DH) parameter were found to depend on how the wall shear stress magnitude was defined in the presence of flow reversals. Many of the proposed HWP were found to provide essentially the same information about disturbed flow at the normal carotid bifurcation. RRT is recommended as a robust single metric of low and oscillating shear. On the other hand, gradient-based HWP may be of limited utility in light of possible redundancies with other HWP, and practical challenges in their measurement. Further investigations are encouraged before these findings should be extrapolated to other vascular territories.

Sirolimus Therapy to Halt the Progression of ADPKD

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Reducing Polycystic Liver Volume in ADPKD: Effects of Somatostatin Analogue Octreotide

BACKGROUND AND OBJECTIVES No medical treatment is available for polycystic liver disease, a frequent manifestation of autosomal-dominant polycystic kidney disease (ADPKD). In a prospective, randomized, double-blind, crossover study, 6 months of octreotide (40 mg every 28 days) therapy limited kidney volume growth more effectively than placebo in 12 patients with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this secondary, post hoc analysis of the above study, octreotide-induced changes in liver volumes compared with placebo and the relationship between concomitant changes in liver and kidney volumes were evaluated. Those analyzing liver and kidney volumes were blinded to treatment. RESULTS Liver volumes significantly decreased from 1595 +/- 478 ml to 1524 +/- 453 ml with octreotide whereas they did not appreciably change with placebo. Changes in liver volumes were significantly different between the two treatment periods (-71 +/- 57 ml versus +14 +/- 85 ml). Octreotide-induced liver volume reduction was fully explained by a reduction in parenchyma volume from 1506 +/- 431 ml to 1432 +/- 403 ml. Changes in liver volumes were significantly correlated with concomitant changes in kidney volumes (r = 0.67) during octreotide but not during placebo treatment. Liver and kidney volume changes significantly differed with both treatments (octreotide: -71 +/- 57 ml versus +71 +/- 107; placebo: +14 +/- 85 ml versus +162 +/- 114), but net reductions in liver (-85 +/- 103 ml) and kidney (-91 +/- 125 ml) volume growth on octreotide versus placebo were similar. CONCLUSIONS Octreotide therapy reduces liver volumes in patients with ADPKD and is safe.