Quantification of myocardial infarct area based on TRAFFn relaxation time maps:comparison with cardiovascular magnetic resonance late gadolinium enhancement, T1ρ and T2 in vivo

Abstract Background: Two days after myocardial infarction (MI), the infarct consists mostly on necrotic tissue, and the myocardium is transformed through granulation tissue to scar in two weeks after the onset of ischemia in mice. In the current work, we determined and optimized cardiovascular magnetic resonance (CMR) methods for the detection of MI size during the scar formation without contrast agents in mice. Methods: We characterized MI and remote areas with rotating frame relaxation time mapping including relaxation along fictitious field in nth rotating frame (RAFFn), T1ρ and T2 relaxation time mappings at 1, 3, 7, and 21 days after MI. These results were compared to late gadolinium enhancement (LGE) and Sirius Red-stained histology sections, which were obtained at day 21 after MI. Results: All relaxation time maps showed significant differences in relaxation time between the MI and remote area. Areas of increased signal intensities after gadolinium injection and areas with increased TRAFF2 relaxation time were highly correlated with the MI area determined from Sirius Red-stained histology sections (LGE: R² = 0.92, P < 0.01, TRAFF2: R² = 0.95, P < 0.001). Infarct area determined based on T1ρ relaxation time correlated highly with Sirius Red histology sections (R² = 0.97, P < 0.01). The smallest overestimation of the LGE-defined MI area was obtained for TRAFF2 (5.6 ± 4.2%) while for T1ρ overestimation percentage was > 9% depending on T1ρ pulse power. Conclusion: T1ρ and TRAFF2 relaxation time maps can be used to determine accurately MI area at various time points in the mouse heart. Determination of MI size based on TRAFF2 relaxation time maps could be performed without contrast agents, unlike LGE, and with lower specific absorption rate compared to on-resonance T1ρ relaxation time mapping

Capturing exchange using periodic radiofrequency irradiation

Abstract The dynamics of spin system coupled by chemical exchange between two sites with different chemical shifts during periodic radiofrequency (RF) irradiation was here investigated. When the instantaneous π-flip of effective frequency during the course of frequency sweep was applied, a significant increase of exchange-induced relaxation rate constants was observed for small tip angle of magnetization in the laboratory frame of reference. This increase of the rate constants corresponds to the side bands generated by the periodic irradiation during the RF pulses. The exchange-induced relaxation rate constants depend on the exchange conditions, the RF power and the irradiation period. The described phenomenon promises applications for studying protein dynamics and for generating exchange specific relaxation contrasts in MRI

Statistical evaluation of different mathematical models for diffusion weighted imaging of prostate cancer xenografts in mice

Abstract Purpose: To evaluate fitting quality and repeatability of four mathematical models for diffusion weighted imaging (DWI) during tumor progression in mouse xenograft model of prostate cancer. Methods: Human prostate cancer cells (PC-3) were implanted subcutaneously in right hind limbs of 11 immunodeficient mice. Tumor growth was followed by weekly DWI examinations using a 7T MR scanner. Additional DWI examination was performed after repositioning following the fourth DWI examination to evaluate short term repeatability. DWI was performed using 15 and 12 b-values in the ranges of 0-500 and 0-2000 s/mm², respectively. Corrected Akaike information criteria and F-ratio were used to evaluate fitting quality of each model (mono-exponential, stretched exponential, kurtosis, and bi-exponential). Results: Significant changes were observed in DWI data during the tumor growth, indicated by ADCm, ADCs, and ADCk. Similar results were obtained using low as well as high b-values. No marked changes in model preference were present between the weeks 1−4. The parameters of the mono-exponential, stretched exponential, and kurtosis models had smaller confidence interval and coefficient of repeatability values than the parameters of the bi-exponential model. Conclusion: Stretched exponential and kurtosis models showed better fit to DWI data than the mono-exponential model and presented with good repeatability

Docetaxel chemotherapy response in PC3 prostate cancer mouse model detected by rotating frame relaxations and water diffusion

