Дисертації з теми "Late gadolinium magnetic resonance imaging"

Background: Cardiomyopathies are an important and heterogeneous group of diseases of the heart muscle in which tissue characterization has been extensively studied only ex-vivo so far. Cardiac magnetic resonance (CMR) can provide in vivo the detection of post-contrast deposition (so called Late Gadolinium Enhancement, LGE). The role of LGE in the differential diagnosis of cardiac diseases has advanced through the years, in particular thanks to its capability to differentiate post-ischemic scar (with subendocardial or transmural coronary artery-related deposition) versus non-ischemic scar of different aetiologies. Among cardiomyopathies, the prognostic significance of LGE pattern is not well established, with the exception of hypertrophic cardiomyopathy. Detection in vivo of LGE in different cardiomyopathies has been used as a surrogate of fibrosis, even if the real basis of contrast deposition is not well understood. To this regard, dilated cardiomyopathy (DCM) is characterized by diffuse interstitial fibrosis with or without replacement-type fibrosis, which are associated with worse prognosis. Another myocardial disease in which CMR offers the capability of a non-invasive tissue characterization is Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), an inherited heart muscle disease with progressive loss of myocardium and replacement by fibrofatty tissue. The extensively application of CMR to these cardiomyopathies and its comparison with traditional invasive and non-invasive techniques for diagnostic and prognostic purposes has been limited so far. Aim: in order to assess the clinical significance of LGE in DCM and ARVC, the following lines were pursued: 1) in patients with DCM the diagnostic and the prognostic value of LGE, in particular evaluating the possible different significance of various LGE patterns, total amount of LGE against survival, heart failure and ventricular arrhythmias; 2) in patients with ARVC the comparison between CMR findings and: 1a) traditional electrocardiographic features; 1b) scar detction by endocardial voltage mapping (EVM), and 1c) the prognostic significance of LGE; 3) the significance of CMR tissue abnormalities by comparing LGE and specimen heart and/or endomyocardial biopsy (EMB) findings in DCM and ARVC. Material and Methods: Between January 2007 and December 2010 we prospectively evaluated two different groups of patients referred to our Tertiary Referral Centre for a complete invasive and non-invasive evaluation for unexplained left ventricle (LV) dilatation (DCM Group, A) and for suspected ARVC (ARVC Group, B). DCM Group (A): we prospectively evaluated 210 patients referred for unexplained LV dilatation with subacute-chronic onset (≥ 1 month), with or without previous history of heart failure, who underwent during the same hospitalization to a complete screening including CMR with LGE, angiography and EMB. ARVC group (B): we prospectively evaluated 52 patients who were referred to our Tertiary Centre for susptected ARVC and in which the diagnosis was reached according to 1994 Task Force Criteria and 2010 Modified Criteria. Data on clinical history, ECG, ECG Holter monitoring, echocardiography, CMR and EMB in selected cases were collected. In a subgroup of patients an electrophysiological study with EVM was performed. For each subject enrolled, a clinical, ECG and echocardiographic follow-up was obtained. Results: Group A. On the basis of coronary angiography, patients were divided into two groups: ischemic (99 patients) and DCM (111 patients). Ischemic group patients were then excluded from the analysis. Compared to angiography, CMR showed an excellent accuracy (96.5%) for the identification of non-ischemic versus ischemic aetiology for LV dilatation. In the DCM group (111 patients) LGE was present (with a non-ischemic pattern) in 67 cases (60.4%) and absent in 44 (39.6%); no differences between RV and LV volumes and ejection fraction (EF) were found between the two groups. Out of 67 patients with positive LGE, a “gray” pattern was present in 12 patients (17.9%), a midwall/subepicardial stria in 49 (73.1%), a septal junction pattern (anterior and/or posterior) either isolated in 4 (5.9%) or associated with other patterns in 25 patients (37.3%) and finally a spotty (“patchy”) pattern in 2 (2.9%). Among patients with positive LGE, the extent of LGE was 6.3%+/-8.8% of LV mass. Fifty-eight patients underwent to EMB: 33/58 patients (56.9%) showed replacement-type fibrosis, of this subgroup 23 patients (69.7%) showed LGE on CMR. Out of 13/58 patients (22%) without replacement-type fibrosis on EMB, LGE was present in 9/13 (69.2%) patients: in this subgroup the most frequent LGE pattern was midwall/subepicardial stria (n=8/9; 89%) and one patient (11%) showed a “patchy” LGE pattern . Compared to EMB, CMR showed a low accuracy for fibrosis detection. The range of follow-up in LGE group was 8 years-1 month. Kaplan-Meier curves for composite end-point and ventricular arrhythmias showed a significant differences between patients with and without LGE on CMR (Wilcoxon-Breslow: p< 0.05). The amount of LGE%, by univariate analysis, was strongly associated with ventricular arrhythmias (HR 1.05, 95% CI 1.02 to 1.08; p<0.0001). This association was unchanged in multivariate analysis adjusted for a EF<30% (model 5): HR 1.067, 95% CI 1.034 to 1.1; p<0.0001.With an associated HR of 2.5, the presence of LGE was among the strongest multivariate predictors for the combined end point, surpassed only by age < 49 years. ROC curve analysis revealed a LGE percentage of 3.5 as optimal discriminator for the occurrence of ventricular arrhythmic events with an associated HR of 4.11 (95% CI 1.3 to 12.7; p<0.001). Group B: On the basis of clinical and CMR evaluation, 24 patients (46%) were defined as “classic ARVC phenotype”; 14 (27%) as “left dominant phenotype”, and finally 14 (27%) as “biventricular ARVC phenotype”. Comparison between ECG and CMR showed that ECG indexes of LV dilatation are ST-segment elevation and T-wave inversion beyond V3 (p<0.05); among tissue characterization parameters, only LV LGE has an identifiable ECG abnormality, i.e. ST segment elevation (p<0.05). On EVM, endocardial voltages of RV was abnormal in 21/23 (91%) patients, with a total of 45 electroanatomic scars (EAS). RV LGE was found in 9/23 (39%) patients, with a total of 23 RV LGE scars: there was a mismatch in 24 RV scars, with 22 EAS not confirmed by LGE. In 9/12 (75%) patients with abnormal RV EVM/normal RV LGE, ≥1 LGE were identified in the LV. The patients of ARVC group enrolled for the follow-up were 52 (34 males; mean age 33+/-15 years). The mean LV ejection fraction was 57+/-8%; the mean fractional area change of RV was 39+/-10%. The mean follow-up was 25.6 months (range 38+/-4 months). Considering only the major events (aborted sudden death/ ventricular fibrillation; sudden death; non sudden death/heart transplantation) these occurred in 12 (7 in the LGE group, 5 in the non-LGE group).Kaplan-Meier curves did not show difference between LGE presence/absence for all events and major events. Kaplan-Meier curves did not show difference between three phenotypes detected by CMR both for all events and major events. Conclusions: CMR can provide a wide range of information in DCM and ARVC, beyond traditional imaging modalities. In the setting of DCM, CMR shows high accuracy in the detection of non-ischemic aetiology compared with angiography. LGE identifies the patients with increased risk of ventricular arrhythmic events. Compared to EMB, CMR with LGE imaging shows low accuracy for fibrosis detection, probably due to resolution power of CMR. However, an integrated approach with CMR and EMB may be useful in cases with negative EMB/positive LGE to identify epicardial lesion, which are not caught by EMB due to its endocardial approach. In the setting of ARVC, CMR confirms its superiority in assessing the full spectrum of morpho-functional and tissue abnormalities of a disease that should be as a biventricular cardiomyopathy. The ECG indexes able to identify LV dilatation are ST-segment elevation and T-wave inversion beyond V3; as far as tissue characterization parameters are concerned, LV LGE was associated to ST segment elevation. The correlation between EVM and CMR confirms that EVM allows an accurate identification of RV EAS in patients with ARVC and supports its clinical use for substrate-based mapping and catheter ablation of RV tachycardias as well as for imaging-guided EMB. Currently available LGE CMR appears to visualize unsatisfactorily RV scars and this limits its usefulness in ARVC diagnosis and guiding interventional RV procedures. However, the high prevalence of LV involvement in ARVC patients is in keeping with the current perspective of biventricular disease and points out the diagnostic relevance of LV scar detection by LGE CMR.
Introduzione: Le cardiomiopatie rappresentano un gruppo eterogeneo di malattie del muscolo cardiaco la cui caratterizzazione tissutale finora è stata eseguita prevalentemente mediante analisi ex vivo. La risonanza magnetica cardiaca (RMC), grazie all’utilizzo di apposite sequenze e all’impiego di un mezzo di contrasto (gadolinio, visibile come Late Gadolinium Enhancement, LGE), rende possibile una caratterizzazione tissutale in vivo. L’analisi della sede ed estensione dell’LGE permette di differenziare la cicatrice miocardica post-infartuale (LGE sub endocardico o trans murale) rispetto ad altre cicatrici di tipo non ischemico. Nelle diverse cardiomiopatie, il significato prognostico dei depositi di LGE non è del tutto chiarito, se non in parte per la cardiomiopatia ipertrofica. In generale la presenza di LGE nel contesto di una cardiomiopatia viene identificato con la presenza di fibrosi miocardica, nonostante il meccanismo di deposito del gadolinio non sia uguale nelle diverse eziologie di cardiomiopatie, non necessariamente associate a fibrosi miocardica. Nell’ambito delle cardiomiopatie, la cardiomiopatia dilatativa (non dovuta ad una eziologia ischemica) (CMD) si caratterizza da un punto di vista istologico per la presenza di fibrosi interstiziale, con o senza fibrosi sostitutiva, entrambe associate ad una prognosi infausta. Una diversa patologia miocardica in cui la RMC offre una eccezionale capacità di caratterizzazione tissutale è la Cardiomiopatia Aritmogena del Ventricolo Destro (CAVD), una miocardiopatia dovuta ad una progressiva atrofia miocardica con successiva sostituzione fibroadiposa. Benché la RMC stia consolidando il suo ruolo nella pratica clinica, non è stata ancora eseguita una applicazione estensiva della RMC in queste due differenti cardiomiopatie a scopo diagnostico e prognostico, ed ancor più manca una analisi sistematica delle correlazioni tra i diversi quadri radiologici ed i tradizionali parametri invasivi e non-invasivi di queste cardiomiopatie. Scopo dello Studio: al fine di valutare il significato clinico e prognostico dell’LGE nelle CMD e nella CAVD sono state perseguite le seguenti linee di ricerca: 1) nei pazienti affetti da CMD il significato prognostico dell’LGE nelle DCM, con particolare riferimento ad un end-point di eventi combinati ed all’outcome aritmico; 2) nei pazienti affetti da CAVD il confronto tra i diversi aspetti alla RMC ed 1a) i quadri elettrocardiografici; 1b) il confronto con dati ottenuti dal mappaggio endocavitario del ventricolo destro (“Endocardial Voltage Mapping”, EVM); 1c) il significato prognostico dell’LGE; 3) il significato della alterazioni di caratterizzazione tissutale alla RMC confrontati con i dati istologici dei pazienti con biopsia endomiocardica (BEM) o che sono andati incontro a decesso/trapianto cardiaco nei due gruppi. Materiali e Metodi: tra il Gennaio 2007 e il Dicembre 2010 sono stati arruolati prospetticamente i pazienti riferiti presso il nostro Centro per una valutazione invasiva per il riscontro di una dilatazione del ventricolo sinistro (Gruppo CMD, A) o per sospetta CAVD (Gruppo CAVD, B). Gruppo CMD (A): sono stati valutati 210 riferiti per riscontro di dilatazione ventricolare con esordio subacuto-cronico (≥ 1 mese), con o senza pregressa storia di scompenso cardiaco, che durante la stessa ospedalizzazione sono stati sottoposti a coronarografia, RMC con contrasto e BEM. Gruppo CAVD (B): 52 soggetti riferiti presso il nostro Centro per sospetta CAVD e la cui diagnosi è stata raggiunta in accordo con i correnti criteri clinico-strumentali recentemente modificati. Durante la stessa ospedalizzazione sono stati sottoposti RMC con contrasto e studio elettrofisiologico con EVM e BEM in casi selezionati. Ogni paziente appartenente ad entrambi i gruppi è stato sottoposto ad un follow-up clinico-strumentale. Resultati: Gruppo A. Sulla base dei risultati della coronarografia i pazienti sono stati suddivisi in due gruppi in base alla presenza o meno di coronaropatia: in 99 è stato definita una eziologia ischemica alla base della disfunzione ventricolare, 111 non mostravano alcuna coronaropatia (gruppo CMD). Il gruppo dei soggetti ischemici è stato escluso dalla successive analisi. Rispetto all’angiografia coronarica, la RMC ha dimostrato un’ottima accuratezza diagnostica (96.5%) nell’escludere una eziologia ischemica. Nel gruppo A la presenza di un LGE di tipo non-ischemico è stata riscontrata in 67 casi (60.4%) mentre era assente in 44 (39.6%). Nessuna differenza nei volumi ventricolari e funzione sistolica è stata riscontrata nei due sottogruppi. Nei 67 pazienti con LGE era presente un pattern di tipo “gray” in 12, tipo stria “midural”/epicardica in 49 (73.1%), alla giunzione settale tra ventricolo destro e sinistro isolatamente in 4 (5.9%), associato ad altri pattern in 25 (37.3%), ed infine tipo “patchy” in 2 casi (2.9%). Nei pazienti con LGE, l’estensione media era pari al 6.3%+/-8.8% della massa del ventricolo sinistro. In 58 casi è stata eseguita la BEM: 33/58 pazienti (56.9%) mostravano aspetti di fibrosi sostitutiva; di questi, 23/33 (69.7%) mostravano anche LGE alla RMC. In 13/58 casi (22%) si riscontrava una BEM negativa: in questo sottogruppo di soggetti era presente un LGE in 9/13 (69.2%): nella maggioranza dei casi (8/9 pari all’89%) l’LGE era tipo stria “midmural”/epicardica, in uno solo (11%) tipo “patchy”. Nel gruppo A il range del follow-up è 8 anni-1 mese. Le curve di sopravvivenza Kaplan-Meier per eventi combinati ed aritmie ventricolari maggiori hanno mostrato una differenza significativa tra i due gruppi di pazienti con una prognosi peggiore nel gruppo con LGE (Wilcoxon-Breslow: p< 0.05). La quantità totale di LGE si è dimostrata associata alle aritmie ventricolari (HR 1.05, 95% CI 1.02-1.08; p<0.0001); tale correlazione rimaneva anche all’analisi multivariata aggiustata per una frazione d’eiezione inferiore al 30% (HR 1.067, 95% CI 1.034-1.1; p<0.0001).I pazienti con LGE mostravano un rischio di 2.5 per la comparsa di aritmie ventricolari e mediante l’analisi della curva ROC la percentuale di LGE pari a 3.5% è risultato il miglior valore predittivo di eventi aritmici (HR 4.11 (95% CI 1.3-12.7; p<0.001). Gruppo B. Sulla base dei risultati della RMC, 24 soggetti (46%) sono stati definiti affetti da un forma “classica”, 14 (27%) “dominante sinistra”, e 14 (27%) “biventricolare”. Analizzando la correlazione tra ECG e RMC, gli unici predittori della dilatazione del ventricolo sinistro sono risultati la presenza di un sopraslivellamento del tratto ST e le T invertite oltre V3 (p<0.05); nelle sequenze per la caratterizzazione tissutale la presenza di LGE a carico del ventricolo sinistro era associata ad un sopraslivellamento del tratto ST. Dall’analisi di confronto tra mappaggio endocavitario (EVM) e LGE è emerso che in 21/23 (91%) si dimostrava la presenza di un voltaggio ridotto, per un totale di 45 cicatrici elettroanatomiche. La presenza di LGE a carico del ventricolo destro si è riscontrata in 9/23 (39%) casi, per un totale di 23 cicatrici alla RMC: in 24 casi vi è stato un mismatch tra le due metodiche nel riconoscere le cicatrici di sostituzione fibro-adiposa. In 9/12 (75%) dei soggetti con EVM patologico/RMC normale, sono state riscontrate aree di LGE in almeno una regione del ventricolo sinistro. Il follow-up medio dei pazienti con CAVD arruolati nel follow-up (52; 34 maschi; età media 33+/-15 anni) è stato di 25.6 mesi (38+/-4 mesi). Considerando come eventi maggiori la morte cardiaca (abortita o meno), la fibrillazione/tachicardia ventricolare, morte/trapianto cardiaco gli eventi combinati sono stati 12 (7 nel gruppo con LGE e 5 in quelli senza LGE). Non si è dimostrata alcuna differenza in termini di tempo libero da eventi nei tre gruppi. Conclusioni: La RMC nell’ambito dello studio della CMD e della CAVD offre delle capacità diagnostiche al di là delle tradizionali metodiche di imaging. Nella CMD presenta un’ottima accuratezza diagnostica, rispetto alla ventricolo-coronarografia, nell’escludere una eziologia ischemica alla base della dilatazione e disfunzione ventricolare. La presenza di LGE nella DCM è in grado inoltre di individuare i paziente a maggior rischio aritmico. Tuttavia se confrontata con la BEM, l’accuratezza diagnostica della RMC rimane bassa, probabilmente a causa del suo potere di risoluzione spaziale che limita il riconoscimento di piccole aree di fibrosi miocardica. D’altra parte, la RMC è in grado di vedere lesioni epicardiche che non sono raggiunte dalla BEM supportando così l’importanza di una valutazione combinata delle due metodiche nelle CMD. Nei soggetti con CAVD, la RMC si conferma tecnica di imaging capace di esplorare l’intero spettro di alterazioni morfo-funzionali e tissutali della CAVD, che spesso è una malattia bi ventricolare e non può essere esclusiva del ventricolo destro. Il confronto tra ECG e RMC indica la presenza di un sopraslivellamento del tratto ST e l’inversione delle onde T come predittori della dilatazione del ventricolo sinistro; la presenza di LGE a carico del ventricolo sinistro è associato ad un sopraslivellamento del tratto ST. Analizzando i dati relativi al mappaggio elettronatomico, emerge come quest’ultimo riconosca più cicatrici di quanto non riesca a fare la RMC, probabilmente per la difficoltà di riconoscere un LGE a carico della parete assai assottigliata del ventricolo destro. Tuttavia la capacità della RMC di riconoscere le lesioni anche a carico del ventricolo sinistro, laddove il mappaggio elettroanatomico non viene applicato, suggerisce un sinergismo diagnostico tra le due metodiche. Probabilmente il breve tempo di follow-up nel quale si è indagato il significato prognostico dell’LGE a carico del ventricolo sinistro ha reso non significativa la differenza in termini di tempo libero da eventi nei tre gruppi. Studi futuri su casistiche più numerose, tipizzate dal punto di vista genetico e con RMC seriate, delucideranno meglio il significato prognostico di un coinvolgimento precoce del ventricolo sinistro.

