Michael V. McConnell

Positive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles.

Contrast agents incorporating superparamagnetic iron‐oxide nanoparticles have shown promise as a means to visualize labeled cells using MRI. Labeled cells cause significant signal dephasing due to the magnetic field inhomogeneity induced in water molecules near the cell. With the resulting signal void as the means for detection, the particles behave as a negative contrast agent, which can suffer from partial‐volume effects. In this paper, a new method is described for imaging labeled cells with positive contrast. Spectrally selective RF pulses are used to excite and refocus the off‐resonance water surrounding the labeled cells so that only the fluid and tissue immediately adjacent to the labeled cells are visible in the image. Phantom, in vitro, and in vivo experiments show the feasibility of the new method. A significant linear correlation (r = 0.87, P < 0.005) between the estimated number of cells and the signal was observed. Magn Reson Med 53:999–1005, 2005.

Identification of Anomalous Coronary Arteries and Their Anatomic Course by Magnetic Resonance Coronary Angiography

BACKGROUND Anomalous coronary arteries are a rare but recognized cause of myocardial ischemia and sudden death. Identification currently requires x-ray angiography, which may have difficulty defining the three-dimensional course of the anomalous vessel. Magnetic resonance coronary angiography (MRCA) has been shown to image coronary artery anatomy noninvasively. We hypothesize that MRCA may be useful in the identification of anomalous coronary arteries and their anatomic course. METHODS AND RESULTS Sixteen patients (9 men, 7 women, age 44 to 81 years) with anomalous aortic origins of the coronary arteries by conventional x-ray angiography underwent MRCA. Multiple images of the major epicardial coronary arteries were obtained by use of a breathhold, fat-suppressed, segmented-k space, gradient-echo technique by investigators blinded to all patient data. Anomalous coronary artery pathology, by x-ray angiography, included right-sided left main coronary artery (n = 3), right-sided left circumflex artery (n = 6), separate left-sided left anterior descending and left circumflex arteries (n = 2), left-sided right coronary artery (n = 4), and an anteriorly displaced right coronary artery (n = 1). MRCA correctly identified the anomalous coronary vessel(s) in 14 of 15 patients. In 1 patient, the anomalous vessel was incorrectly identified, and in 2 patients the course of the anomalous vessel was not clearly seen; one of these was a nondominant, anomalous right coronary artery. CONCLUSIONS MRCA is a useful technique for the noninvasive identification of anomalous coronary arteries and their anatomic course.

Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development

MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.

Contrast agent‐enhanced, free‐breathing, three‐dimensional coronary magnetic resonance angiography

For free‐breathing, high‐resolution, three‐dimensional coronary magnetic resonance angiography (MRA), the use of intravascular contrast agents may be helpful for contrast enhancement between coronary blood and myocardium. In six patients, 0.1 mmol/kg of the intravascular contrast agent MS‐325/AngioMARK™ was given intravenously followed by double‐oblique, free‐breathing, three‐dimensional inversion‐recovery coronary MRA with real‐time navigator gating and motion correction. Contrast‐enhanced, three‐dimensional coronary MRA images were compared with images obtained with a T2 prepulse (T2Prep) without exogenous contrast. The contrast‐enhanced images demonstrated a 69% improvement in the contrast‐to‐noise ratio (6.6 ± 1.1 vs. 11.1 ± 2.5; P < 0.01) compared with the T2Prep approach. By using the intravascular agent, extensive portions (> 80 mm) of the native left and right coronary system could be displayed consistently with sub‐millimeter in‐plane resolution. The intravascular contrast agent, MS‐325/AngioMARK™, leads to a considerable enhancement of the blood/muscle contrast for coronary MRA compared with T2Prep techniques. The clinical value of the agent remains to be defined in a larger patient series. J. Magn. Reson. Imaging 1999;10:790–799.

Continuous wireless pressure monitoring and mapping with ultra-small passive sensors for health monitoring and critical care

Continuous monitoring of internal physiological parameters is essential for critical care patients, but currently can only be practically achieved via tethered solutions. Here we report a wireless, real-time pressure monitoring system with passive, flexible, millimetre-scale sensors, scaled down to unprecedented dimensions of 1 × 1 × 0.1 cubic millimeters. This level of dimensional scaling is enabled by novel sensor design and detection schemes, which overcome the operating frequency limits of traditional strategies and exhibit insensitivity to lossy tissue environments. We demonstrate the use of this system to capture human pulse waveforms wirelessly in real time as well as to monitor in vivo intracranial pressure continuously in proof-of-concept mice studies using sensors down to 2.5 × 2.5 × 0.1 cubic millimeters. We further introduce printable wireless sensor arrays and show their use in real-time spatial pressure mapping. Looking forward, this technology has broader applications in continuous wireless monitoring of multiple physiological parameters for biomedical research and patient care.

MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion

miR-21 modulates abdominal aortic aneurysm development by regulating cell proliferation and apoptosis within the aortic wall. miR-21, a Red Alert for AAA Abdominal aortic aneurysms (AAAs) constitute a major public health burden, with few treatment options. In this common condition associated with increased age, male gender, high blood pressure, and especially smoking, the major conduit vessel within the abdomen slowly enlarges and may rupture, often fatally. MicroRNAs are short molecules that can simultaneously regulate translation of multiple genes. One example, microRNA-21 (miR-21), has been shown to control gene expression patterns that influence a variety of cellular processes including maturation, migration, proliferation, and survival. In a new study, Maegdefessel et al. investigated the role of miR-21 in two well-established mouse models of AAA: one in which the aorta is exposed to enzymatic degradation of supporting tissue and another in which mice predisposed to vascular disease spontaneously form AAA in response to the peptide hormone angiotensin II. In both models, miR-21 expression increased within the aortic wall as the AAA developed. miR-21 was also elevated in samples of aorta from patients with AAA compared with healthy controls. Nicotine, the major constituent of tobacco, accelerated AAA growth in both mouse models and caused an even larger increase in miR-21 expression. This appeared to be a protective response because preventing an increase in miR-21 with an inhibitor increased AAA growth and rupture rates in both models. In contrast, exogenous supplementation of miR-21 slowed aneurysm growth and prevented rupture, even in the presence of nicotine. This was partly mediated through miR-21’s suppressive effects on the protein PTEN (phosphatase and tensin homolog). Cell culture studies demonstrated that inflammatory stimuli, known to influence AAA development, increased miR-21 expression. These results suggest that enhanced miR-21 expression is an endogenous response to pathological aortic dilation and may offer a new therapeutic pathway that could be targeted to treat AAA in patients. Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid–modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.

Multicontrast black-blood MRI of carotid arteries: comparison between 1.5 and 3 tesla magnetic field strengths.

To compare black‐blood multicontrast carotid imaging at 3T and 1.5T and assess compatibility between morphological measurements of carotid arteries at 1.5T and 3T.

Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations

These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for healthcare delivery systems to disseminate cardiac and vascular imaging findings related to the performance of cardiovascular magnetic resonance (CMR) examinations.

MRI of Rabbit Atherosclerosis in Response to Dietary Cholesterol Lowering

Direct imaging of the atherosclerotic plaque, rather than the angiographic lumen, may provide greater insight into the response of atherosclerosis to cholesterol-lowering therapy. Aortic plaque was studied in vivo by MRI in rabbits undergoing dietary cholesterol intervention. Thirty-one rabbits underwent aortic balloon injury and high-cholesterol diet for 4 months and then were assigned to low-cholesterol versus continued high-cholesterol diet for up to an additional 16 months. High-resolution (310 micrometer) fast spin-echo MRI of the abdominal aorta was performed at 4, 12, and 20 months and compared with histology. MRI demonstrated a significant reduction in % area stenosis in rabbits placed on low-cholesterol diet (44.6+/-2. 1% at 20 months versus 55.8+/-1.5% at 4 months, P=0.0002). In contrast, % area stenosis increased in rabbits maintained on high-cholesterol diet (69.8+/-3.8% at 20 months versus 55.8+/-1.5% at 4 months, P=0.001). Similarly, plaque thickness decreased significantly in the low-cholesterol group (0.60+/-0.05 mm at 20 months versus 0.85+/-0.06 mm at 4 months, P=0.006), with a trend toward increase in the high-cholesterol group (1.02+/-0.08 mm at 20 months versus 0.85+/-0.06 mm at 4 months, P=0.1). Thus, in rabbits undergoing dietary cholesterol lowering, MRI detected regression of aortic atherosclerotic plaque in vivo. Plaque progression was seen with maintenance of high-cholesterol diet. MRI is a promising noninvasive technology for directly imaging atherosclerosis and its response to therapeutic interventions.

Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t

Cell therapy has demonstrated the potential to restore injured myocardium. A reliable in vivo imaging method to localize transplanted cells and monitor their restorative effects will enable a systematic investigation of this therapeutic modality. The dual MRI capability of imaging both magnetically labeled mouse embryonic stem cells (mESC) and their restorative effects on cardiac function in a murine model of acute myocardial infarction is demonstrated. Serial in vivo MR detection of transplanted mESC and monitoring of the mESC‐treated myocardium was conducted over a 4‐week period using a 1.5 T clinical scanner. During the 4‐week duration, the mESC‐treated myocardium demonstrated sustained improvement of the left ventricular (LV) ejection fraction and conservation of LV mass. Furthermore, no significant difference of their restorative effects on the cardiac function was created by the magnetic labeling of mESC. Thus, in vivo MRI enables simultaneous detection of transplanted mESC and their therapeutic effect on the injured myocardium. Magn Reson Med 2006.