Abstract MRI is a common method of prostate cancer diagnosis. Several MRI‐derived markers, including the apparent diffusion coefficient (ADC) based on diffusion‐weighted imaging, have been shown to provide values for prostate cancer detection and characterization. The hypothesis of the study was that docetaxel chemotherapy response could be picked up earlier with rotating frame relaxation times TRAFF2 and TRAFF4 than with the continuous wave T1ρ, adiabatic T1ρ, adiabatic T2ρ, T1, T2 or water ADC. Human PC3 prostate cancer cells expressing a red fluorescent protein were implanted in 21 male mice. Docetaxel chemotherapy was given once a week starting 1 week after cell implantation for 10 randomly selected mice, while the rest served as a control group (n = 11). The MRI consisted of relaxation along a fictitious field (RAFF) in the second (RAFF2) and fourth (RAFF4) rotating frames, T1 and T2, continuous wave T1ρ, adiabatic T1ρ and adiabatic T2ρ relaxation time measurements and water ADC. MRI was conducted at 7 T, once a week up to 4 weeks from cell implantation. The tumor volume was monitored using T2‐weighted MRI and optical imaging. The histology was evaluated after the last imaging time point. Significantly reduced RAFFn, T1ρ, T2ρ and conventional relaxation times 4 weeks after tumor implantation were observed in the treated tumors compared with the controls. The clearest short‐ and long‐term responses were obtained with T1, while no clear improvement in response to treatment was detected with novel methods compared with conventional methods or with RAFFn compared with all others. The tumor volume decreased after a two‐week time point for the treated group and increased significantly in the control group, which was supported by increasing red fluorescent light emission in the control tumors. Decreased relaxation times were associated with successful chemotherapy outcomes. The results indicate altered relaxation mechanisms compared with higher dose chemotherapies previously published

AAV8-mediated sVEGFR2 and sVEGFR3 gene therapy combined with chemotherapy reduces the growth and microvasculature of human ovarian cancer and prolongs the survival in mice

Abstract Background: Vascular endothelial growth factors (VEGFs) are major regulators of intratumoral angiogenesis in ovarian cancer (OVCA). Overexpression of VEGFs is associated with increased tumor growth and metastatic tendency and VEGF-targeting therapies are thus considered as potential treatments for OVCA. Here, we examined the antiangiogenic and antitumoral effects on OVCA of adeno-associated virus 8 (AAV8)-mediated expression of soluble VEGF receptors (sVEGFRs) sVEGFR2 and sVEGFR3 together with paclitaxel and carboplatin chemotherapy. Materials and methods: Immunodeficient mice were inoculated with human OVCA cell line SKOV-3m. Development of tumors was confirmed with magnetic resonance imaging (MRI) and mice were treated with gene therapy and paclitaxel and carboplatin chemotherapy. The study groups included (I) non-treated control group, (II) blank control vector AAV8-CMV, (III) AAV8-CMV with chemotherapy, (IV) AAV8-sVEGFR2, (V) AAV8-sVEGFR3, (VI) AAV8-sVEGFR2 and AAV8-sVEGFR3, and (VII) AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy. Antiangiogenic and antitumoral effects were evaluated with immunohistochemical stainings and serial MRI. Results: Reduced intratumoral angiogenesis was observed in all antiangiogenic gene therapy groups. The combined use of AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy suppressed ascites fluid formation and tumor growth, thus improving the overall survival of mice. Antitumoral effect was mainly caused by AAV8-sVEGFR2 while the benefits of AAV8-sVEGFR3 and chemotherapy were less prominent. Conclusions: Combined use of the AAV8-sVEGFR2 and AAV8-sVEGFR3 with chemotherapy reduces intratumoral angiogenesis and tumor growth in OVCA mouse model. Results provide preclinical proof-of-concept for the use of soluble decoy VEGFRs and especially the AAV8-sVEGFR2 in the treatment of OVCA

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10-3per year [95% CI, -6.49×10-3to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH