Edward G. Walsh

Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease ☆: Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) Study

OBJECTIVES We sought to develop and validate a definition of coronary microvascular dysfunction in women with chest pain and no significant epicardial obstruction based on adenosine-induced changes in coronary flow velocity (i.e., coronary velocity reserve). BACKGROUND Chest pain is frequently not caused by fixed obstructive coronary artery disease (CAD) of large vessels in women. Coronary microvascular dysfunction is an alternative mechanism of chest pain that is more prevalent in women and is associated with attenuated coronary volumetric flow augmentation in response to hyperemic stimuli (i.e., abnormal coronary flow reserve). However, traditional assessment of coronary volumetric flow reserve is time-consuming and not uniformly available. METHODS As part of the Womens Ischemia Syndrome Evaluation (WISE) study, 48 women with chest pain and normal coronary arteries or minimal coronary luminal irregularities (mean stenosis = 7%) underwent assessment of coronary blood flow reserve and coronary flow velocity reserve. Blood flow responses to intracoronary adenosine were measured using intracoronary Doppler ultrasonography and quantitative angiography. RESULTS Coronary volumetric flow reserve correlated with coronary velocity reserve (Pearson correlation = 0.87, p < 0.001). In 29 (60%) women with abnormal coronary microcirculation (mean coronary flow reserve = 1.84), adenosine increased coronary velocity by 89% (p < 0.001) but did not change coronary cross-sectional area. In 19 (40%) women with normal microcirculation (mean flow reserve = 3.24), adenosine increased coronary velocity and area by 179% (p < 0.001) and 17% (p < 0.001), respectively. A coronary velocity reserve threshold of 2.24 provided the best balance between sensitivity and specificity (90% and 89%, respectively) for the diagnosis of microvascular dysfunction. In addition, failure of the epicardial coronary to dilate at least 9% was found to be a sensitive (79%) and specific (79%) surrogate marker of microvascular dysfunction. CONCLUSIONS Coronary flow velocity response to intracoronary adenosine characterizes coronary microvascular function in women with chest pain in the absence of obstructive CAD. Attenuated epicardial coronary dilation response to adenosine may be a surrogate marker of microvascular dysfunction in women with chest pain and no obstructive CAD.

The impact of myocardial flow reserve on the detection of coronary artery disease by perfusion imaging methods: an NHLBI WISE study.

Myocardial flow reserve (MFR) is not routinely assessed in myocardial perfusion imaging (MPI) studies but has been hypothesized to affect test accuracy when assessing disease severity by coronary vessel lumenography. Magnetic resonance imaging (MRI) is an emerging diagnostic technique that can both perform MPI and assess MFR. We studied women (n = 184) enrolled in the Womens Ischemia Syndrome Evaluation (WISE) study with symptoms suggesting ischemic heart disease. Tests performed were coronary angiography and MPI by both MR and gated radionuclide single photon emission computed tomography (gated-SPECT). The MFR index was calculated using the MR data acquired at baseline and under vasodilation (dipyridamole) conditions. The study was structured with a pilot and an implementation phase. During the pilot phase (n = 46) data were unmasked and an MFR threshold was defined to divide patients into those with an adequate (AMFRI) or inadequate (IMFRI) MFR index. During the implementation phase, the MFR index threshold was prospectively applied to patients (n = 138). In the implementation phase, MPI ischemia detection accuracy compared to severe (> or = 70%) coronary artery diameter narrowing by angiography was higher in the AMFRI vs. the IMFRI group for MRI (86% vs. 70%, p < 0.05) and gated-SPECT (89% vs. 67%, p < 0.01). The IMFRI group (n = 55, 30% of study population) had a higher resting rate-pressure product compared with the AMFRI group (10,599 +/- 2871 vs. 9378 +/- 2447 bpm mm Hg, p < 0.01), consistent with higher resting myocardial flow. When compared with each other, MRI and gated-SPECT MPI showed no difference in accuracy among MFR groups. Myocardial perfusion patterns in the IMFRI group may have resulted in atypical perfusion patterns, which either masked or mimicked epicardial coronary artery disease.

