Les maladies cardio-vasculaires demeurent une cause majeure de mortalité et morbidité dans les sociétés développées. La recherche de déterminants prédictifs d’évènements vasculaires représente toujours un enjeu d’actualité face aux coûts croissants des dépenses reliées aux soins médicaux et à l’élargissement des populations concernées, notamment face à l’occidentalisation des pays émergeants comme l’Inde, le Brésil et la Chine. La cardiologie nucléaire occupe depuis trente ans, une place essentielle dans l’arsenal des méthodes diagnostiques et pronostiques des cardiopathies. De plus, de nouvelles percées permettront de dépister d’une façon plus précoce et précise, la maladie athérosclérotique cardiaque et périphérique chez les populations atteintes ainsi qu’en prévention primaire. Nous présenterons dans cette thèse, deux approches nouvelles de la cardiologie nucléaire. La dysfonction endothéliale est considérée comme le signal pathologique le plus précoce de l’athérosclérose. Les facteurs de risques cardiovasculaires traditionnels atteignent la fonction endothéliale et peuvent initier le processus d’athérosclérose même en l’absence de lésion endothéliale physique. La quantification de la fonction endothéliale coronarienne comporte donc un intérêt certain comme biomarqueur précoce de la maladie coronarienne. La pléthysmographie isotopique, méthodologie développée lors de ce cycle d’étude, permet de quantifier la fonction endothéliale périphérique, cette dernière étant corrélée à la fonction endothéliale coronarienne. Cette méthodologie est démontrée dans le premier manuscrit (Harel et. al., Physiol Meas., 2007). L’utilisation d’un radiomarquage des érythrocytes permet la mesure du flot artériel au niveau du membre supérieur pendant la réalisation d’une hyperémie réactive locale. Cette nouvelle procédure a été validée en comparaison à la pléthysmographie par jauge de contrainte sur une cohorte de 26 patients. Elle a démontré une excellente reproductibilité (coefficient de corrélation intra-classe = 0.89). De plus, la mesure du flot artérielle pendant la réaction hyperémique corrélait avec les mesure réalisées par la méthode de référence (r=0.87). Le deuxième manuscrit expose les bases de la spectroscopie infrarouge comme méthodologie de mesure du flot artériel et quantification de la réaction hyperémique (Harel et. al., Physiol Meas., 2008). Cette étude utilisa un protocole de triples mesures simultanées à l’aide de la pléthysmographie par jauge de contrainte, radio-isotopique et par spectroscopie infrarouge. La technique par spectroscopie fut démontrée précise et reproductible quant à la mesure des flots artériels au niveau de l’avant-bras. Cette nouvelle procédure a présenté des avantages indéniables quant à la diminution d’artéfact et à sa facilité d’utilisation. Le second volet de ma thèse porte sur l’analyse du synchronisme de contraction cardiaque. En effet, plus de 30% des patients recevant une thérapie de resynchronisation ne démontre pas d’amélioration clinique. De plus, ce taux de non-réponse est encore plus élevé lors de l’utilisation de critères morphologiques de réponse à la resynchronisation (réduction du volume télésystolique). Il existe donc un besoin urgent de développer une méthodologie de mesure fiable et précise de la dynamique cardiaque. Le troisième manuscrit expose les bases d’une nouvelle technique radio-isotopique permettant la quantification de la fraction d’éjection du ventricule gauche (Harel et. al. J Nucl Cardiol., 2007). L’étude portant sur 202 patients a démontré une excellente corrélation (r=0.84) avec la méthode de référence (ventriculographie planaire). La comparaison avec le logiciel QBS (Cedar-Sinai) démontrait un écart type du biais inférieur (7.44% vs 9.36%). De plus, le biais dans la mesure ne démontrait pas de corrélation avec la magnitude du paramètre pour notre méthodologie, contrairement au logiciel alterne. Le quatrième manuscrit portait sur la quantification de l’asynchronisme intra-ventriculaire gauche (Harel et. al. J Nucl Cardiol, 2008). Un nouveau paramètre tridimensionnel (CHI: contraction homogeneity index) (médiane 73.8% ; IQ 58.7% - 84.9%) permis d’intégrer les composantes d’amplitude et du synchronisme de la contraction ventriculaire. La validation de ce paramètre fut effectuée par comparaison avec la déviation standard de l’histogramme de phase (SDΦ) (médiane 28.2º ; IQ 17.5º - 46.8º) obtenu par la ventriculographie planaire lors d’une étude portant sur 235 patients. Ces quatre manuscrits, déjà publiés dans la littérature scientifique spécialisée, résument une fraction des travaux de recherche que nous avons effectués durant les trois dernières années. Ces travaux s’inscrivent dans deux axes majeurs de développement de la cardiologie du 21ième siècle. / Cardiovascular diseases remain a major cause of mortality and morbidity in developed countries. The search for predictive determinants of vascular events represents a relevant and timely goal, considering the increasing costs of medical care and the progress in developing countries such as India, Brazil and China. Nuclear cardiology has, for 30 years, played an essential role in the diagnosis and prognosis of various cardiac and vascular diseases. Moreover, new developments will allow earlier and more specific detection of cardiac and peripheral atherosclerosis disease in affected individuals and in primary prevention. In this thesis, we will focus on advances in two major themes of nuclear cardiology. Endothelial dysfunction is regarded as the earliest pathological markers of atherosclerosis. Traditional cardiovascular risks factors impair endothelial function and can initiate the atherosclerosis process, even in the absence of overt endothelial disruption. Quantification of coronary endothelial function is, therefore, of considerable interest as an early biomarker for coronary disease. The radionuclide plethysmography methodology developed during the course of my doctoral studies allows the quantification of peripheral endothelial function, which has been correlated with coronary endothelial function. This methodology is detailed in the first manuscript (Harel et. al., Physiol Meas., 2007). The use of red blood cell radio-labeling permits arterial flow to be measured in the upper limb during local reactive hyperemia. This new procedure was validated against strain gauge plethysmography in a cohort of 26 patients with excellent reproducibility (intraclass coefficient of correlation = 0.89). Moreover, the arterial measurements of flow during the hyperemic reaction correlated well with the reference method (r=0.87). The second manuscript exposes the basis of infrared spectroscopy as a method for measuring arterial flow and quantifying the hyperemic reaction (Harel et. al., Physiol Meas., 2008). The study protocol consisted of simultaneous measurements by strain gauge, radionuclide and infrared spectroscopy plethysmography. The spectroscopy technique was shown to be precise and reproducible for forearm measurement of arterial blood flow. This novel procedure came major advantages in reducing artifacts and in its ease of use. The second axis of my thesis relates to the analysis of cardiac contraction synchrony. Indeed, more than 30% of patients receiving resynchronization therapy do not show clinical improvement. Moreover, this non-response rate is even higher if we consider morphological criteria of resynchronization (end-systolic volume reduction). There is therefore, an urgent need to improve a methodology to reliably and precisely measure cardiac dynamics so as to identify and monitor potential responders. The third manuscript exposes the basis of a new radionuclide technique to quantify left ventricle ejection fraction (Harel et. al. J Nucl Cardiol., 2007). The study of 202 patients showed an excellent correlation (r=0.84) with the reference method (planar ventriculography). The comparison with QBS software (Cedar-Sinai), showed a lower standard deviation of bias (7.44% vs 9.36%). Moreover, unlike the alternative software, the bias did not correlate with the magnitude of the ejection fraction. The fourth manuscript relates to the quantification of the left intra-ventricular synchronism (Harel et. al. J Nucl Cardiol, 2008). A new three-dimensional parameter (CHI: contraction homogeneity index) (median 73.8%; IQ 58.7% - 84.9%) was defined to allow the integration of amplitude and synchrony components of ventricular contraction. Validation of this parameter was undertaken out by comparing the standard deviation of the histogram of phase (SDΦ) (median 28.2º; IQ 17.5º- 46.8º) obtained by planar ventriculography in a study of 235 patients. These four manuscripts, already published in the specialized scientific literature, summarize a fraction of the research tasks that we have carried out during the three last years, representing two major axes of nuclear cardiology advancement in the 21st century.

