Eric Y. Yang

Carotid Arterial Wall Characteristics Are Associated With Incident Ischemic Stroke But Not Coronary Heart Disease in the Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— Ultrasound measurements of arterial stiffness are associated with atherosclerosis risk factors, but limited data exist on their association with incident cardiovascular events. We evaluated the association of carotid ultrasound-derived arterial stiffness measures with incident coronary heart disease (CHD) and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Methods— Carotid arterial strain and compliance, distensibility and stiffness indices, pressure–strain, and Young elastic moduli were measured in 10 407 individuals using ultrasound. Hazard ratios for incident CHD (myocardial infarction, fatal CHD, coronary revascularization) and stroke in minimally adjusted (age, sex, center, race) and fully adjusted models (minimally adjusted model+diabetes, height, weight, total cholesterol, high-density lipoprotein cholesterol, tobacco use, systolic blood pressure, antihypertensive medication use, and carotid intima-media thickness) were calculated. Results— The mean age was 55.3 years. Over a mean follow-up of 13.8 years, 1267 incident CHD and 383 ischemic stroke events occurred. After full adjustment for risk factors and carotid intima-media thickness, all arterial stiffness parameters (carotid arterial strain hazard ratio [HR], 1.14 [95% CI, 1.02–1.28]; arterial distensibility HR, 1.19 [1.02–1.39]; stiffness indices HR, 1.14 [1.04–1.25]; pressure–strain HR, 1.17 [1.06–1.28]; Young elastic moduli HR, 1.13 [1.03–1.24]), except arterial compliance (HR, 1.02 [0.90–1.16], were significantly associated with incident stroke but not with CHD. Conclusions— After adjusting for cardiovascular risk factors, ultrasound measures of carotid arterial stiffness are associated with incident ischemic stroke but not incident CHD events despite that the 2 outcomes sharing similar risk factors. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00005131.

Robotic Measurement of Arm Movements After Stroke Establishes Biomarkers of Motor Recovery

Background and Purpose— Because robotic devices record the kinematics and kinetics of human movements with high resolution, we hypothesized that robotic measures collected longitudinally in patients after stroke would bear a significant relationship to standard clinical outcome measures and, therefore, might provide superior biomarkers. Methods— In patients with moderate-to-severe acute ischemic stroke, we used clinical scales and robotic devices to measure arm movement 7, 14, 21, 30, and 90 days after the event at 2 clinical sites. The robots are interactive devices that measure speed, position, and force so that calculated kinematic and kinetic parameters could be compared with clinical assessments. Results— Among 208 patients, robotic measures predicted well the clinical measures (cross-validated R2 of modified Rankin scale=0.60; National Institutes of Health Stroke Scale=0.63; Fugl-Meyer=0.73; Motor Power=0.75). When suitably scaled and combined by an artificial neural network, the robotic measures demonstrated greater sensitivity in measuring the recovery of patients from day 7 to day 90 (increased standardized effect=1.47). Conclusions— These results demonstrate that robotic measures of motor performance will more than adequately capture outcome, and the altered effect size will reduce the required sample size. Reducing sample size will likely improve study efficiency.

An Improved Model for Disease Progression in Patients From the Alzheimer's Disease Neuroimaging Initiative

The objective of this analysis was to develop a semi‐mechanistic nonlinear disease progression model using an expanded set of covariates that captures the longitudinal change of Alzheimers Disease Assessment Scale (ADAS‐cog) scores from the Alzheimers Disease Neuroimaging Initiative study that consisted of 191 Alzheimer disease patients who were followed for 2 years. The model describes the rate of progression and baseline disease severity as a function of influential covariates. The covariates that were tested fell into 4 categories: (1) imaging volumetric measures, (2) serum biomarkers, (3) demographic and genetic factors, and (4) baseline cognitive tests. Covariates found to affect baseline disease status were years since disease onset, hippocampal volume, and ventricular volume. Disease progression rate in the model was influenced by age, total cholesterol, APOE ε4 genotype, Trail Making Test (part B) score, and current levels of impairment as measured by ADAS‐cog. Rate of progression was slower for mild and severe Alzheimer patients compared with moderate Alzheimer patients who exhibited faster rates of deterioration. In conclusion, this model describes disease progression in Alzheimer patients using novel covariates that are important for understanding the worsening of ADAS‐cog scores over time and may be useful in the future for optimizing study designs through clinical trial simulations.

Association of gender with morbidity and mortality after isolated coronary artery bypass grafting. A propensity score matched analysis

INTRODUCTION There is conflicting evidence about the impact of gender on outcomes after coronary artery bypass grafting (CABG). METHODS We performed a multivariate logistic regression and propensity score matched analyses in 13,115 patients (75% men) who underwent CABG between January 1, 1995 and December 31, 2009. The primary outcome was in-hospital mortality. Secondary outcomes included post-operative respiratory failure, stroke, myocardial infarction, sternal and leg wound infections, atrial fibrillation (AF), renal failure, need for postoperative intra-aortic balloon pump (IABP) support, and length of hospital stay. RESULTS A higher proportion of women (184; 5.6%) suffered in-hospital death compared to men (264; 2.7%), p<0.0001. After propensity score matching (n=3600 total, 1800 in each group), female gender was an independent predictor of mortality after isolated CABG (odds ratio [OR]=1.84; 95% confidence interval [CI] 1.22-2.78). Women also experienced a higher incidence of postoperative complications including stroke (3.8% vs. 2.3%, OR 1.37; 95% CI 1.08-1.73) and leg wound infection (3.4% vs. 1.7%, OR 1.75; 95% CI 1.36-2.54) on multivariate regression analyses. However, these differences were not significant after propensity score matching. We also observed a lower risk of post-operative AF (21.2% vs. 22.1%, OR 0.78; 95% CI 0.70-0.86) in women that remained significant after propensity matching (O.R. 0.76; 95% C.I. 0.65-0.90). Length of hospital stay was longer in women compared with men (11.9 ± 9.0 vs. 10.4 ± 9.2 days, p<0.0001). CONCLUSIONS Female gender is an independent predictor of increased mortality and a lower incidence of post-operative AF after isolated CABG.

Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes

AIM The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimers disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHOD Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTS CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSION CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology.

Automatic quantification of muscle volumes in magnetic resonance imaging scans of the lower extremities.

Muscle volume measurements are essential for an array of diseases ranging from peripheral arterial disease, muscular dystrophies, neurological conditions to sport injuries and aging. In the clinical setting, muscle volume is not routinely measured due to the lack of standardized ways for its repeatable quantification. In this paper, we present magnetic resonance muscle quantification (MRMQ), a method for the automatic quantification of thigh muscle volume in magnetic resonance imaging (MRI) scans. MRMQ integrates a thigh segmentation and nonuniform image gradient correction step, followed by feature extraction and classification. The classification step leverages prior probabilities, introducing prior knowledge to a maximum a posteriori classifier. MRMQ was validated on 344 slices taken from 60 MRI scans. Experiments for the fully automatic detection of muscle volume in MRI scans demonstrated an averaged accuracy, sensitivity and specificity for leave-one-out cross-validation of 88.3%, 93.6% and 87.2%, respectively.

The Effect of Lipid Modification on Peripheral Artery Disease after Endovascular Intervention Trial (ELIMIT)

METHODS A total of 102 patients were randomized to either mono-therapy with simvastatin (40 mg daily) or triple-therapy with simvastatin (40 mg daily), extended-release niacin (1500 mg daily), and ezetimibe (10 mg daily). MRI was performed at baseline and 6, 12, and 24 months. SFA wall, lumen, and total vessel volumes were quantified. MRI-derived SFA parameters and lipids were analyzed with multilevel models and nonparametric tests, respectively. RESULTS Baseline characteristics did not differ between mono and triple-therapy groups, except for ethnicity (p = 0.02). SFA wall, lumen, and total vessel volumes increased non-significantly for both groups between baseline and 24-months. Non-high-density lipoprotein cholesterol was significantly reduced at 12 months with triple-therapy compared with mono-therapy (p = 0.01). CONCLUSION No significant differences were observed between mono-therapy using simvastatin and triple-therapy with simvastatin, extended-release niacin, and ezetimibe for 24-month changes in SFA wall, lumen, and total vessel volumes. CLINICAL TRIAL REGISTRATION INFORMATION NCT00687076; Link: http://clinicaltrials.gov/ct2/show/NCT00687076.

Real-Time Co-Registration Using Novel Ultrasound Technology: Ex Vivo Validation and In Vivo Applications

