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2.  Noninvasive Assessment of Hypoxia in Rabbit Advanced Atherosclerosis Using 18F-fluoromisonidazole PET Imaging 
Background
Hypoxia is an important microenvironmental factor influencing atherosclerosis progression by inducing foam-cell formation, metabolic adaptation of infiltrated macrophages and plaque neovascularization. Therefore, imaging plaque hypoxia could serve as a marker of lesions at risk.
Methods and Results
Advanced aortic atherosclerosis was induced in 18 rabbits by atherogenic diet and double balloon endothelial denudation. Animals underwent 18F-FMISO PET and 18F-fluorodeoxyglucose (18F-FDG) PET imaging after 6–8 months (atherosclerosis induction) and 12–16 months (progression) of diet initiation. Four rabbits fed standard chow served as controls. Radiotracer uptake of the abdominal aorta was measured using standardized uptake values (SUV). Following imaging, plaque hypoxia (pimonidazole), macrophages (RAM-11), neovessels (CD31) and hypoxia-inducible factor-1α (HIF-1α) were assessed by immunohistochemistry. 18F-FMISO uptake increased with time on diet (SUVmean, 0.10±0.01 in non-atherosclerotic animals versus 0.20±0.03 (P=0.002) at induction and 0.25±0.03 (P<0.001) at progression). Ex vivo PET imaging corroborated the 18F-FMISO uptake by the aorta of atherosclerotic rabbits. 18F-FDG uptake also augmented in atherosclerotic animals, with a SUVmean of 0.43±0.02 at induction versus 0.35±0.02 in non-atherosclerotic animals (P=0.031), and no further increase at progression. By immunohistochemistry, hypoxia was mainly located in the macrophage-rich areas within the atheromatous core, whereas the macrophages close to the lumen were hypoxia-negative. Intraplaque neovessels were found predominantly in macrophage-rich hypoxic regions (pimonidazole+/HIF-1α+/RAM-11+).
Conclusions
Plaque hypoxia increases with disease progression and is present in macrophage-rich areas associated with neovascularization. 18F-FMISO PET imaging emerges as a new tool for detection of atherosclerotic lesions.
doi:10.1161/CIRCIMAGING.113.001084
PMCID: PMC4083834  PMID: 24508668
plaque hypoxia; atherosclerosis; positron emission tomography; angiogenesis
3.  A Statin-Loaded Reconstituted High-Density Lipoprotein Nanoparticle Inhibits Atherosclerotic Plaque Inflammation 
Nature communications  2014;5:3065.
Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.
doi:10.1038/ncomms4065
PMCID: PMC4001802  PMID: 24445279
4.  Increased Neovascularization in Advanced Lipid-Rich Atherosclerotic Lesions Detected by Gadofluorine-M–Enhanced MRI 
Background
Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M–enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis.
Methods and Results
Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M–enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29±0.21 versus 3.00±0.32; P=0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P=0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P=0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis (r=0.67; P<0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels.
Conclusion
Gadofluorine-M–enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.
doi:10.1161/CIRCIMAGING.108.801712
PMCID: PMC4073689  PMID: 19808627
atherosclerosis; MRI; vulnerable plaque; contrast media; molecular imaging
5.  Usability of Implementing a Tablet-Based Decision Support and Integrated Record-Keeping (DESIRE) Tool in the Nurse Management of Hypertension in Rural Kenya 
In sub-Saharan Africa (SSA), cardiovascular disease (CVD) is the leading cause of death among individuals over the age of 30. Hypertension, a major risk factor for CVD, contributes significantly to the CVD burden in SSA. In order to address the human resource challenge of managing hypertension in low- and middle-income countries (LMICs), task-shifting hypertension care from physicians to nurses has been proposed. To support this task-shifting strategy, the Academic Partnership Providing Access to Healthcare (AMPATH) has developed an Android tablet-based electronic Decision Support and Integrated Record-Keeping (DESIRE) tool to record patient data and assist with clinical decision-making. We investigated the usability of the DESIRE tool in the setting of nurse management of hypertension in rural western Kenya through the use of “mock patient” encounters and “think aloud” exercises. Fiftyseven critical incidents were identified and twenty-three design changes were suggested. Optimization of the tool has the potential to broadly impact treatment of non-communicable diseases in LMICs by providing a model of electronic decision-support in task shifting.