Applied cancer research is heavily focused on the development of diagnostic tools with high sensitivity and specificity that are able to accurately detect the presence and anatomical location of neoplastic cells, as well as therapeutic strategies that are effective at curing or controlling the disease while being minimally invasive and having negligible side effects. Recently, much effort has been placed on the development of nanoparticles as diagnostic imaging and therapeutic agents, and several of these nanoplatforms have been successfully adopted in both the research and clinical arenas. This thesis describes the development of a nanoparticulate liposome system for use in a number of applications including multimodality imaging with computed tomography (CT) and magnetic resonance (MR), longitudinal vascular imaging, image-based biodistribution assessment, and CT detection of neoplastic and inflammatory lesions. Extensive in vitro and in vivo characterization was performed to determine the physico-chemical properties of the liposome agent, including its size, morphology, stability and agent loading, as well as its pharmacokinetics, biodistribution, tumor targeting and imaging performance. Emphasis was placed on the in vivo CT-based quantification of liposome accumulation and clearance from healthy and tumor tissues in a VX2 carcinoma rabbit model, gaining insight not only on the spatial but also the temporal biodistribution of the agent. The thesis concludes with a report that describes the performance of liposomes and CT imaging to detect and localize tumor and inflammatory lesions as compared to that of 18F-fluorodeoxyglucose (FDG) – positron emission tomography (PET). The outcome of the study suggests that liposome-CT could be employed as a competitive method for whole body image-based disease detection and localization. Overall, this work demonstrated that this liposome agent along with quantitative imaging systems and analysis tools, has the potential to positively impact cancer treatment outcome through improved diagnosis and staging, as well as enable personalization of treatment delivery via target delineation. However, in order to prove clinical benefit, steps must be taken to advance this agent through the regulatory stages and obtain approval for its use in humans. Ultimately, the clinical adoption of this multifunctional agent may offer improvements for disease detection, spatial delineation and therapy guidance.