OBJECTIVE The study objective was to evaluate whether a novel global position system (GPS)-like position-sensing technology will enable accurate co-registration of images between imaging modalities. Co-registration of images obtained by different imaging modalities will allow for comparison and fusion between imaging modalities, and therefore has significant clinical and research implications. We compared ultrasound (US) and magnetic resonance imaging (MRI) scans of carotid endarterectomy (CEA) specimens using a novel position-sensing technology that uses an electromagnetic (EM) transmitter and sensors mounted on a US transducer. We then evaluated in vivo US-US and US-MRI co-registration. METHODS Thirteen CEA specimens underwent 3.0 Tesla MRI, after which images were uploaded to a LOGIQ E9 3D (GE Healthcare, Wauwatosa, WI) US system and registered by identifying two to three common points. A similar method was used to evaluate US-MRI co-registration in patients with carotid atherosclerosis. For carotid intima-media thickness (C-IMT) measurements, 10 volunteers underwent bilateral carotid US scans co-registered to three-dimensional US maps created on the initial visit, with a repeat scan 2 days later. RESULTS For the CEA specimens, there was a mean of 20 (standard error [SE] 2.0) frames per MRI slice. The mean frame difference, over 33 registration markers, between MRI and US scans for readers 1 and 2 was -2.82 ± 19.32 and 2.09 ± 14.68 (mean ± 95% CI) frames, respectively. The US-MRI intraclass correlation coefficients (ICCs) for the first and second readers were 0.995 and 0.997, respectively. For patients with carotid atherosclerosis, the mean US frames per MRI slice (9 [SE 2.3]) was within range of that observed with CEA specimens. Inter-visit, intra-reader, and inter-reader reproducibility of C-IMT measurements were consistently high (side-averaged ICC >0.9). CONCLUSION Accurate co-registration between US and other modalities is feasible with a GPS-like technology, which has significant clinical and research applicability.

Twins lead to the prevention of atherosclerosis: Preliminary findings of international twin study 2009

Introduction Atherosclerosis is an inflammatory process in which the artery wall thickens as a result of plaque deposition, but this process may be preceded by increased arterial stiffness. We sought to evaluate the influence of genetics and shared and unshared environmental components on the onset of atherosclerosis. Methods A total of 135 monozygotic (MZ) and 70 dizygotic (DZ) twin pairs (mean age 49 ± 16 years) underwent carotid intima media thickness (IMT; carotid analyzer) and arterial stiffness (augmentation index on brachial artery [Aixbra], pulse wave velocity on aorta [PWVao]; TensioMed Arteriograph) measurements. Results Age-adjusted intraclass correlations were greater in MZ than in DZ pairs for proximal right common carotid artery (CCA; MZ = 0.19, DZ = 0.06), proximal and distal left CCA (MZ = 0.27, DZ = 0.06; MZ = 0.27, DZ = 0.13, respectively), and proximal left internal carotid artery (ICA; MZ = 0.39, DZ = −0.54), suggesting a moderate genetic effect. Heritability was estimated to be 18% (95% confidence interval [CI] = 3–33) for proximal right CCA, 26% and 27% for proximal and distal left CCA, respectively, and 38% (95% CI = 26–49) for proximal left ICA. Regarding distal right CCA and proximal right ICA, no genetic effects were detected. Age-adjusted intraclass correlation of Aixbra and PWVao were 0.65 (95% CI = 0.55–0.72) and 0.46 (95% CI = 0.33–0.57) in MZ, 0.42 (95% CI = 0.24–0.57) and 0.28 (95% CI = 0.08–0.47) in DZ pairs; heritability 45% (95% CI = 12–71%) and 42% (95% CI = 2–57%) adjusted by age, respectively. Conclusions The investigated parameters appeared to be only moderately influenced by genetic factors. Environmental factors of relevance for these measures appeared not to be shared within family but related to individual experience (e.g., smoking habits, diet, and physical activity). Atherosclerosis detection at an early stage is necessary for treatment to prevent serious complications such as stroke and heart attack.

Ultrasound Imaging of Carotid Intima-Media Thickness: an Office-Based Tool to Assist Physicians in Cardiovascular Risk Assessment

Traditional coronary heart disease risk prediction schemes such as the Framingham Risk Score, although useful, do not adequately identify all individuals who experience an adverse coronary heart disease event. Therefore, additional tools, including biomarkers, genetic markers, and imaging markers, are being evaluated for their value in improving cardiovascular risk assessment. Of the two accepted imaging markers of atherosclerosis, namely coronary artery calcium score (CACS) measured by CT scan and carotid intima-media thickness (CIMT) measured by ultrasound, CIMT has the potential to be widely adopted as a clinical tool for physician offices. Ultrasound-based CIMT measurement is safe but has several challenges, including reproducibility and operator-dependency. We review and present data with respect to the added value of CIMT and information about plaque presence or absence in improving coronary heart disease risk prediction and further provide information related to adequate scanning protocols. New developments in the area of automated CIMT measurement, three-dimensional, ultrasound-based plaque volume estimation are promising and have the potential to create a quantum leap in our ability to measure, characterize, and monitor carotid atherosclerosis and in turn prediction of cardiovascular disease risk.