Rare Diseases: don't stop the research

Project location: ITALY
Project start date: January 2001 - Project end date: January 2002
Project number: 2001-15
Beneficiary: ARMR

Fellowship for a research study on Takayasu arterisis

The Nando Peretti Foundation is financing the Association for the Research on Rare Diseases (ARMR) with a one year fellowship carried on by Dr. Luca Antiga in the Clinic Research Center of Rare Diseases "Aldo e Cele Daccò". The research aims to study the development of a rare disease, Takayasu arteritis, from the points of view of anatomy and hemodynamics.

Takayasu arteritis causes arterial wall inflammation in big arteries, which leads to progressive loss of mechanical properties, formation of stenoses, occlusions and, less frequently, dilations and aneurisms. The induced anatomic alterations of affected vessels can make conventional angiographic investigations difficult to interpret and not sufficient for the characterization of the pathology.

The research project is designed to study the development of Takayasu arteritis making use of magnetic resonance investigation, image processing and numerical modeling. A group of patients affected by Takayasu arteritis will undergo periodic magnetic resonance investigations. Acquired data will be transferred to calculators for subsequent advanced image processing, which will lead to detailed 3D reconstruction and characterization of injured vessels. Computational fluid dynamics will be performed based on reconstructed 3D models, to characterize hemodynamics.

The first step is the set up of the methodology on test cases, which has partially been accomplished. The final step is the application of the methodology to patients referenced by Clinic Research Center for Rare Diseases "Aldo e Cele Daccò".

Final results

The project is aimed to develop and apply novel methods for the study of geometry and local hemodynamics of arterial tracts in patients affected by Takayasu arteritis.

Takayasu arteritis is a rare chronic inflammatory arterial disease of unknown origin, which causes severe alterations in vessel walls mechanical properties and morphology, leading to luminal narrowing, occlusions, dilatations and aneurysms. The inflammatory processes take place mainly on media and adventitia, with associated increase in vasa vasorum vascularization between the two laminae. Intimal thickening is observed, but it is considered secondary to the underlying inflammation. Takayasu arteritis is characterized by an alternation of active and quiescent phases, which can produce effects in short time scales. However, as a long term effect, the chronic nature of the disease leads to the recruitment of collateral vascularization to adapt to the impaired blood supply. The lesions tend to by localized in specific sites along the affected artery.

The objectives of the project are multiple. Firstly, to provide an accurate characterization of vascular geometry for diseased arterial tracts in a non invasive way. Vascular anatomy is acquired by means of magnetic resonance angiography, which is usually performed on those patients on which echo-Doppler investigation is not completely informative. State-of-the-art computational techniques for three-dimensional reconstruction and geometric analysis, developed in the context of the project, are then applied to the acquired images, so to disclose the complex anatomy of diseased tracts. In particular, the possibility of following single patients at fixed time intervals, which have been fixed to six months, will provide a unique picture of the morphological changes of the diseased tracts at various stages of disease activity.

A second objective is the characterization of blood flow patterns which develop inside the diseased tracts. To this extent, the three-dimensional models reconstructed for geometric characterization are further processed with ad-hoc developed methods and employed in computational fluid dynamics simulations. The aim is to have a picture of how the disease affects blood flow patterns in the various stages of activity. Moreover, since Takayasu arteritis exhibits a focal behaviour, causing lesions develop at particular sites, it is informative to document the eventual role played by local hemodynamic factors in the acute phase.

From a practical point of view, effort has been taken to provide the physician with a better insight on vessel morphology and hemodynamics of single patients. Particle tracking techniques were developed in order to provide a useful visualization of blood flow, evidencing recirculations or high particle residence time regions.

Up to now, the development and the optimization of the techniques involved in the project have been successfully accomplished. Moreover, the first acquisition on the abdominal aorta of a Takayasu arteritis patient has been performed. The patient had underwent a graft implantation at the iliac bifurcation, and had one kidney not perfused. The results of the geometric reconstruction and analysis evidenced that the abdominal aorta is characterized by a narrowing at the suprarenal level followed by an abrupt dilation at the level of the renal artery. The lumen of the renal artery appears to be smaller than normal. The iliac graft is patent. Flow dynamics computation disclosed the development of complex blood flow patterns both at the level of the dilation and at the upper part of the iliac bifurcation graft. The latter consists in a small recirculation region past the entrance of the graft, caused by a slight abrupt increase in vessel lumen (may be caused by a post-implantation narrowing of the aorta proximal to the graft), which does not seem to have particular consequences on iliac arteries patency. In contrast, the complex flow patterns developing inside the aortic dilation, at the level of the patent renal artery, have two negative effects on blood flow. The first is the onset of a large recirculation region inside the dilation, resulting in high particle residence times, typically responsible of an increased interaction of circulating cells and proteins with the vessel wall and among themselves. Secondly, the dilation has implications in flow patterns developing at the entrance of the patent renal artery. In fact it can be observed that the renal artery is perfused by retrograde flow only, which have an effect on pressure and flow rate of the artery supplying the kidney. The second acquisition on this same patient, programmed for November 2002, will allow to confirm or correct the hypotheses formulated on the first acquisition.