Myocardial scar, a non-viable tissue which occurs on the myocardium due to the insufficient blood supply to the heart muscle, is one of the leading causes of life-threatening heart disorders, including arrhythmias. Analysis of myocardial scar is important for predicting the risk of arrhythmia and locations of re-entrant circuits in patients’ hearts. For applications, such as computational modeling of cardiac electrophysiology aimed at stratifying patient risk for post-infarction arrhythmias, reconstruction of the intact geometry of scar is required. Currently, 2D multi-slice late gadolinium-enhanced magnetic resonance imaging (LGEMRI) is widely used to detect and quantify myocardial scar regions of the heart. However, due to the anisotropic spatial dimensions in 2D LGE-MR images, creating scar geometry from these images results in substantial reconstruction errors. For applications requiring reconstructing the intact geometry of scar surfaces, 3D LGE-MR images are more suited as they are isotropic in voxel dimensions and have a higher resolution. While many techniques have been reported for segmentation of scar using 2D LGEMR images, the equivalent studies for 3D LGE-MRI are limited. Most of these 2D and 3D techniques are basic intensity threshold-based methods. However, due to the lack of optimum threshold (Th) value, these intensity threshold-based methods are not robust in dealing with complex scar segmentation problems. In this study, we propose an algorithm for segmentation of myocardial scar from 3D LGE-MR images based on Markov random field based continuous max-flow (CMF) method. We utilize the segmented myocardium as the region of interest for our algorithm. We evaluated our CMF method for accuracy by comparing its results to manual delineations using 3D LGE-MR images of 34 patients. We also compared the results of the CMF technique to ones by conventional full-width-at-half-maximum (FWHM) and signal-threshold-to-reference-mean (STRM) methods. The CMF method yields a Dice similarity coefficient (DSC) of 71 +- 8.7% and an absolute volume error (|VE|) of 7.56 +- 7 cm3. Overall, the CMF method outperformed the conventional methods for almost all reported metrics in scar segmentation. We present a comparison study for scar geometries obtained from 2D vs 3D LGE-MRI. As the myocardial scar geometry greatly influences the sensitivity of risk prediction in patients, we compare and understand the differences in reconstructed geometry of scar generated using 2D versus 3D LGE-MR images beside providing a scar segmentation study. We use a retrospectively acquired dataset of 24 patients with a myocardial scar who underwent both 2D and 3D LGE-MR imaging. We use manually segmented scar volumes from 2D and 3D LGE-MRI. We then reconstruct the 2D scar segmentation boundaries to 3D surfaces using a LogOdds-based interpolation method. We use numerous metrics to quantify and analyze the scar geometry including fractal dimensions, the number-of-connected-components, and mean volume difference. The higher 3D fractal dimension results indicate that the 3D LGE-MRI produces a more complex surface geometry by better capturing the sparse nature of the scar. Finally, 3D LGE-MRI produces a larger scar surface volume (27.49 +- 20.38 cm3) than 2D-reconstructed LGE-MRI (25.07 +- 16.54 cm3).

Gadolinium endohedral metallofullerenes (EMFs) have shown the potential to become next generation magnetic resonance imaging (MRI) contrast agents due to their significantly improved efficiency and safety, as well as multi-day body retention which allows for a longer surgery and observation compared to current contrast agents. In Chapter 1, I have reviewed the development of gadolinium EMF based MRI contrast agents. In Chapter 2, I have described my study of Gd3N@C80 and Gd3N@C84 metallofullerenols as next generation MRI contrast agents. The metallofullerenols are synthesized and characterized utilizing UV-vis, IR, X-ray photoelectron spectroscopy (XPS) and dynamic light scattering (DLS). In addition, relaxivity data were obtained for the two metallofullerenes, and the results showed that Gd3N@C84 metallofullerenol had enhanced relaxivity compared to Gd3N@C80 metallofullerenol. This result is consistent with the observation of magnetic resonance images of the samples at different concentrations. The enhanced relaxivity was attributed to the special "egg shape" of the Gd3N@C84 cage. In Chapter 3, I have described the relaxivity study of Gd3N@C80 (without functionalization) in oleic acid, which could be used as an MRI contrast agent for more hydrophobic bioenvironments. The results show that Gd3N@C80 has a reasonable relaxation effect (relaxivity ~10 mM-1S-1 at 1.4 T) in oleic acid and could be a viable contrast agent even without functionalization. In Chapter 4, I have discussed the outlook of gadolinium EMF-based MRI contrast agents and suggested several directions for future work.
Master of Science

La première partie de cette thèse porte sur l'étude du no-reflow ou obstruction microvasculaire en IRM cardiaque. Dans une première étude, nous avons mesuré l'incidence du no-reflow dans une population de 25 patients pris en charge pour infarctus du myocarde sans sus-décalage du segment ST. Nous avons trouvé que 32% de ces patients présentaient un no-reflow et que la présence de no-reflow était associée à une taille d'infarctus significativement plus importante ainsi qu'une élévation plus importante des enzymes cardiaques. Dans une deuxième étude nous avons comparé la performance diagnostique du myocardial blush grade (MBG) pour le diagnostic du no-reflow avec l'IRM cardiaque sur les séquences de rehaussement tardif post-gadolinium. Cette étude a été réalisée dans une population de 39 patients pris en charge pour un premier épisode de STEMI. Nous avons trouvé que le MBG sous-estimait la présence de no-reflow à la phase aiguë de l'infarctus après reperfusion optimale en comparaison avec l'IRM. La deuxième partie de cette thèse concerne la quantification de l'infarctus du myocarde en IRM cardiaque de rehaussement tardif post-gadolinium. Nous avons comparé une technique d'évaluation semi-quantitative visuelle rapide avec la planimétrie manuelle classique sur une population de 103 patients pris en charge pour syndrome coronarien aigu. La taille de l'infarctus était évaluée par ces deux méthodes en IRM cardiaque réalisée 4 jours après admission. Nous avons trouvé une excellente corrélation et un bon niveau de concordance entre les deux méthodes d'évaluation de la taille d'infarctus, avec des temps de posttraitements beaucoup plus courts pour l'analyse visuelle rapide. Enfin, la troisième partie de cette thèse aborde le sujet de l'utilisation de l'IRM cardiaque comme outil de mesure dans les essais thérapeutiques sur la reperfusion myocardique. Nous avons utilisé l'IRM cardiaque pour évaluer l'efficacité de l'utilisation de la cyclosporine A à la phase aigüe de l'infarctus reperfusé et son effet sur remodelage ventriculaire à 6 mois. Dans cette étude 28 patients ont été étudiés en IRM cardiaque 5 jours et 6 mois après un infarctus du myocarde. Nous avons trouvé une persistance de la réduction significative de 23% de taille de l'infarctus à 6 mois dans le groupe traité par cyclosporine par rapport au groupe contrôle. Il n'y avait pas d'effet négatif de la cyclosporine A sur le processus de remodelage ventriculaire gauche
We assessed the presence and extent of microvascular obstruction (MVO) and its relationship with infarct size and left ventricular (LV) functional parameters after acute non-ST elevated myocardial infarction (NSTEMI). 25 patients with first acute NSTEMI underwent a complete cardio magnetic resonance (CMR) study 72 hours after admission. MO was detected in 32% of patients and was significantly associated with a larger infarct size. There were no significant difference between both groups for the LV functional parameters but patients with MO showed a higher troponin-I and CK release. We studied the relation between Myocardial Blush Grade (MBG) and gadolinium-enhanced CMR for the assessment of MVO in 39 patients with acute ST elevated myocardial infarction (STEMI) treated by primary PCI. No statistical relation was found between MBG and MVO extent at CMR (p=0.63). MBG underestimates MVO after an optimal revascularization in AMI compared to CMR.We compared the performance and post-processing time of a global visual scoring method to standard quantitative planimetry and we compared both methods to the peak values of myocardial biomarkers. 103 patients admitted with reperfused AMI to our intensive care unit had a complete CMR study 4±2 days after admission. There was an excellent correlation between quantitative planimetry and visual global scoring for the hyperenhancement extent’s measurement (r=0.94; y=1.093x+0.87; SEE=1.2; P<0.001) and there was also a good concordance between the two approaches with significantly shorter mean post-processing time for the visual scoring method. There was also significant levels of correlation between the enzymatic peak values and the visual global scoring method. The visual global scoring method allows a rapid and accurate assessment of the myocardial global delayed enhancement. This study examined the effect of a single dose of cyclosporine A used at the time of reperfusion, on LV remodeling and function by cardiac magnetic resonance (CMR) in the early days and 6 months after AMI.28 patients of the original cyclosporine A study had an acute (day 5) and a follow-up (6 months) CMR study. There was a persistent 23% reduction of the absolute infarct size at 6 months without any dementrial effect in the cyclosporine A group compared with the control group of patients. Cyclosporine A used at the moment of AMI reperfusion persistently reduces infarct size and does not have a detrimental effect on LV remodeling

This thesis deals with the synthesis of dendritic gadolinium complexes based on DOTA, with a view to obtaining enhanced relaxivities. Li addition to the inherently long electronic relaxation time and high paramagnetic moment of the gadolinium (III) ion, the speed of rotation of its complexes in solution is a decisive parameter in the determination of the relaxivity. This parameter is dependent on the molecular mass of the complex. Initially, the enantioselective synthesis of novel a-substituted analogues of DOTA was attempted but was not successful due to difficulties encountered in attaining the tetraalkylation of cyclen and the purification of the products obtained. Therefore, further studies were carried out based on the known [Gd(gDOTA)]" system. The synthesis of three medium M(_W) dendrons, each with a focal primary amino group was carried out. Their structures may be described as dendrimeric analogues of poly(ethylene glycol). Two of these structures were successfully coupled to the gadolinium (III) chelate, [Gd.gDOTA]. The acid-catalysed epimerisation of the statistical distribution of stereoisomers yielded solely the (RRRR)/(SSSS) isomeric pair. This system had previously been shown to undergo fast water exchange. The coupling and deprotection procedure yielded paramagnetic dendritic complexes with molecular weights of 2013 and 3535.Relaxivity measurements were carried out on these systems and the results showed significantly higher relaxivities of 18 and 21 mM(^-1) s(^-1) respectively, compared with a value of 7.8 mM(^-1) s(^-1) for the parent compound. Examination of NMRD profiles for the larger system showed a decrease in the rotational correlation time to 310 ps at 298 K, as expected. However, this was accompanied by an increase in the inner-sphere water exchange lifetime to 570 ns at 298 K. Therefore, although an improvement in relaxivity was obtained through a coupling to the slower rotation of the system in solution, this enhancement was limited by the accompanying decrease in the rate of water exchange. The best fitting procedure of the NMRD profiling procedure revealed the presence of 8 second-sphere water molecules at an average distance of 4Å. The second sphere contribution was shown to be the dominant contributor to the overall relaxivity. This accounted for >50% of the increased relaxivity.

Synovitis is an important feature in arthritis and is commonly visualised using contrast enhanced magnetic resonance imaging (MRI). Currently, the reference standard for assessing synovitis is gadolinium enhanced MRI which requires an intravenous injection and carries significant potential risks such as nephrogenic systemic fibrosis. Removing the necessity for using gadolinium will reduce these risks and result in greater patient acceptance of MRI investigation of synovitis. The aims of this thesis were to investigate the use of MRI imaging sequences and include them in a novel non-contrast MRI protocol, The COSMOS protocol (contrast-obviated MRI scanning of synovitis) to identify synovitis in the knees of patients with osteoarthritis. Potential sequences, both qualitative and quantitative, that could be included in the COSMOS protocol were identified initially through (i) a comprehensive review of the literature and (ii) review of historic images within a large research centre. The sequences were then trialled, optimised and then assessed on a large cohort of patients with knee osteoarthritis in order to determine the protocol’s suitability to identify synovitis without contrast. The results of the new COSMOS protocol show that it is feasible and practical to delineate synovitis in the knee using MRI without the use of intravenous gadolinium contrast. The characteristics of the tissues within the knee can be measured using magnetisation transfer ratio and T1 values to provide empirical differentiation of structures. The identification of a distinct range in T1 values for synovitis provided data that was exploited to produce a further inversion recovery sequence that was optimised to supress synovitis in patients with knee osteoarthritis (OA). While further work is required to validate the COSMOS protocol, this thesis has demonstrated that it is possible to image synovitis without intravenous gadolinium contrast agents in a cohort of patients with a clinical diagnosis of OA knee.

RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd-LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T1(50 min)) after injection of 0.05 mmol/kg Gd-LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx-001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T150 min at 1 h post-drug was significantly longer than pre-drug tumor T150 min in all three tumor models, with the T150 min remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T150 min of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd-LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics.

Photodynamic therapy (PDT) and Magnetic resonance imaging (MRI) are two techniques used in therapeutic and diagnostic purpose respectively. PDT can selectively kill the cancer cells by utilizing light and photosensitizer, while MRI provides invasive imaging on our interior bodies. If these two techniques combine, the probe can act as both PDT and MRI agent at the same time. This theranostic agents can bring great efficiency in the cancer treatment. In this project, a porphyrin-cyclen gadolinium based dual functions bio-probe, PZnGdL, is designed for diagnostic and photodynamic therapeutic functions. PZnGdL demonstrated a great T1 signal enhancement for MRI, in which its T1 relaxivity is 15.06 mM-1s-1 (at 1.4T, 37oC). The T1 relaxivity is five-fold higher than the clinically approved MRI contrasting agent Gd-DOTA, (2.92 at 1.4T, 37oC). Furthermore, PZnGdL exhibits low dark toxicity and high photocytotoxicity. Therefore, its photodynamic therapeutic index (PDI) in HeLa cells is as high as 1348 upon 1 J/cm2 light irradiation. Results from the present study show that PZnGdL is an effective photodynamic therapy agent as well as a safe and promising MRI contrasting agent.

Dans ce travail, les s´séquences Imagerie par Résonance Magnétique (IRM) radiales à temps d’écho ultra-court (UTE) sont analysées pour évaluer leur potentiel dans l’étude non-invasive de différents modèles expérimentaux de maladies pulmonaires chez la souris. Chez le petit animal, les séquences radiales UTE peuvent efficacement limiter l’impact négatif sur la qualité de l’image dû au déphasage rapide des spins causé par les nombreuses interfaces air/tissu. En plus, les séquences radiales UTE sont moins sensibles aux artefacts de mouvement par rapport aux séquences Cartésiennes classiques. En conséquence, chez le petit animal, les séquences radiales UTE peuvent permettre d’obtenir des images du poumon avec une résolution bien inférieure au millimètre avec des rapports signal/bruit importants dans le parenchyme pulmonaire, tout en travaillant en conditions physiologiques (animaux en respiration spontanée). Dans cette thèse, il sera démontré que les séquences d’IRM protonique UTE sont outils efficaces dans l’étude quantitative et non-invasive de différents marqueurs distinctifs de certaines pathologies pulmonaires d’intérêt général. Les protocoles développés serontsimples, rapides et non-invasifs, faciles à implémenter, avec une interférence minimale sur la pathologie pulmonaire étudiée et, en définitive, potentiellement applicables chez l’homme. Il sera ainsi démontré que l’emploi des agents de contraste, administrés via les voies aériennes, permet d’augmenter la sensibilité des protocoles développés. Parallèlement, dans cette thèse des protocoles suffisamment flexibles seront implémentés afin de permettre l’étude d’un agent de contraste paramagnétique générique pour des applications aux poumons
In this work, ultra-short echo time (UTE) Magnetic Resonance Imaging (MRI) sequences are investigated as flexible tools for the noninvasive study of experimental models of lung diseases in mice. In small animals radial UTE sequences can indeed efficiently limit the negative impact on lung image quality due to the fast spin dephasing caused by the multiple air/tissue interfaces. In addition, radial UTE sequences are less sensitive to motion artifacts compared to standard Cartesian acquisitions. As a result, radial UTE acquisitions can provide lung images in small animals at sub-millimetric resolution with significant signal to noise ratio in the lung parenchyma, while working with physiological conditions (freely-breathing animals). In this thesis, UTE proton MRI sequences were shown to be efficient instruments to quantitatively investigate a number of hallmarks in longitudinal models of relevant lung diseases with minimal interference with the lung pathophysiology, employing easilyimplementable fast protocols. The synergic use of positive contrast agents, along with anadvantageous administration modality, was shown to be a valuable help in the increase of sensitivity of UTE MRI. At the same time, UTE MRI was shown to be an extremely useful and efficacious sequence for studying positive contrast agents in lungs

Les travaux de cette thèse s’inscrivent dans le contexte clinique visant à optimiser le geste lors des interventions endoventriculaires cardiaques. Cette recherche se concentre principalement sur le guidage en vue du diagnostic et du traitement des affections endoventriculaires à l’aide de cathéters. L’intervention considérée est la biopsie endoventriculaire utilisée pour diagnostiquer les patients atteints de sarcoïdose cardiaque. En effet, le cathéter doit être guidé avec précision vers la zone de fibrose. Cependant, l’absence d’informations visuelles précises sur la localisation de la fibrose pendant l’intervention accroît le risque de faux négatifs pour les échantillons prélevés. De plus, il existe un risque de complications telles que la perforation myocardique, également appelée tamponnade cardiaque. Les objectifs de cette thèse sont articulés en deux parties distinctes :La première partie, préopératoire, consiste à élaborer un modèle 3D du cœur, englobant le ventricule gauche, le ventricule droit et le myocarde. Ce modèle est construit à partir de segmentations d’images d’IRM, notamment des séquences ciné pour les structures principales et LGE pour localiser les zones de fibrose. Les méthodes de segmentation développées reposent sur l’apprentissage profond, et la méthode de segmentation de la fibrose fait l’objet d’une publication en cours. La seconde partie, peropératoire, vise à assis- ter la procédure en fournissant des informa- tions précises sur l’anatomie et la localisation de la zone fibrosée. Cela permet d’optimiser le positionnement du cathéter en périphérie de cette zone fibrosée, contribuant ainsi à améliorer la précision et l’efficacité de l’intervention. Enfin, l’ensemble de la chaîne de traitement a été expérimenté avec succès sur trois patients, procurant ainsi un retour d’expérience du clinicien. Ces avancées visent à réduire les risques liés à la biopsie endoventriculaire et à accroître la précision du diagnostic de la sarcoïdose cardiaque, ouvrant ainsi la voie à des progrès significatifs dans la prise en charge de cette pathologie
The research in this thesis is situated in the clinical context aimed at optimizing procedures during cardiac endoventricular interventions. This study primarily focuses on guidance for the diagnosis and treatment of endoventricular conditions using catheters. The specific intervention under consideration is the endoventricular biopsy used for diagnosing patients with cardiac sarcoidosis. Indeed, the catheter must be precisely guided to the fibrotic zone. However, the lack of precise visual information on the location of fibrosis during the intervention increases the risk of false negatives for the collected samples. Additionally, there is a risk of complications such as myocardial perforation, also known as cardiac tamponade. The objectives of this thesis are articulated in two distinct parts: The first part, preoperative, involves developing a 3D model of the heart, encompassing the left ventricle, right ventricle, and myocardium. This model is constructed from segmentations of MRI images, including cine sequences for the main structures and late gadolinium-enhanced (LGE) images to locate fibrotic zones. The segmentation methods developed rely on deep learning, and the fibrosis segmentation method is the subject of an ongoing publication. The second part, intraoperative, aims to assist the procedure by providing precise information about the anatomy and location of the fibrotic zone. This optimizes the positioning of the catheter on the periphery of this fibrotic zone, thereby contributing to improving the precision and efficiency of the intervention. Finally, the entire processing pipeline has been successfully tested on three patients, providing valuable feedback for clinicians. These advancements aim to reduce the risks associated with endoventricular biopsy and enhance the precision of cardiac sarcoidosis diagnosis, paving the way for significant progress in the management of this pathology

Gadolinium oxide nanoparticles were coated with silica and functionalised with gold and anti-PSMA antibodies, to create an MRI contrast agent for potential use in the detection of prostate cancer. This work is presented as an alternative to toxic gadolinium based contrast agents, while maintaining high contrast abilities and the potential for selective cell targeting.

Imaging techniques have become much more in demand in modern medicine, especially in fields of disease prognosis, diagnosis and therapeutics. This is because a better understanding of different diseases, characteristics of each patient and further optimizing treatment planning, are all enhanced by advanced imaging techniques. Since each imaging modality has its own merits and intrinsic limitations, combining two or more complementary imaging modalities has become an interesting research area. In this study, gadolinium (Gd3+) doped CdTe quantum dots (QDs) were synthesized and used as multimodal imaging probes of two highly complementary imaging modalities: optical imaging and magnetic resonance imaging. The new imaging probes were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-vis absorbance spectra, fluorescence spectra (FL) and magnetic resonance imaging (MRI). The optical / MRI imaging probes were further functionalized by conjugating with the axonal tracer dextran amine (10 kDa) for non-invasive axonal tracing observations. Biocompatibility and MRI contrast effect of prepared multimodal imaging probes were investigated by in vitro cell experiments and MRI scanner. Ultimately, it is hoped that this imaging probe will help us better understand the regeneration mechanisms in real time without sacrificing animals at intervening time-points.