Inferior Frontal Regions Underlie the Perception of Phonetic Category Invariance

The problem of mapping differing sensory stimuli onto a common category is fundamental to human cognition. Listeners perceive stable phonetic categories despite many sources of acoustic variability. What are the neural mechanisms that underlie this perceptual stability? In this functional magnetic resonance imaging study, a short-interval habituation paradigm was used to investigate neural sensitivity to acoustic changes within and between phonetic categories. A region in the left inferior frontal sulcus showed a pattern of activation consistent with phonetic invariance: insensitivity to acoustic changes within a phonetic category and sensitivity to changes between phonetic categories. Left superior temporal regions, in contrast, showed graded sensitivity to both within- and between-category changes. These results suggest that perceptual insensitivity to changes within a phonetic category may arise from decision-related mechanisms in the left prefrontal cortex and add to a growing body of literature suggesting that the inferior prefrontal cortex plays a domain-general role in computing category representations.

Encapsulation of Particle Ensembles in Graphene Nanosacks as a New Route to Multifunctional Materials

Hybrid nanoparticles with multiple functions are of great interest in biomedical diagnostics, therapies, and theranostics but typically require complex multistep chemical synthesis. Here we demonstrate a general physical method to create multifunctional hybrid materials through aerosol-phase graphene encapsulation of ensembles of simple unifunctional nanoparticles. We first develop a general theory of the aerosol encapsulation process based on colloidal interactions within drying microdroplets. We demonstrate that a wide range of cargo particle types can be encapsulated, and that high pH is a favorable operating regime that promotes colloidal stability and limits nanoparticle dissolution. The cargo-filled graphene nanosacks are then shown to be open structures that rapidly release soluble salt cargoes when reintroduced into water, but can be partially sealed by addition of a polymeric filler to achieve slow release profiles of interest in controlled release or theranostic applications. Finally, we demonstrate an example of multifunctional material by fabricating graphene/Au/Fe3O4 hybrids that are magnetically responsive and show excellent contrast enhancement as multimodal bioimaging probes in both magnetic resonance imaging and X-ray computed tomography in full-scale clinical instruments.

Prognostic value of global MR myocardial perfusion imaging in women with suspected myocardial ischemia and no obstructive coronary disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study.

OBJECTIVES The purpose of this study was to assess the prognostic value of global magnetic resonance (MR) myocardial perfusion imaging (MPI) in women with suspected myocardial ischemia and no obstructive (stenosis <50%) coronary artery disease (CAD). BACKGROUND The prognostic value of global MR-MPI in women without obstructive CAD remains unknown. METHODS Women (n = 100, mean age 57 ± 11 years, age range 31 to 76 years), with symptoms of myocardial ischemia and with no obstructive CAD, as assessed by coronary angiography, underwent MR-MPI and standard functional assessment. During follow-up (34 ± 16 months), time to first adverse event (death, myocardial infarction, or hospitalization for worsening anginal symptoms) was analyzed using global MPI and left ventricular ejection fraction (EF) data. RESULTS Adverse events occurred in 23 (23%) women. Using univariable Cox proportional hazards regression modeling, variables found to be predictive of adverse events were global MR-MPI average uptake slope (p < 0.05), the ratio of MR-MPI peak signal amplitude to uptake slope (p < 0.05), and EF (p < 0.05). Two multivariable Cox models were formed, 1 using variables that were performance site dependent: ratio of MR-MPI peak amplitude to uptake slope together with EF (chi square: 13, p < 0.005); and a model using variables that were performance site independent: MR-MPI slope and EF (chi square: 12, p < 0.005). Each of the 2 multivariable models remained predictive of adverse events after adjustment for age, disease history, and Framingham risk score. For each of the Cox models, patients were categorized as high risk if they were in the upper quartile of the model and as not high risk otherwise. Kaplan-Meier analysis of time to event was performed for high risk versus not high risk for site-dependent (log rank: 15.2, p < 0.001) and site-independent (log rank: 13.0, p < 001) models. CONCLUSIONS Among women with suspected myocardial ischemia and no obstructive CAD, MR-MPI-determined global measurements of normalized uptake slope and peak signal uptake, together with global functional assessment of EF, appear to predict prognosis.

Comparative MRI Compatibility of 316L Stainless Steel Alloy and Nickel–Titanium Alloy Stents

The initial success of coronary stenting is leading to a proliferation in peripheral stenting. A significant portion of the stents used in a clinical setting are made of 316 low carbon stainless steel (SS). Other alloys that have been used for stent manufacture include tantalum, MP35N, and nickel-titanium (NiTi). The ferromagnetic properties of SS cause the production of artifacts in magnetic resonance imaging (MRI). The NiTi alloys, in addition to being known for their shape memory or superelastic properties, have been shown to exhibit reduced interference in MRI. Thus, the objective of this study was to determine the comparative MRI compatibility of SS and NiTi stents. Both gradient echo and spin-echo images were obtained at 1.5 and 4.1 T field strengths. The imaging of stents of identical geometry but differing compositions permitted the quantification of artifacts produced due to device composition by normalizing the radio frequency shielding effects. These images were analyzed for magnitude and spatial extent of signal loss within the lumen and outside the stent. B1 mapping was used to quantify the attenuation throughout the image. The SS stent caused significant signal loss and did not allow for visibility of the lumen. However, the NiTi stent caused only minor artifacting and even allowed for visualization of the signal from within the lumen. In addition, adjustments to the flip angle of standard imaging protocols were shown to improve the quality of signal from within the lumen.

Monodisperse Magnetite Nanoparticles Coupled with Nuclear Localization Signal Peptide for Cell‐Nucleus Targeting

Functionalization of monodisperse superparamagnetic magnetite (Fe(3)O(4)) nanoparticles for cell specific targeting is crucial for cancer diagnostics and therapeutics. Targeted magnetic nanoparticles can be used to enhance the tissue contrast in magnetic resonance imaging (MRI), to improve the efficiency in anticancer drug delivery, and to eliminate tumor cells by magnetic fluid hyperthermia. Herein we report the nucleus-targeting Fe(3)O(4) nanoparticles functionalized with protein and nuclear localization signal (NLS) peptide. These NLS-coated nanoparticles were introduced into the HeLa cell cytoplasm and nucleus, where the particles were monodispersed and non-aggregated. The success of labeling was examined and identified by fluorescence microscopy and MRI. The work demonstrates that monodisperse magnetic nanoparticles can be readily functionalized and stabilized for potential diagnostic and therapeutic applications.

The adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease

It is well established that aging and vascular processes interact to disrupt cerebral hemodynamics in older adults. However, the independent effects of cerebral perfusion on neurocognitive function among older adults remain poorly understood. We examined the associations among cerebral perfusion, cognitive function, and brain structure in older adults with varying degrees of vascular disease using perfusion magnetic resonance imaging (MRI) arterial spin labeling (ASL).

The impact of hypertension on cerebral perfusion and cortical thickness in older adults.

Hypertension may increase risk for dementia possibly because of its association with decreased cortical thickness. Disturbed cerebral autoregulation is one plausible mechanism by which hypertension impacts the cerebral structure, but the associations among hypertension, brain perfusion, and cortical thickness are poorly understood. The current sample consisted of 58 older adults with varying levels of vascular disease. Diagnostic history of hypertension and antihypertensive medication status was ascertained through self-report, and when available, confirmed by medical record review. All participants underwent arterial spin labeling and T1-weighted magnetic resonance imaging to quantify total and regional cortical perfusion and thickness. Analysis of covariance adjusting for medical variables showed that participants with hypertension exhibited reduced temporal and occipital brain perfusion and total and regional cortical thickness relative to those without hypertension. The effects of hypertension on total brain perfusion remained unchanged even after adjustment for age, although no such pattern emerged for cortical thickness. Decreased total brain perfusion predicted reduced thickness of the total brain and of the frontal, temporal, and parietal lobe cortices. Antihypertensive treatment was not associated with total cerebral perfusion or cortical thickness. This study provides initial evidence for the adverse effects of a diagnostic history of hypertension on brain hypoperfusion and reduced cortical thickness. Longitudinal studies are needed to investigate the role of hypertension and its interaction with other contributing factors (e.g., age) in the manifestation of cerebral hypoperfusion and reduced cortical thickness.

Overlearning hyperstabilizes a skill by rapidly making neurochemical processing inhibitory-dominant

Overlearning refers to the continued training of a skill after performance improvement has plateaued. Whether overlearning is beneficial is a question in our daily lives that has never been clearly answered. Here we report a new important role: overlearning in humans abruptly changes neurochemical processing, to hyperstabilize and protect trained perceptual learning from subsequent new learning. Usually, learning immediately after training is so unstable that it can be disrupted by subsequent new learning until after passive stabilization occurs hours later. However, overlearning so rapidly and strongly stabilizes the learning state that it not only becomes resilient against, but also disrupts, subsequent new learning. Such hyperstabilization is associated with an abrupt shift from glutamate-dominant excitatory to GABA-dominant inhibitory processing in early visual areas. Hyperstabilization contrasts with passive and slower stabilization, which is associated with a mere reduction of excitatory dominance to baseline levels. Using hyperstabilization may lead to efficient learning paradigms.