The follow-up nature of the project and the time required for the development of the computational techniques do not allow to draw conclusions after one year of work. However, the project has made it possible to set up a long-term process which will provide a unique insight on the effects of Takayasu arteritis on morphology and hemodynamics.

According to this, the first months of work have been mainly dedicated to methodological issues, which can be summarized into four groups: image acquisition, three-dimensional modeling, geometric analysis and fluid-dynamical analysis. As to image acquisition, magnetic resonance angiography (MRA) was chosen among the available acquisition methods because of its low invasiveness (the contrast medium used is well tolerated even in patients with renal disease) and the high detail provided. In addition to these advantages, MRA is particularly well suited for the study of patients which cannot be investigated by means of Doppler ultrasound, such as overweight patients with diseased thoracic and abdominal vessels, which are common among Takayasu patients.


Press review

Consegnate in Prefettura le Borse di Studio per la lotta alle malattie rare
L'iniziativa dell'Associazione ARMR per aiutare lo sviluppo di progetti innovativi nel Centro "Aldo e Cele Daccò" di Ranica
Da: L'Eco di Bergamo, 21 Novembre 2001
di Heidi Busetti

Un premio alla ricerca. Sette Borse di studio e quattro premi sono stati consegnati nei giorni scorsi ad undici studiosi, durante la cerimonia organizzata dall'Associazione per la Ricera sulle Malattie Rere nel Palazzo della Prefettura. L'Associazione - fondata nel 1996 - ha proprio lo scopo di promuovere la conoscenza delle cause e la ricerca di terapie per la cura delle malattie rare. Una ricerca che si avvale anche di giovani studiosi e per questo tra gli obiettivi dell'Associazione c'è l'aiuto finanziario per la formazione di giovani ricercatori sia italiani che stranieri che collaborino a progetti di ricerca da effettuare nel Centro di Ricerca per le Malattie Rare "Aldo e Cele Daccò". Alla cerimonia - seguita da una cena - sono intervenuti il Prefetto Andrea De Martino; il Questore Salvatore Presenti; la Presidentessa dell'Associazione Daniela Guadalupi gennaro; il Vice-Sindaco Franco Tentorio; il Comandante dell'Accademia della Guardia di Finanza, Giuseppe Quaranta; il Comandante della Guardia di Finanza, Riccardo Piccinni e ancora Vincenzo Procacci, Comandante dei Carabinieri; Mariano Cenniccola, Comandante interregionale dei Carabinieri; Don Antonio Mazzi e Silvio Garattini, direttore dell'Istituto Farmacologico Mario Negri di Milano. "Questa è la sera delle ricerche - ha detto il Prefetto - un grazie dunque a quanti nella loro vita, giorno dopo giorno, animano il sistema della ricerca italiana, e questo sia a livello scientifico che a livello organizzativo e sociale. Sicuramente uno degli obiettivi più importanti della ricerca è quello di rendere migliore la vita nei diversi campi del sapere umano". Le sette Borse di Studio sono state divise in due categorie: "Borse Senior" (18 milioni ciascuna) e "Borse Junior" (12 milioni). A riceverle sono state, per la prima categoria, Regiane Aparecida Cabinato, Luca Antiga e Simona Bruno. Per la catergoria "Junior" sono stati premiati Elena Binda, Simona Brioschi, Francesco Marconi e Silvia Contaretti. Le Borse di Studio sono state finanziate da diversi Enti, quali la Fondazione Nando Peretti, il Rotary Club Orbetello Costa d'Argento, La Bracco spa, e una Borsa intitolata a "Maria Teresa Conterno". I quattro premi dell'Associazione per la ricerca sulle Malattie Rare sono stati, invece, ricevuti da Diana Bracco per la sua figura di mecenate in campo artistico; Anna Naddeo Astori, per la sensibilità dimostrata nei confronti della società; Elsa Peretti, per la ricerca dell'arte del gioiello, e a Giuseppe Remussi, per la ricerca nell'ambito delle malattie renali e dei trapianti d'organo.

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