PMCID: PMC4074025  PMID: 23920776
Decision Support Systems; Clinical; Electronic Health Records; User-Computer Interface; Root Cause Analysis
6.  Rationale and design of dal-PLAQUE: A study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography 
American heart journal  2011;162(2):214-221.e2.
dal-PLAQUE is a placebo-controlled multicenter study designed to assess the effect of dalcetrapib on imaging measures of plaque inflammation and plaque burden. dal-PLAQUE is a multimodality imaging study in the context of the large dal-HEART Program. Decreased high-density lipoprotein cholesterol is linked to increased risk of coronary heart disease (CHD). Dalcetrapib, a compound that increases high-density lipoprotein cholesterol by modulating cholesteryl ester transfer protein, is being studied to assess if it can reduce the progression of atherosclerotic disease and thereby decrease cardiovascular morbidity and mortality. Patients with CHD or CHD-risk equivalents were randomized to receive 600 mg dalcetrapib or placebo daily for 24 months, in addition to conventional lipid-lowering medication and other medications for cardiovascular risk factors. The primary outcomes are the effect of dalcetrapib on 18F-fluorodeoxyglucose positron emission tomography target-to-background ratio after 6 months and magnetic resonance imaging (MRI) plaque burden (wall area, wall thickness, total vessel area, and wall area/total vessel area ratio) after 12 months. Secondary objectives include positron emission tomography target-to-background ratio at 3 months and MRI plaque burden at 6 and 24 months; plaque composition at 6, 12, and 24 months; and aortic compliance at 6 months. A tertiary objective is to examine the dynamic contrast-enhanced MRI parameters of plaque neovascularization. In total, 189 subjects entered screening, and 130 were randomized. dal-PLAQUE will provide important information on the effects of dalcetrapib on markers of inflammation and atherosclerotic plaque burden and, thereby, on the safety of cholesteryl ester transfer protein modulation with dalcetrapib. Results are expected in 2011.
doi:10.1016/j.ahj.2011.05.006
PMCID: PMC4047820  PMID: 21835280
7.  Optimizing 18F-FDG PET/CT Imaging of Vessel Wall Inflammation –The Impact of 18F-FDG Circulation Time, Injected Dose, Uptake Parameters, and Fasting Blood Glucose Levels 
Purpose
18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is increasingly used for imaging of vessel wall inflammation. However, limited data is available regarding the impact of methodological variables, i. e. patient’s pre-scan fasting glucose, the FDG circulation time, the injected FDG dose, and of different FDG uptake parameters, in vascular FDG-PET imaging.
Methods
195 patients underwent vascular FDG-PET/CT of the aorta and the carotids. Arterial standard uptake values (meanSUVmax) as well as target-to-background-ratios (meanTBRmax) and the FDG blood pool activity in the superior vein cava (SVC) and the jugular veins (JV) were quantified. Vascular FDG uptake classified according to tertiles of patient’s pre-scan fasting glucose levels, the FDG circulation time, and the injected FDG dose was compared using ANOVA. Multivariate regression analyses were performed to identify the potential impact of all variables described on the arterial and blood pool FDG uptake.
Results
Tertile analyses revealed FDG circulation times of about 2.5 h and prescan glucose levels of less than 7.0 mmol/l showing favorable relations between the arterial and blood pool FDG uptake. FDG circulation times showed negative associations with the aortic meanSUVmax values as well as SVC- and JV FDG blood pool activity but a positive correlation with the aortic- and carotid meanTBRmax values. Pre-scan glucose was negatively associated with aortic- and carotid meanTBRmax and carotid meanSUVmax values, but correlated positively with the SVC blood pool uptake. Injected FDG dose failed to show any significant association with the vascular FDG uptake.