The goal of this thesis was to produce an animal model that develops atherosclerotic plaque featuring plaque neovascularization leading to intraplaque hemorrhage and is suitable for noninvasive imaging studies. Several strategies were tested for their effectiveness in producing such plaques in the rabbit aorta, including: a high cholesterol diet, vascular endothelial growth factor injections, therapeutic contrast ultrasound, and balloon catheter injury. It was found that a combination of the high cholesterol diet and balloon injury was able to achieve plaque neovascularization in a manner dependent on circulating plasma cholesterol levels. In addition, a contrast-enhanced magnetic resonance imaging technique implemented in the animal model was able to detect plaque neovascularization and monitor its change over time in a single group of animals. In conclusion, an animal model was created where plaque neovascularization occurs in a predictable fashion and can be studied with non-invasive magnetic resonance imaging.

Dynamic nuclear polarization and dissolution of 13C-labeled metabolite allows dynamic imaging of metabolism in-vivo. However, the spatial and temporal resolutions of magnetic resonance spectroscopic imaging are limited by the duration of free-induction decay acquisitions and the T1-based, non-recoverable polarization decay. This thesis describes the implementation of a spectral-spatial radiofrequency excitation pulse with a `flyback' echo-planar readout trajectory to dynamically image [1-13C]-pyruvate and [1-13C]-lactate in an interleaved manner. This technique excites a single resonance of either [1-13C]-pyruvate or [1-13C]-lactate and generates dynamic images with 5mm in-plane resolution. Metabolite dynamics extracted from the images and the corresponding non-localized spectroscopic data reveal similar kinetic rates upon fitting to a kinetic model. This demonstrates the feasibility of probing metabolism in heterogeneous tissues in-vivo with dynamic interleaved 13C MR imaging.

There is mounting evidence to support combined therapy with radiation (RT) and antiangiogenic agents (AA) for the treatment of brain tumors. However, the therapeutic benefit of this combined treatment hinges on the specific dose, schedule, and duration of each treatment. Early biomarkers that reflect tumor physiological responses provide key information that could guide these aspects of treatment. Pre-clinical tumor models are invaluable tools for identifying potential biomarkers, their optimal timing for measurement and their ability to guide therapy in clinical translation. This thesis demonstrates the feasibility and potential of serial MRI to guide the design, delivery and measure of early response to combined AA and RT in a murine intracranial glioma model. We identified promising biomarker changes reflecting early treatment response that may ultimately facilitate individualized spatio-temporal delivery of radiotherapy (RT) and anti-angiogenic agents (AA) for brain tumors.