The aim of this research was to use novel functional imaging approaches to investigate connectivity between key brain regions affected in late-life depression (LLD), Alzheimer‟s disease (AD) and dementia with Lewy bodies (DLB). Using functional magnetic resonance imaging (fMRI), spontaneous low-frequency fluctuations (SLFs) in the blood oxygenation level dependent (BOLD) signal were measured at rest. SLFs represent synchronisation of neuronal activity; therefore differences between subjects reflect differences in underlying networks. Methods The first resting-state study investigated connectivity in LLD and involved 33 subjects aged 65 years and over; 17 control and 16 LLD subjects. It was planned to apply this methodology in the dementia study also. However, a global synchronicity pattern was evident in some subjects, which had not previously been seen in the LLD study. Methods were investigated to correct for these spurious fluctuations, thought to be unrelated to neuronal activity (e.g. physiological artefacts), meaning connectivity of neuronal origin only was investigated. The second study investigated connectivity in 47 subjects aged 60 years and over; 16 control, 16 AD and 15 DLB subjects. Additional pre-processing steps were used to remove non-neuronal fluctuations, informed by the previous study. All subjects were scanned using a 3 Tesla MRI System. Functional connectivity was measured by extracting the mean BOLD signal time-series from seed regions in the brain and cross-correlating with all other brain voxels using the FMRIB Software Library (FSL) tools. Results In the LLD study, control subjects showed frontal connectivity with the head of caudate nucleus, whereas the LLD group showed a more widespread pattern of connectivity. LLD subjects showed significantly greater connectivity than controls between the bilateral caudate and a number of brain regions, whereas controls showed no brain regions of greater connectivity than LLD subjects. Pre-processing methods, to correct for non-neuronal fluctuations, were found to remove global synchronicity and improve data accuracy. In the second study, AD and DLB subjects showed significantly greater functional connectivity with a number of seed regions compared to the control group. No brain regions showed significantly greater connectivity in control compared to AD or DLB subjects. Additionally, specific seed regions showed greater connectivity in AD compared to DLB, and vice versa. Conclusions This study reported abnormalities in connectivity in LLD, AD and DLB. The potential outcome of these findings is that they will inform greater understanding of the neurobiology of these disorders and in turn aid in early diagnosis and in the development of specific treatments to target the abnormally functioning brain regions.

More than one-third of all Magnetic Resonance Imaging (MRI) scans employ image-enhancing contrast agents to increase the differential signal intensity between diseased and normal tissue. Because current clinical contrast agents exhibit low relaxivity (mM-1 s-1), low dose efficiency, and rapid secretion, we have designed a group of protein-based MRI contrast agents with multiple gadolinium binding sites. In this study, the developed purification method for Class ProCA-3 agents allows for a quick and cost-effective way to abstract up to 109 mg of pure, soluble protein from a 1L E. Coli cell pellet devoid of DNA or RNA “contamination” for extensive animal studies. Circular dichroism far-UV spectra ensure the metal stability of the agents, revealing maintenance of their native α-helical structure in the presence and absence of metal ions. Furthermore, substantial evidence supports the high dose efficiency of these agents, exhibiting up to five folds higher relaxivity than their analogous commercial competitors.

Magnetic Resonance Imaging instruments rely on a contrast agent to provide high-resolution images of tissues in vivo. However, current clinical contrast agents are hindered by low relaxivity and fast correlation time, necessitating high injection dosages. These concerns, among others, have driven the development of a class of protein-based contrast agents (ProCAs), by design of lanthanide binding sites into a scaffold protein. ProCA1 has a higher reported relaxivity and dosage efficiency than current contrast agents. In this study, expression and Glutathione-S-Transferase purification procedures were optimized, and a refolding method for rapid production of ProCA1 has been developed to enable studies of conformation, metal binding, relaxivity, and in vivo applications. Several ProCA1 variants with 4-5 charged ligand residues were shown to have strong gadolinium binding affinity (Kd of 10-12 M) and metal selectivity. Several options to improve ProCA1 have been explored, including addition of a polyethylene chain or a bombesin tag.

Abstract The purpose of the present study was to implement a unique low-field open magnetic resonance scanner for perioperative imaging in neurosurgery. A paradigm was created for joint intraoperative/interventional MRI, including premises, surgical practice and an operational model. The feasibility of the paradigm was tested in clinical work. The joint use of the facilities between the Departments of Neurosurgery and Diagnostic Radiology was found to enhance the economic rationale and provide for perioperative imaging. It was also found to be organizationally viable in the long run. Intraoperative MRI was implemented and studied in connection with neuronavigation and other intraoperative instruments, tools and imaging modalities. The unique shut down possibility of the magnet enabled staged operating-imaging practice, use of non-MRI-compatible instruments and devices, multimodal imaging with navigation, and avoidance of safety risks associated with operating in magnetic fringe fields. Two dynamic contrast enhanced MR imaging sequences, which used undersampled projection reconstruction, were implemented in the low-field scanner. The applicability of these imaging sequences to follow contrast enhancement of meningiomas was studied in laboratory experiments and in two patient cases. The laboratory experiments showed a nearly linear response in signal intensity to the concentration of gadopentetate dimeglumine in purified water up to 1.25 mM. The patient cases showed results consistent with an earlier study performed at high-field strength. The potential of low-field MRI study including dynamic contrast enhanced imaging to predict surgical and histopathologic characteristics of meningiomas was studied in a series of 21 patients. Dynamic contrast enhanced imaging could be used to evaluate microvessel densities of meningiomas. Surgical bleeding, blood loss during operation, progesterone receptor expression and collagen content were statistically best correlated to the relative intensity of meningioma on FLAIR images. Tissue hardness correlated best with relative intensity on T2-weighted images.

Described here is the development of a protein cages as efficient and potentially relevant MRI contrast agents. Three approaches are outlined to fuse high affinity Gd³⁺ chelating moieties to the surfaces of protein cages. In the first approach, a metal binding peptide has been genetically engineered into the subunit of Cowpea chlorotic mottle virus (CCMV) and to the small heat shock protein cage from Methanococcus jannaschii (HSP). The genetic fusion resulted in a 200x binding enhancement of Gd³⁺ to CCMV in comparison with wild type CCMV and metal binding functionality was added to the HSP protein cage. In a second approach DOTA-Gd was attached to CCMV by reactions with endogenous lysine residues on the surface of the viral capsids and resulted in r1 = 2,806 at 61 MHz for the 28nm diameter particle. Directed by the results of earlier generations of protein cage based contrast agents a next generation MRI contrast agent was designed. In this work a DTPA-Gd containing polymer was grown in the interior of HSP resulting in T1 particle relaxivities of 4,200mM⁻¹ sec⁻¹ for the 12nm particle. Relaxivity parameters were determined and this analysis suggests that the rotational correlation time of the Gd³⁺ chelate has been optimized while the exchange life time of Gd³⁺-bound water is slower than optimal. This synthetic approach holds much promise for the development of future generations of contrast agents. Throughout the evolution of the protein cage based contrast agents there has also been and evolution of our ability to characterize these cages with mass spectrometric techniques. Specifically refined methodologies are presented for QTof characterization of protein cage at the level of amino acids, protein subunits, protein complexes and their cellular expression. Furthermore, correct charge state assignment is crucial to assigning an accurate mass to supramolecular complexes such as protein cages analyzed by electrospray mass spectrometry. Conventional charge state assignment techniques fall short of reliably and unambiguously predicting the correct charge state for many supramolecular complexes. We provide an explanation of the shortcomings of the conventional techniques and have developed a robust charge state assignment method that is applicable to all spectra.

There is an increasing interest for nanomaterials in biomedical applications and in this work, nanoparticles of gadolinium oxide (Gd₂O₃) have been investigated as a novel contrast agent for Magnetic Resonance Imaging (MRI). Relaxation properties have been studied in aqueous solutions as well as in cell culture medium and the nanoparticles have been explored as cell labeling agents. The fluorescent properties of the particles were used to visualize the internalization in cells and doped particles were also investigated as a multimodal agent that could work as a fluorescent marker for microscopy and as a contrast enhancer for MRI.

Results show that in aqueous solutions, there is a twofold increase in relaxivity for Gd₂O₃ compared to commercial agent Gd-DTPA. In cell culture medium as well as in cells, there is a clear T₁ effect and a distinct increase in signal intensity in T₁-mapped images. Fluorescent studies show that the Gd₂O₃ nanoparticles doped with 5% terbium have interesting fluorescent properties and that these particles could work as a multimodal contrast agent.

This study shows that Gd₂O₃ nanoparticles possess excellent relaxation properties that are retained in more biological environments. Gd₂O₃ particles are suitable as a T₁ contrast agent, but seem also be adequate for T₂ enhancement in for instance cell labeling experiments.

There is an increasing interest for nanomaterials in biomedical applications and in this work, nanoparticles of gadolinium oxide (Gd2O3) have been investigated as a novel contrast agent for Magnetic Resonance Imaging (MRI). Relaxation properties have been studied in aqueous solutions as well as in cell culture medium and the nanoparticles have been explored as cell labeling agents. The fluorescent properties of the particles were used to visualize the internalization in cells and doped particles were also investigated as a multimodal agent that could work as a fluorescent marker for microscopy and as a contrast enhancer for MRI. Results show that in aqueous solutions, there is a twofold increase in relaxivity for Gd2O3 compared to commercial agent Gd-DTPA. In cell culture medium as well as in cells, there is a clear T1 effect and a distinct increase in signal intensity in T1-mapped images. Fluorescent studies show that the Gd2O3 nanoparticles doped with 5% terbium have interesting fluorescent properties and that these particles could work as a multimodal contrast agent. This study shows that Gd2O3 nanoparticles possess excellent relaxation properties that are retained in more biological environments. Gd2O3 particles are suitable as a T1 contrast agent, but seem also be adequate for T2 enhancement in for instance cell labeling experiments.

Late-life depression (LLD) is common illness, frequently associated with neuropsychological impairment. Disruption of frontal-subcortical and limbic networks may play a key role in LLD and can be examined using magnetic resonance imaging (MRI). Grey matter (GM) can be examined using T1-weighted MRI, white matter (WM) using diffusion tensor imaging (DTI), and functional connectivity using resting-state functional MRI (fMRI). To clarify the roles of GM, WM and functional connectivity in LLD, systematic reviews and meta-analyses of T1-weighted MRI, DTI and resting-state fMRI studies of depression were performed. The literature provided evidence for GM and WM abnormalities within frontal-subcortical and limbic networks, and increased functional connectivity within the default-mode network, in depression. To examine whether results gained from different techniques are complementary, multi-modal MRI was used to compare GM, WM and functional connectivity between thirty-six participants with LLD and twenty-five control participants. WM integrity was widely reduced in LLD, without significant group differences in GM or functional connectivity. To investigate whether neuropsychological deficits represent independent processes with specific neural correlates, or whether they can be explained by a core deficit, the relationships between neuropsychological and MRI measures were explored. Executive function and processing speed were found to represent core deficits that contribute to impairment in other domains; and impaired performance was correlated with reduced frontal WM integrity. Episodic memory deficits were dependent on executive function and processing speed; and associated with reduced frontal and hippocampal WM integrity. The relationships between age at onset, severity and MRI measures of GM, WM and functional connectivity were also investigated. Later onset was associated with reduced WM integrity, in line with the vascular hypothesis. Earlier onset was associated with greater duration of illness and reduced hippocampal volume, consistent with the glucocorticoid cascade hypothesis. Severity was not associated with any MRI measure. This thesis strongly supports the hypothesis that WM abnormalities in frontal-subcortical and limbic networks play a key role in LLD, with abnormalities related to neuropsychological impairment and compatible with the vascular hypothesis.