Conclusion
FDG circulation times and pre-scan blood glucose levels significantly impact FDG uptake within the aortic and carotid wall and may bias the results of image interpretation in patients undergoing vascular FDG-PET/CT. FDG dose injected was less critical. Therefore, circulation times of about 2.5 h and pre-scan glucose levels less than 7.0 mmol/l should be preferred in this setting.
doi:10.1007/s00259-013-2569-6
PMCID: PMC4024166  PMID: 24271038
FDG-PET; FDG Dose; FDG Circulation Time; Pre-scan Glucose; Vessel Wall Inflammation
8.  Arterial and Fat Tissue Inflammation are Highly Correlated - A Prospective 18F-FDG PET/CT Study 
Purpose
There is evidence that the link between obesity and cardiovascular disease might relate to inflammation in both fat tissue and the arterial wall. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake is a surrogate marker of vessel wall inflammation. The aim of the study was to measure FDG uptake in both regions using PET and identify links between adipose and arterial inflammation.
Methods
173 cardiovascular patients were prospectively imaged with FDG-PET/CT. Arterial FDG uptake was measured in the carotid arteries and ascending aorta. The same was done in fat tissue in the neck, the pre-sternal region (all subcutaneous) and the pericardium. FDG uptake wasquantified as average maximal target-to-background ratio (meanTBRmax).Multivariate regression analyses were performed to identify significant associations between arterial and adipose tissue FDG uptake and clinical variables as given by the standardized correlation coefficient (β).
Results
FDG uptake values within all fat tissue regions were highly predictive of vascular FDG uptake in both the carotids (neck subcutaneous: β:0.262, p<0.0001) and aorta (chest pericardial: β:0.220, p=0.008 and chest subcutaneous: β:0.193, p=0.019). Obesity was significantly associated with elevated FDG uptake in adipose tissue (neck subcutaneous: β:0.470, p<0.0001; chest subcutaneous: β:0.619, p=0.028; chest pericardial: β:0.978, p=0.035).
Conclusion
FDG uptake in diverse fat tissue regions was significantly associated with arterial FDG uptake, a reasonable surrogate of inflammation. Increasing body weight significantly predicted the level of fatty inflammation. FDG-PET therefore provides imaging evidence for an inflammatory link between fat tissue and the vasculature in patients with cardiovascular disease.
doi:10.1007/s00259-013-2653-y
PMCID: PMC4024167  PMID: 24442596
FDG-PET; Inflammation; Atherosclerosis; Fat Tissue; Carotid Arteries; Aorta
9.  Preclinical evaluation of MR-attenuation correction versus CT-attenuation correction on a sequential whole-body MR/PET scanner 
Investigative radiology  2013;48(5):313-322.
OBJECTIVES
The application of attenuation correction for combined MR/PET systems is still a major challenge for accurate quantitative PET. CT attenuation correction (CTAC) is the current clinical standard for PET/CT scans. MR, unlike CT, has no direct information about photon attenuation but rather proton densities. On combined MR/PET scanners, MR-based attenuation correction (MRAC) consists of assigning empirical attenuation coefficients to MR signal intensities. The objective of the current study was to evaluate the MRAC implemented on the combined MR/PET scanner versus the CTAC with the same PET data in an animal model.
MATERIALS AND METHODS
MR/PET acquisition was performed using a clinically approved sequential MR/PET scanner (Philips Ingenuity TF). CT and MR/PET images of 20 NZW rabbits were retrospectively analyzed. Animals were positioned on a customized animal bed to avoid movement between CT and MR/PET scanners. PET images from both methods (MRAC and CTAC) were generated. Voxel-by-voxel and region-of-interest (ROI) analyses were performed to determine differences in standardized uptake values (SUV). ROIs were drawn on the coregistered CT images for aorta, liver, kidney, spine and soft tissue (muscle) and superimposed on the PET images.