This thesis presents a high-resolution volumetric technique to measure the longitudinal relaxation time T1 in the vessel wall using MRI. The method of Variable Flip Angles (VFA) was applied using a new strategy for flip angle selection that allows measurement of T1 with high accuracy (< 10% mean error) and precision (T1-to-noise ratio > 10) over the wide range of anticipated values (300-3000ms) in the vessel wall. This strategy was validated in simulation, phantom and volunteer spinal cord experiments. Initial validation of vessel wall T1 measurements was performed in ex-vivo thoracic aorta samples from cholesterol-fed rabbits. For in-vivo vessel wall T1 mapping, the technique was augmented with spatial saturation bands for flow suppression and applied to the carotid arteries of three volunteers. Preliminary results from volunteers suggest that this approach may be useful in characterizing T1 changes associated with high-risk atherosclerotic disease.

BACKGROUND: MRI is increasingly being used for rectal cancer staging. The purpose of this study was to summarize published evidence to determine the accuracy of MRI for T-category, lymph node (LN) metastases, and circumferential resection margin (CRM) involvement in rectal cancer. METHODS: Sensitivity, specificity, and diagnostic odds ratios (DOR) were estimated using hierarchical summary receiver operating characteristics modeling and bivariate random effects modeling. RESULTS: MRI was more specific for CRM (94%, 95%CI 88-97) than for T-category (75%, 95%CI 68-80) and LN’s (71%, 95%CI 59-81) but was more sensitive for T-category (87%, 95%CI 81-92) than for CRM (77%, 95%CI 57-90) and LN’s (77%, 95%CI 69-84). DOR was higher for CRM (56.1, 95%CI 15.3-205.8) than for LN’s (8.3, 95%CI 4.6-14.7) and T-category (20.4, 95%CI 11.1-37.3). CONCLUSIONS: MRI has good accuracy for both CRM and T-category and should be considered for preoperative rectal cancer staging. In contrast, LN assessment is poor on MRI.

This thesis investigated the role of CBF assessment in the management of stroke in children with sickle cell disease (SCD). It is divided into two parts. In the first part, a systematic review of CBF assessment using different imaging modalities in SCD children was designed. The prevalence of CBF abnormalities was found to be equal to or higher than those of structural MRI and transcranial Doppler (TCD) in SCD children who have not experienced stroke. Studies reviewed suggested CBF assessment in SCD could aid in addressing brain abnormalities at the tissue level. In the second part, the arterial spin labeling (ASL) technique was used to depict CBF abnormalities in SCD children. ASL demonstrated perfusion abnormalities that seem to remain invisible in TCD measurements; CBF interhemispheric asymmetries were associated with clinically silent infarctions with no corresponding flow velocity interhemispheric asymmetries assessed with TCD.

Purpose: To compare hemodynamic of malignant and benign SRMs on CT and CEUS. Method: Seventy biopsy proven SRM underwent CEUS. Sixty-three had CT. After injection of 0.2 ml of Definity, 3min and after 0.9 ml infusion, 30 sec of data were acquires. Lesion hemodynamics relative to the cortex was evaluated both qualitatively and quantitatively. Results: Considering 15 and 20 HU as enhancement threshold, 10% to 13% of patients did not enhance on CT, while all lesions enhanced on CEUS. Papillary RCCs showed hypovascularity with 100% specificity. In other RCCs, PI, WI slope 5 to45%, 50 to100%, 10 to 90%, WO slope 100 to 50%, 100 to 10%, WO intensity at peak+30 seconds were statistically higher than benign SRMs. Conclusion: All solid SRMs enhance on CEUS, while CT does not show vascularity in 10-13% of solid SRMs. CEUS can differentiate malignant from benign SRMs by evaluating their hemodynamics.

The goal of this thesis was to produce an animal model that develops atherosclerotic plaque featuring plaque neovascularization leading to intraplaque hemorrhage and is suitable for noninvasive imaging studies. Several strategies were tested for their effectiveness in producing such plaques in the rabbit aorta, including: a high cholesterol diet, vascular endothelial growth factor injections, therapeutic contrast ultrasound, and balloon catheter injury. It was found that a combination of the high cholesterol diet and balloon injury was able to achieve plaque neovascularization in a manner dependent on circulating plasma cholesterol levels. In addition, a contrast-enhanced magnetic resonance imaging technique implemented in the animal model was able to detect plaque neovascularization and monitor its change over time in a single group of animals. In conclusion, an animal model was created where plaque neovascularization occurs in a predictable fashion and can be studied with non-invasive magnetic resonance imaging.