Osteoarthritis of the metacarpo/metatarsophalangeal joint is a major cause of lameness in the horse. Magnetic resonance imaging and particularly delayed gadolinium enhanced imaging of cartilage (dGEMRIC) and T2 cartilage mapping in humans has been shown to visualize cartilage matrix changes in osteoarthritis early in the disease process. T2 mapping is a non-invasive technique characterizing hyaline articular cartilage and repair tissue. In dGEMRIC, the negatively charged administered Gd-DTPA2−, penetrates hyaline cartilage in an inverse relationship to the proteoglycan concentration thereof. In osteoarthritis, proteoglycan concentration is decreased with increased penetration of Gd-DTPA2− due to a relative decrease in negative charge of the proteoglycan-depleted cartilage. This study was performed on normal cadaver limbs of twelve euthanized racing Thoroughbreds. Six horses’ midcondylar distal third metacarpals/metatarsals (Mc3s/Mt3s) underwent six precontrast inversion recovery (IR) sequences for dGEMRIC T1 relaxation time calculation, as well as T2 mapping sequences using a 1.5T machine. Gd-DTPA2- was injected intra-articularly and the same six IR sequences repeated at 30, 60, 120, and 180 minutes post-injection at the same midcondylar sites. The distal Mc3/Mt3 cartilage thickness was measured histologically and compared to selected images of the T1 and T2 weighted sequences. T1 and T2 maps were created by fitting the respective data into mono-exponential relaxation equations for each pixel, and mean values of certain regions of interest were calculated. A second group of six horses’ fore and hind limbs were randomly assigned to two groups and the limbs either chilled or frozen, allowed to return to room temperature and scanned similarly to the first control group. Chilling and freezing effects on dGEMRIC and T2 mapping results were evaluated. The main conclusions from this study are that IR and proton density weighted (T2 mapping) sequences can measure distal Mc3/Mt3 cartilage thickness where the cartilage doesn’t overlap with that of the proximal phalanx. However, accurate measurement was hampered by the thin cartilage in this region. dGEMRIC mapping, using intra-articular Gd-DTPA2- is a feasible technique and T1 relaxation times decrease in a similar fashion to that of the human, with the optimal time of scanning after intra-articular Gd-DTPA2- injection being 60-120 minutes. There is little effect on T1 or T2 relaxation time and mapping images after chilling and freezing of the limbs except where the magic angle effect predominates in the T2 mapping sequences. Limitations of this study include relatively coarse spatial resolution of the thin cartilage, the overlap of the distal Mc3/Mt3 cartilage with the adjacent phalanx and the relatively low number of limbs used, resulting in low statistical power, particularly in the frozen limbs’ study. In spite of these limitations, this study provides technical information and reference values of dGEMRIC and T2 mapping in the cadaver distal Mc3/Mt3 of the normal Thoroughbred horse of value for forthcoming studies. Future studies need to evaluate intravenous administration of Gd-DTPA2- and cartilage mapping in live exercised vs. non-exercised horses. Ultimately, dGEMRIC and T2 mapping of horse metacarpo/metatarso-phalangeal joints with differing degrees of osteoarthritis should be used to attempt to diagnose early cartilage degeneration to endeavour to halt or delay its progression.
Thesis (PhD)--University of Pretoria, 2013.
gm2013
Companion Animal Clinical Studies
unrestricted

Placental function is central for normal pregnancy and in many of the major pregnancy disorders. We used magnetic resonance imaging techniques to investigate placental function in normal pregnancy, in early and late preeclampsia and in intrauterine growth restriction. We also investigated maternal body mass index and height, as risk factors for preeclampsia. A high body mass index and a short maternal stature increase the risk of preeclampsia, of all severities. The association seems especially strong between short stature and early preeclampsia, and a high body mass index and late preeclampsia. (Study I) Using diffusion-weighted magnetic resonance imaging, we found that the placental perfusion fraction decreases with increasing gestational age in normal pregnancy. Also, the placental perfusion fraction is smaller in early preeclampsia, and larger in late preeclampsia, compared with normal pregnancies. That these differences are in opposite directions, suggests that there are differences in the underlying pathophysiology of early and late preeclampsia. (Study II) Using magnetic resonance spectroscopy, we found that the phosphodiester spectral intensity fraction and the phosphodiester/phosphomonoester spectral intensity ratio increases with increasing gestational age. Also, we found that the phosphodiester spectral intensity fraction and the phosphodiester/phosphomonoester spectral intensity ratio are higher in early preeclampsia, compared with early normal pregnancy. These findings indicate increased apoptosis with increasing gestational age in normal pregnancy, and increased apoptosis in early preeclampsia. (Study III) The placental perfusion fraction is smaller in intrauterine growth restriction than in normal pregnancy. Fetal growth, Doppler blood flow in maternal and fetal vessels, infant birth weight and plasma markers of placental function are all correlated to the placental perfusion fraction. The placental perfusion fraction examination seems therefore to offer a fast, direct estimate of the degree of placental dysfunction. (Study IV) In conclusion: Our findings in studies I-III all support the hypothesis of partly different pathophysiology between early and late preeclampsia, and suggest a strong link between early preeclampsia and placental dysfunction. Study IV shows that the placental perfusion fraction has potential to contribute to the clinical assessment of placental dysfunction.

Les chélates de Gd sont largement utilisés en tant qu’agents de contraste en imagerie par résonance magnétique. En 2015, un lien a été établi entre l’observation d’hypersignaux T1 de certaines structures cérébrales et le nombre d’administrations préalables de ces chélates de Gd reçues par les patients. Cette observation fortuite pose la question de la tolérance à long-terme de ces molécules. L’ion Gd³⁺ ayant un rayon ionique très proche de celui du Ca²⁺, il interfère avec de nombreux processus biologiques Ca²⁺-dépendants. Sa chélation par un ligand améliore considérablement sa tolérance. Les chélates de Gd sont répartis en 2 classes : macrocycliques et linéaires, différant par leur stabilité thermodynamique et donc leur tendance à se dissocier. Il est classiquement admis que les chélates de Gd ne traversent pas la barrière hémato-encéphalique saine. L’observation de ces hypersignaux au niveau du noyau dentelé du cervelet, du globus pallidus et parfois d’autres structures, remet en cause ce postulat.Les travaux de cette thèse visent à étudier le mécanisme d’accumulation du Gd dans le système nerveux central (voies de passage, localisations, spéciation du Gd accumulé). Les potentiels effets neurotoxiques associés à la présence de Gd dans le cerveau ont aussi été recherchés.Nous avons mis en évidence chez le Rat que l’accumulation cérébrale est d’autant plus importante que la stabilité thermodynamique du chélate de Gd est faible, confirmant les observations cliniques. Les hypersignaux T1 sont en effet liés à des injections répétées de chélates linéaires de Gd. Nous avons aussi établi qu’une insuffisance rénale modérée potentialise la capture cérébrale de Gd dans le cas d’un chélate de Gd linéaire. Nous avons observé que les structures cérébrales accumulent d’autant plus de Gd qu’elles sont riches en fer endogène. Une augmentation de la zincurie, après administration de chélates de Gd linéaires, a également été observée, suggérant un phénomène de transmétallation.La combinaison des techniques de fluorescence X (XRF), de microscopie électronique en transmission (TEM) et du NanoSIMS, a permis l’observation des dépôts de Gd à différentes échelles et sous différentes formes. Cela a permis de documenter les voies de passage du Gd, le rôle des métaux endogènes et du phosphore. L’analyse XRF a permis d’observer qu’au sein des noyaux cérébelleux profonds du Rat, la majorité du Gd est accumulée sous la forme de structures allongées et ramifiées. Ces structures pourraient être des vaisseaux sanguins. Le Gd serait accumulé dans l’espace périvasculaire. En TEM, des dépôts insolubles de Gd ont été observés dans les lames basales de vaisseaux, dans l’interstitium cérébelleux, et dans l’espace périvasculaire. Ces dépôts à l’apparence épineuse sont riches en phosphore, suggérant des dépôts de GdPO₄. Du Gd et du phosphore ont également été identifiés dans des cellules gliales, au sein de pigments intracellulaires de lipofuscine. Aucun dépôt de Gd n’a été trouvé chez des rats traités par un chélate de Gd macrocyclique.L’hypothèse mécanistique établie consiste en l’accès précoce des chélates de Gd au liquide céphalo-rachidien (LCR), puis leur diffusion passive dans le parenchyme proche des ventricules cérébraux, à travers l’épendyme. Arrivés dans des zones riches en métaux endogènes et/ou en phosphore, leschélates de Gd les moins stables thermodynamiquement se dissocieraient, le Gd se liant à des macromolécules endogènes, ou précipitant. La circulation du LCR le long des artérioles pénétrantes piègerait également du Gd au niveau périvasculaire. Les chélates de Gd intacts seraient éliminés par le système glymphatique périvasculaire ou « drainage périartériel intrapariétal ». On retrouve aussi du Gd probablement dissocié à ce niveau.Hormis une hypoactivité, non spécifique, les études neurocomportementales, histopathologiques et neurochimiques menées chez le Rat n’ont pas permis de mettre en évidence une toxicité avérée, même à des doses élevées
Gd chelates are widely used as contrast agents in magnetic resonance imaging. In 2015, the finding of T1 hyperintensities in brain structures was associated with the prior administrations of these agents in patients. This observation raised the question of the long-term tolerance of these molecules. The Gd³⁺ ionic radius is very close to that of Ca²⁺, and therefore this lanthanide interferes with numerous Ca²⁺-dependent biological processes. Its chelation by a ligand considerably improves its tolerance. Gd chelates are categorized into 2 classes: macrocylic and linear agents, differing in their thermodynamic stabilities, and therefore in their ability to dissociate. It is classically admitted that Gd chelates do not cross the healthy blood-brain-barrier. The observation of these hyperintensities, in the dentate nucleus of the cerebellum, the globus pallidus, and sometimes other structures, questioned this assumption.This thesis aimed to study the mechanism of Gd accumulation in the central nervous system: access pathways, tissue and subcellular location, Gd speciation). Potential neuro-toxicological effects associated with long term Gd presence in the brain were also researched.Using a rat model, we evidenced that the lower the thermodynamic stability of Gd chelates, the greater the cerebral Gd concertation was, thus confirming clinical observations. T1 hyperintensities exclusively appeared following administrations of linear Gd chelates. We also established that moderate renal failure potentiates Gd brain uptake in the case of linear Gd chelate. We also observed that brain structures accumulate even more Gd that their endogenous Fe concentration is high. Administration of linear Gd chelates resulted in an increased zincuria. Gadolinium vs. Zn transmetalation may be responsible for this effect.The combination of X fluorescence, transmission electronic microscopy, and NanoSIMS, showed Gd deposits at various scales and in various forms. It allowed us to document Gd pathways, and the role of endogenous metals and phosphorus in this phenomenon. X fluorescence analysis depicted, in rat deep cerebellar nuclei, that the majority of Gd was accumulated in the form of elongated and ramified structures, believed to be blood vessels where Gd would be retained in the perivascular area. By means of electron microscopy in rats, Gd insoluble deposits were observed in basal lamina of vessels, in cerebellar interstitium, and in the perivascular space. These Gd deposits, of spiny aspect, were rich in phosphorus, thus suggesting the presence of GdPO₄. Co-presence of Gd and phosphorous was also identified into glial cells, accumulated in intracellular lipofuscine pigments. No Gd deposits were found in rats treated with a macrocyclic Gd chelate.The established mechanistic hypothesis consists in the early access of Gd chelates to cerebrospinal fluid, followed by their passive diffusion into the parenchyma close to cerebral ventricles, through the ependyma. Encountering areas rich in endogenous metals and/or phosphorus, the less thermodynamically stable Gd chelates would dissociate, and Gd would bind endogenous macromolecules, or precipitate. Cerebrospinal fluid circulation along penetrating arterioles would also trap Gd at the perivascular level. Intact Gd chelates would be eliminated through perivascular glymphatic pathway, or “intramural periarterial drainage”, where probably dissociated Gd is also found.Except a non-specific hypoactivity, neurobehavioural, histopathological and neurochemical studies performed in rats did not demonstrate any obvious neurotoxicity, even at high doses