RESULTS
Voxel-by-voxel comparison of PET showed excellent correlation between MRAC and CTAC SUV values (R=0.99, p<0.0001). The mean of the difference of SUVs between all respective MRAC and CTAC voxels was −0.94% (−0.06±0.30SD), confirming slight underestimation of MRAC. The ROI-based comparison similarly showed MRAC SUV values were underestimated compared to CTAC. The mean difference between MRAC and CTAC for all ROIs was 10.8% (−0.08±0.06SD, R=0.99, p< 0.0001) and −9.7% (−0.15±0.12SD, R=0.99, p<0.0001) for SUVmean and SUVmax, respectively. The highest differences were found in the spine (SUVmean −26.1% (−0.11)) and areas close to large bones such as the back muscles (SUVmean −16.8% (−0.04)).
CONCLUSIONS
In this study, we have compared MRAC and CTAC methods for PET attenuation correction in an animal model. We have confirmed that the MRAC method implemented on a sequential MR/PET scanner underestimates PET values by less than 10% in most regions, except areas containing or close to large bone structures such as the spine or the back muscles. Bone segmentation is therefore suggested to be included in the MR attenuation map in order to minimize the quantification error of MRAC methods compared to the gold standard CTAC. Further clinical studies need to be carried out to validate the clinical use of MRAC.
doi:10.1097/RLI.0b013e31827a49ba
PMCID: PMC3638002  PMID: 23296082
10.  Histopathologic Characteristics of Atherosclerotic Coronary Disease and Implications of the Findings for the Invasive and Noninvasive Detection of Vulnerable Plaques 
Objectives
The goal of this study was to identify histomorphologic characteristics of atherosclerotic plaques and to determine the amenability of some of these components to be used as markers for invasive and noninvasive imaging.
Background
Rupture of the atherosclerotic plaques is responsible for the majority of acute coronary events, and the culprit lesions demonstrate distinct histopathologic features. It has been tacitly believed that plaque rupture (PR) is associated with angiographically minimally occlusive lesions.
Methods
We obtained 295 coronary atherosclerotic plaques, including stable (fibroatheroma [FA]; n = 105), vulnerable (thin-cap fibroatheroma [TCFA]; n = 88), and disrupted plaques (plaque rupture [PR]; n = 102) from the hearts of 181 men and 32 women who had died suddenly. The hierarchical importance of fibrous cap thickness, percent luminal stenosis, macrophage area, necrotic core area, and calcified plaque area was evaluated by using recursive partitioning analysis. Because clinical assessment of fibrous cap thickness is not possible by noninvasive imaging, it was excluded from the second set of partitioning analysis.
Results
Thickness of the fibrous cap emerged as the best discriminator of plaque type; the cap thickness measured <55 μm in ruptured plaques, and all FA were associated with >84-μm cap thickness. Although the majority of TCFA were found in the 54- to 84-μm thickness group, those with <54-μm thickness were more likely to show <74% luminal stenosis (area under the curve: FA, 1.0; TCFA, 0.89; PR, 0.90). After exclusion of cap thickness, analysis of the plaque characteristics revealed macrophage infiltration and necrotic core to be the 2 best discriminators of plaque types (area under the curve: FA, 0.82; TCFA, 0.58; PR, 0.72). More than 75% cross-section area stenosis was seen in 70% of PR and 40% of TCFA; only 5% PR and 10% TCFA were <50% narrowed.
