Glioblastoma (GBM), a highly aggressive form of brain tumor, is a disease marked by extensive invasion into the surrounding brain. Interstitial fluid flow (IFF), or the movement of fluid within the spaces between cells, has been linked to increased invasion of GBM cells. Better characterization of IFF could elucidate underlying mechanisms driving this invasion in vivo . Here, we develop a technique to non-invasively measure interstitial flow velocities in the glioma microenvironment of mice using dynamic contrast-enhanced magnetic resonance imaging (MRI), a common clinical technique. Using our in vitro model as a phantom “tumor” system and in silico models of velocity vector fields, we show we can measure average velocities and accurately reconstruct velocity directions. With our combined MR and analysis method, we show that velocity magnitudes are similar across four human GBM cell line xenograft models and the direction of fluid flow is heterogeneous within and around the tumors, and not always in the outward direction. These values were not linked to the tumor size. Finally, we compare our flow velocity magnitudes and the direction of flow to a classical marker of vessel leakage and bulk fluid drainage, Evans blue. With these data, we validate its use as a marker of high and low IFF rates and IFF in the outward direction from the tumor border in implanted glioma models. These methods show, for the first time, the nature of interstitial fluid flow in models of glioma using a technique that is translatable to clinical and preclinical models currently using contrast-enhanced MRI.
Purpose Imaging late mechanical activation may identify effective left-ventricular (LV) pacing sites for cardiac resynchronization therapy (CRT). However, there is variability in defining mechanical activation time, with some studies using the time to peak strain (TPS) and some using the time to the onset of circumferential shortening (TOS). We developed improved methods for imaging mechanical activation and evaluated them in heart failure (HF) patients undergoing CRT. Methods We applied active contours to cine displacement encoding with stimulated echoes (DENSE) strain images to detect TOS. Six healthy volunteers underwent MRI at 1.5T, and 50 patients underwent pre-CRT MRI (strain, scar, volumes) and echocardiography, assessment of the electrical activation time (Q-LV) at the LV pacing site, and echocardiography assessment of LV reverse remodeling six months after CRT. TPS at the LV pacing site was measured by DENSE. Results The latest TOS was greater in HF patients vs. healthy subjects (112±28ms vs. 61±7ms, p<0.01). The correlation between TOS and Q-LV was strong (r>0.75; p<0.001) and better than between TPS and Q-LV (r<0.62; p≥0.006). Twenty-three of 50 patients had the latest activating segment in a region other than the mid-ventricular lateral wall, the most common site for the CRT LV lead. Using a multivariable model, TOS/QRS was significantly associated with LV reverse remodeling even after adjustment for overall dyssynchrony and scar (p<0.05), whereas TPS was not (p=0.49). Conclusions Late activation by cine DENSE TOS analysis is associated with improved LV reverse remodeling with CRT and deserves further study as a tool to achieve optimal LV lead placement in CRT.
Animal models have become a popular platform for the investigation of the molecular and systemic mechanisms of pathological cardiovascular physiology. Chronic pacing studies with implantable pacemakers in large animals have led to useful models of heart failure and atrial fibrillation. Unfortunately, molecular and genetic studies in these large animal models are often prohibitively expensive or not available. Conversely, the mouse is an excellent species for studying molecular mechanisms of cardiovascular disease through genetic engineering. However, the large size of available pacemakers does not lend itself to chronic pacing in mice. Here, we present the design for a novel, fully implantable wireless-powered pacemaker for mice capable of long-term (>30 days) pacing. This design is compared to a traditional battery-powered pacemaker to demonstrate critical advantages achieved through wireless inductive power transfer and control. Battery-powered and wireless-powered pacemakers were fabricated from standard electronic components in our laboratory. Mice (n = 24) were implanted with endocardial, battery-powered devices (n = 14) and epicardial, wireless-powered devices (n = 10). Wireless-powered devices were associated with reduced implant mortality and more reliable device function compared to battery-powered devices. Eight of 14 (57.1%) mice implanted with battery-powered pacemakers died following device implantation compared to 1 of 10 (10%) mice implanted with wireless-powered pacemakers. Moreover, device function was achieved for 30 days with the wireless-powered device compared to 6 days with the battery-powered device. The wireless-powered pacemaker system presented herein will allow electrophysiology studies in numerous genetically engineered mouse models as well as rapid pacing-induced heart failure and atrial arrhythmia in mice.
NOS inhibition causes an increase in myocardial T in healthy mice, and this effect is mediated through eNOS. T mapping during NOS inhibition detects coronary microvascular eNOS dysfunction in high-fat-diet mice. T mapping during NOS inhibition may be useful in preclinical studies aiming to investigate mechanisms underlying and therapies for coronary microvascular eNOS dysfunction. Magn Reson Med 79:2246-2253, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
BackgroundIn vivo imaging of oxidative stress can facilitate the understanding and treatment of cardiovascular diseases. We evaluated nitroxide‐enhanced MRI with 3‐carbamoyl‐proxyl (3CP) for the detection of myocardial oxidative stress.MethodsThree mouse models of cardiac oxidative stress were imaged, namely angiotensin II (Ang II) infusion, myocardial infarction (MI), and high‐fat high‐sucrose (HFHS) diet‐induced obesity (DIO). For the Ang II model, mice underwent MRI at baseline and after 7 days of Ang II (n = 8) or saline infusion (n = 8). For the MI model, mice underwent MRI at baseline (n = 10) and at 1 (n = 8), 4 (n = 9), and 21 (n = 8) days after MI. For the HFHS‐DIO model, mice underwent MRI at baseline (n = 20) and 18 weeks (n = 13) after diet initiation. The 3CP reduction rate, Kred, computed using a tracer kinetic model, was used as a metric of oxidative stress. Dihydroethidium (DHE) staining of tissue sections was performed on Day 1 after MI.ResultsFor the Ang II model, Kred was higher after 7 days of Ang II versus other groups (p < 0.05). For the MI model, Kred, in the infarct region was significantly elevated on Days 1 and 4 after MI (p < 0.05), whereas Kred in the noninfarcted region did not change after MI. DHE confirmed elevated oxidative stress in the infarct zone on Day 1 after MI. After 18 weeks of HFHS diet, Kred was higher in mice after diet versus baseline (p < 0.05).ConclusionsNitroxide‐enhanced MRI noninvasively quantifies tissue oxidative stress as one component of a multiparametric preclinical MRI examination. These methods may facilitate investigations of oxidative stress in cardiovascular disease and related therapies.
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