Background: During the recent years, magnetic resonance imaging (MRI) has evolved to become one of the most commend used diagnostic methods. Although MRI is considered safe and a good diagnostic method of foetuses and pregnant women, the research data is too small to claim that it is completely risk-free. Purpose: The purpose of this literature study was to identify possible risks of foetal defects in connection with MRI examination of pregnant women. Method: This essay is a quantitative systematic literature study where 13 articles were included after being searched in three different databases. Result: No significant differences in biological effects or hearing loss in foetuses exposed to MRI were detected. Heat increase could occur in connection with MRI examination and was influenced by the examination time and the field strength. However, the temperature generally stayed below the approved limit values. The using of gadolinium contrast agents could increase the risk of some foetal disease states as well as miscarriage and stillbirth. Conclusion: MRI could be a good alternative for anatomical imaging of pregnant women, although it should be used with great caution because of the limited research base. Thus, more research is needed in this area to determine the impact of MRI and gadolinium contrast agent on foetal development.
Bakgrund: Under de senaste åren har magnetresonanstomografi (MR) utvecklats till att bli en av de mest använda diagnostiska metoderna. Trots att MR anses vara säkert samt en bra diagnostisk metod av foster och gravida, så är forskningsunderlaget för litet för att påstå att det är helt riskfritt. Syfte: Syftet med denna litteraturstudie var att kartlägga vilka eventuella risker som finns för fosterskador i samband med MR-undersökning av gravida kvinnor. Metod: Detta examensarbete är en kvantitativ systematisk litteraturstudie där 13 artiklar inkluderades efter att ha sökts fram i tre olika databaser. Resultat: Inga signifikanta skillnader gällande biologiska effekter eller hörselnedsättning hos foster som blivit exponerade för MR kunde påvisas. Värmeökning kunde ske i samband med MR-undersökning och påverkades av undersökningstiden samt fältstyrkan. Temperaturen höll sig dock i allmänhet under godkända gränsvärden. Vid användande av gadoliniumkontrastmedel kunde det ge ökad risk för somliga sjukdomstillstånd hos fostret samt missfall och dödföddhet. Konklusion: MR skulle kunna vara ett bra alternativ för anatomisk avbildning av gravida kvinnor, men det bör användas med stor varsamhet på grund av det begränsade forskningsunderlaget. Det behöver således forskas mer inom området för att kunna fastställa MR och gadoliniumkontrastmedels påverkan på fostrets utveckling.

Trimetallic nitride endohedral fullerenes (TNT-EMF) have been recognized for their multifunctional capabilities in biomedical applications. Functionalized gadolinium-loaded fullerenes attracted much attention as a potential new nanoplatform for next-generation magnetic resonance imaging (MRI) contrast agents, given their inherent higher 1H relaxivity than most commercial contrast agents. The fullerene cage is an extraordinarily stable species which makes it extremely unlikely to break and release the toxic Gd metal ions into the bioenvironment. In addition, radiolabeled metals could be encapsulated in this robust carbon cage to deliver therapeutic irradiation. In this dissertation, we aim to develop a series of functionalized TNT-EMFs for MRI detection of various pathological conditions, such as brain cancer, chronic osteomyelitis, and gastrointestinal (GI) tract. As a general introduction, Chapter 1 briefly introduces recent progress in developing metallofullerenes for next-generation biomedical applications. Of special interest are MRI contrast agents. Other potential biomedical applications, toxicity, stability and biodistribution of metallofullerenes are also discussed. Finally, the challenges and future outlook of using fullerene in biomedical and diagnosis applications are summarized at the end of this chapter. The large carbon surface area is ideally suited for multiple exo-functionalization approaches to modify the hydrophobic fullerene cage for a more hydrophilic bio-environment. Additionally, peptides and other agents are readily covalently attached to this nanoprobe for targeting applications. Chapter 2 presents the functionalized metallofullerenes conjugated with interleukin-13 peptide exhibits enhanced targeting of U-251 glioblastoma multiforme (GBM) cell lines and can be effectively delivered intravenously in an orthotopic GBM mouse model. Chapter 3 shows, with the specific targeting moiety, the functionalized metallofullerenes can be applied as a non-invasive imaging approach to detect and differentiate chronic post-traumatic osteomyelitis from aseptic inflammation. Fullerene is a powerful antioxidant due to delocalization of the π-electrons over the carbon cage, which can readily react with free radicals and subsequently delivers a cascade of downstream possessions in numerous biomedical applications. Chapter 4 investigates the antioxidative and anti-inflammatory properties of functionalized Gd3N@C80. This nanoplatform would hold great promise as a novel class of theranostic agent in combating oxidative stress and resolving inflammation, given their inherent MRI applications. In chapter 5, Gd3N@C80 is modified with polyethylene glycol (PEG) for working as MRI contrast agents for GI tract. The high molecular weight can prevent any appreciable absorption through the skin or mucosal tissue, and offer considerable advantages for localized agents in the GI tract. Besides the excellent contrast capability, the PEGylated-Gd3N@C80 exhibits outstanding radical scavenging ability, which can potentially eliminate the reactive oxygen species in GI tract. The biodistribution result suggests this nanoplatform can be worked as the potential contrast agent for GI tract at least for 6 hours. A novel amphiphilic Gd3N@C80 derivative is discussed in Chapter 6. It has been noticed for a long time the functionalization Gd3N@C80 contrast agents have higher relaxivity at lower concentrations. The explanation for the concentration dependency is not fully understood. In this work, the amphiphilic Gd3N@C80 derivative is used as the model to investigate the relationship between the relaxivity and concentration of the Gd-based fullerenes. Click chemistry has been extensively used in functionalization due to the high efficiency and technical simplicity of the reaction. Appendix A describes a new type of Sc3N@C80 derivative conducted by employing the click reaction. The structure of Sc3N@C80-alkynyl and Sc3N@C80- alkynyl-benzyl azide are characterized by NMR, MALDI-TOF, UV-Vis, and HPLC. The high yield of the click reaction can provide access to various derivatives which have great potential for application in medical and materials science. The functionalization and characterizations of Ho3N@C80 derivatives are reported in Appendix B. The contrast ability of Ho3N@C80 is directly compared with Gd3N@C80. The Ho-based fullerenes can be performed as the radiotherapeutic agents; the leaching study is performed to test the stability of carbon cage after irradiation. Appendix C briefly shows a new method to develop Gd3N@C80 based targeting platform, which can be used as the probe for chronic post-traumatic osteomyelitis.
PHD

Currently, many diagnostic tools are available in the clinical arena helping physicians to achieve a diagnosis in non-ischemic heart diseases and now, the main issue is change into prognostic assessment both clinical and, above all, arrhythmic. Cardiac magnetic resonance (CMR) has emerged as a clinically applicable and highly reproducible non-invasive imaging technique and so used extensively over the last years. Its value in term of diagnosis is well known and recently investigations are aimed at prognostic purposes and risk stratification. Many studies analyzed the impact of a scar as detected in vivo by contrast-CMR in hypertrophic cardiomyopathy in term of death and ventricular arrhythmias. The same concept was proved for dilated cardiomyopathy identifying a midwall stria as an adverse prognostic marker of cardiovascular death, arrhythmias and less robust marker of heart failure hospitalization. Junctional type of scar was investigated in hypertrophic cardiomyopathy and in right ventricle hypertrophy due to pulmonary artery hypertension, no data concerning its value in dilated cardiomyopathy are reported so far. This learning may be transferred into other kind of heart diseases. Cardiac magnetic resonance tissue characterization doesn’t deal with scar only but also with myocardial tissue edema. Myocardial edema was been strongly studied in acute myocardial infarction in term of area at risk, savage myocardium and to detect hemorrhagic myocardial infarct, but prognostic data regarding other heart diseases are missing. The aims of our studies were the followings: 1. to evaluate the presence and the prevalence of junctional LGE in patient with dilated cardiomyopathy, the possible relationship between junctional LGE and hemodynamic data and the prognostic significance of this pattern in terms of specific endpoints (arrhythmic and heart failure outcome) in opposite of other type of LGE. In order to investigate this hypothesis, data disclosed in the clinical studio have been proved by ex vivo studies. 2. To evaluate the relationship between myocardial edema as evidenced by CMR and electrocardiographic data (T-wave inversion) in a series of consecutive patients admitted for clinically suspected acute myocarditis. Moreover, to evaluate the prognostic value of T wave inversion (as myocardial edema marker) during the acute/subacute disease phase in predicting LV dysfunction during follow-up. 3. To evaluate the presence of a myocardial substrate underlying life-threatening arrhythmias in young adults with mitral valve prolapse. In order to investigate this hypothesis, data collected in the clinical studio have been proved by pathological (ex vivo) study. 4. Since the proof of the relationship between ventricular arrhythmias and scar in specific area of left ventricle in mitral valve patients, to evaluate the morphological features of mitral valve apparatus underling arrhythmic mitral valve prolapse with fibrosis. In order to confirm these observations, data disclosed by the clinical study have been related by ex vivo results in the pathologic study.
Nella corrente pratica clinica, diversi strumenti diagnostici sono già a disposizione del clinico per aiutarlo nella diagnosi differenziale delle cardiopatie non ischemiche, attualmente però la principale sfida risiede nella capacità di stratificarne prognosticamente il rischio clinico e soprattutto aritmico. La risonanza magnetica cardiaca (RMC) si dimostrata una metodica di imaging non invasivo altamente riproducibile e applicabile nella corrente pratica clinica. La sua utilità nella diagnosi differenziale delle varie malattie cardiache è stata ampiamente validata tant'è che negli ultimi anni l'interesse scientifico si è rivolto a studiarne la valenza prognostica. Molti lavori scientifici hanno analizzato l'impatto di una cicatrice fibrosa evidenziata in vivo dalla RMC nella cardimiopatia ipertrofica sulla mortalità cardiaca. Nella cardiomiopatia dilatativa, la presenza di una stria di fibrosi intramurale si è dimostrata in grado di identificare quei pazienti a più alto rischio di morte cardiaca, di aritmie ventricolari maggiori e, in misura minore, di episodi di scompenso cardiaco. Il significato di una fibrosi giunzionale (ossia localizzata alla giunzione tra i due ventricoli) è stato oggetto di studio nei pazienti con cardiomiopatia ipertrofica e nei pazienti con ipertrofia ventricolare destra da ipertensione arteriosa polmonare, nessuno studio ne ha analizzato il valore nella cardiomiopatia dilatativa. La RMC non è in grado di evidenziare la presenza della sola fibrosi ma è in grado di identificare anche aree di edema miocardico. Se questo è già stato oggetto di numerosi studi nell'infarto miocardico acuto in termini di area a rischio, miocardio salvato e infarto emorragico, pochi invece sono i dati sul suo significato in altre cardiopatie. Gli scopi dei nostri studi sono: 1. valutare la presenza e la prevalenza della fibrosi giunzionale nei pazienti con cardiopatia dilatativa, studiare un'eventuale relazione con i parametri emodinamici e indagare una sua possibile valenza prognostica sia in termini di instabilità aritmica che meccanica, dispetto gli altri tipo di fibrosi classicamente riscontrati in questi pazienti. Tali dati in-vivo sono inoltre stati confrontati con riscontri post mortem. 2. analizzare la relazione tra edema tissutale visto alla RMC e parametri elettrocardiografici (onde T negative) nei pazienti con diagnosi clinica di miocardite acuta e successivamente valutarne il valore prognostico in termini di disfunzione ventricolare a distanza. 3. valutare la presenza di un substrato anatomico alla base di aritmie ventricolari in pazienti con prolasso valvolare mitralico sia in vivo che ex vivo. 4. dimostrata nei pazienti con prolasso valvolare mitralico una associazione tra fibrosi in specifiche aree del ventricolo sinistro e la presenza di aritmie ventricolari, valutare eventuali caratteristiche dell'apparato valvolare mitralico che possano essere associate alla presenza di fibrosi. Tale studio in vivo è stato confrontato con un analogo studio ex vivo.

The main goal of this dissertation was to assess prospectively the value of two cardiovascular magnetic resonance methodises (the transmural extent of an late gadolinium enhancement and the contractile reserve during low dose dobutamine administration) as predictors of left ventricular segmental and global functional recovery in patients with left ventricular systolic dysfunction undergoing surgical or percutaneous revascularisation. Taking into account previous studies, revascularisation of the viable myocardium results in an improvement of patient’s symptoms and prognosis. This finding emphasized the need for and importance of noninvasive tests to quantify the amount of viable myocardium in patients with left ventricular dysfunction in order to define the optimal management strategy. On the basis of the research described in the dissertation, the diagnostic value of different cardiovascular magnetic resonance based viability prediction methods was assessed. The superiority of combined viability prediction model incorporating an late gadolinium enhancement and the contractile reserve during low dose dobutamine administration was confirmed. The optimal predictors of the significant improvement of left ventricular ejection fraction were found: the percentage of viable segments from all dysfunctional and revascularised segments in a patient and the absolute value of left ventricular ejection fraction measured during low dose dobutamine administration. On the basis of the... [to full text]
Disertacijoje nagrinėta dviejų magnetinio rezonanso metodikų (vėlyvojo kontrastinės medžiagos kaupimo transmuralumo bei mažų dobutamino dozių sukeliamo miokardo kontraktilinio rezervo) bei šių metodikų derinio vertė, prognozuojant bendrosios bei segmentinės kairiojo skilvelio funkcijos atsistatymą po revaskuliarizacijos (perkutaninės vainikinių arterijų intervencijos ar vainikinių arterijų apeinamųjų jungčių suformavimo operacijos), pacientams, turintiems išeminės kilmės kairiojo skilvelio sistolinę disfunkciją. Kadangi yra nustatyta, jog sėkminga gyvybingo miokardo revaskuliarizacija pagerina kairiojo skilvelio sistolinę disfunkciją turinčių pacientų simptomus bei prognozę, todėl gyvybingo miokardo nustatymas yra svarbus, siekiant parinkti optimalią tokių pacientų gydymo taktiką. Disertacijoje aprašomo tyrimo pagalba buvo nustatyta širdies magnetinio rezonanso vertė, prognozuojant miokardo bendrosios bei segmentinės kontrakcijos atsistatymą bei pagrįsta vėlyvojo kontrastinės medžiagos kaupimo transmuralumo bei mažų dobutamino dozių sukeliamo kontraktilinio rezervo nustatymo metodikų derinimo nauda. Disertacijoje aptarti optimalūs reikšmingo bendrosios kairiojo skilvelio sistolinės funkcijos pagerėjimo prognostiniai rodikliai: gyvybingų segmentų procentas nuo visų išeityje disfunkcinių bei revaskuliarizuotų paciento segmentų bei absoliuti kairiojo skilvelio išstūmimo frakcija, išmatuota mažų dobutamino dozių skyrimo metu. Disertacijos rezultatų pagrindu buvo sukurtas... [toliau žr. visą tekstą]

Background. The diagnosis of fibrotic scar tissue in arrhythmogenic right ventricular cardiomyopathy (ARVC) and other cardiomyopathies is crucial as it forms the substrate for ventricular tachycardia (VT) and fibrillation (VT). Signal-averaged electrocardiography (SAECG) abnormalities are frequent in ARVC and in other cardiomyopathy-related ventricular arrhythmias. The correlation between cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) and parameters of SAECG in ARVC is not known. Method. Thirty-five patients [median age 32 years (IQR 25 – 46)] referred to the ARVC Registry at Groote Schuur Hospital were included in this retrospective study. SAECG was performed with high-amplification and filtered using bidirectional Butterworth filters between 40 and 250 Hz. A filtered averaged QRS (fQRS) was obtained and analysed for fQRS duration, low amplitude signal duration <40 mV (LAS40), and root-mean-square voltage in the last 40ms of the QRS (RMS40). LGE acquired at 5 to 20 minutes after intravenous administration of gadolinium (0.1mmol/kg to 0.2mmol/kg of body mass) was assessed. We evaluated the correlation between SAECG parameters and the presence of LGE. Results. Sixteen patients had definite ARVC, 5 had possible ARVC, 4 had idiopathic VT/VF, 2 had Athlete's heart, 1 had dilated cardiomyopathy (DCM), 1 had hypertrophic cardiomyopathy (HCM), 1 had SVT and 1 had pericardial constriction. LGE was present in 13 (81%) ARVC patients, 2 (40%) with possible ARVC, 1 (50%) with athlete's heart and in all patients with DCM and HCM. Patients with idiopathic VT/VF, pericardial constriction and supraventricular tachycardias had no myocardial LGE on CMR. Comparing patients with LGE and those without LGE on CMR, there were no differences in fQRS, (114ms [102.3 – 119] versus 111ms [99.5 -130], p = 0.608); LAS40 (34.5ms [16.8 - 40.8] versus 31ms [27.5 – 45], p = 0.566) and a RMS40 (23.5 µV [14.3 – 47.5] versus 33 µV [18.5 – 43.5], p= 0.621), respectively. LGE was present in 6 (60%) patients who had VT at presentation, in 9 (56%) with VT at baseline or follow-up and in all (2) patients who survived cardiac arrest. Three oneway analyses of variance (fQRS vs LGE, LAS40 vs LGE and RMS40 vs. LGE) confirmed that there was no correlation between LGE technique on CMR and SAECG for the detection of myocardial fibrosis in ARVC and other myocardial disorders: for fQRS F(1 , 33) = 1.47, p = 0.23,  2 = 0.02; for LAS40 F(1 , 33) =0.95, p = 0.34,  2 = 0.02 and for RMS40 F(1 , 33) = 0.36, p= 0.85,  2 = 0.02. Conclusion. In this study comparing assessment of myocardial fibrosis by LGE CMR and SAECG, there was no correlation between CMR and SAECG in detection of myocardial fibrosis in ARVC and other cardiovascular diseases.