Conclusions
This postmortem study defines histomorphologic characteristics of vulnerable plaques, which may help develop imaging strategies for identification of such plaques in patients at a high risk of sustaining acute coronary events.
doi:10.1016/j.jacc.2012.10.054
PMCID: PMC3931303  PMID: 23473409
acute coronary syndrome; coronary artery disease; high-risk plaque; positive remodeling
11.  Cost-Effectiveness of Percutaneous Coronary Intervention with Drug Eluting Stents versus Bypass Surgery for Patients with Diabetes and Multivessel Coronary Artery Disease: Results from the FREEDOM Trial 
Circulation  2012;127(7):820-831.
Background
Studies from the balloon angioplasty and bare metal stent eras have demonstrated that CABG is cost-effective compared with PCI for patients undergoing multivessel coronary revascularization—particularly among patients with complex CAD or diabetes. Whether these results apply in the drug-eluting stent (DES) era is unknown.
Methods and Results
Between 2005 and 2010, 1900 patients with diabetes and multivessel CAD were randomized to PCI with DES (DES-PCI; n=953) or CABG (n=947). Costs were assessed from the perspective of the U.S. health care system. Health state utilities were assessed using the EuroQOL. A patient-level microsimulation model based on U.S. life-tables and in-trial results was used to estimate lifetime cost-effectiveness. Although initial procedural costs were lower for CABG, total costs for the index hospitalization were $8,622/patient higher. Over the next 5 years, follow-up costs were higher with PCI, owing to more frequent repeat revascularization and higher outpatient medication costs. Nonetheless, cumulative 5-year costs remained $3,641/patient higher with CABG. Although there were only modest gains in survival with CABG during the trial period, when the in-trial results were extended to a lifetime horizon, CABG was projected to be economically attractive relative to DES-PCI, with substantial gains in both life expectancy and quality-adjusted life expectancy and incremental cost-effectiveness ratios <$10,000 per life-year or quality-adjusted life-year gained across a broad range of assumptions regarding the effect of CABG on post-trial survival and costs.
Conclusions
Despite higher initial costs, CABG is a highly cost-effective revascularization strategy compared with DES-PCI for patients with diabetes and multivessel CAD.
doi:10.1161/CIRCULATIONAHA.112.147488
PMCID: PMC3603704  PMID: 23277307
CABG; cost effectiveness; diabetes mellitus; drug eluting stent; percutaneous coronary intervention
12.  Smoking water-pipe, chewing nass, and prevalence of heart disease – A cross-sectional analysis of baseline data from the Golestan Cohort Study, Iran 
Heart (British Cardiac Society)  2012;99(4):272-278.
Objective
Water-pipe and smokeless tobacco use have been associated with several adverse health outcomes. However, little information is available on the association between water-pipe use and heart disease (HD). Therefore, we investigated the association of smoking water-pipe and chewing nass (a mixture of tobacco, lime, and ash) with prevalent HD.
Design
Cross-sectional study.
Setting
Baseline data (collected in 2004–2008) from a prospective population-based study in Golestan Province, Iran.
Participants
50,045 residents of Golestan (40–75 years old; 42.4% male).
Main outcome measures
ORs and 95% CIs from multivariate logistic regression models for the association of water-pipe and nass use with HD prevalence.
Results
A total of 3051 (6.1%) participants reported a history of HD, and 525 (1.1%) and 3726 (7.5%) reported ever water-pipe or nass use, respectively. Heavy water-pipe smoking was significantly associated with HD prevalence (highest level of cumulative use versus never use, OR= 3.75; 95% CI 1.52 – 9.22; P for trend= 0.04). This association persisted when using different cutoff points, when restricting HD to those taking nitrate compound medications, and among never cigarette smokers. There was no significant association between nass use and HD prevalence (highest category of use versus never use, OR= 0.91; 95% CI 0.69 – 1.20).
Conclusions
Our study suggests a significant association between HD and heavy water-pipe smoking. Although the existing evidence suggesting similar biological consequences of water-pipe and cigarette smoking make this association plausible, results of our study were based on a modest number of water-pipe users and need to be replicated in further studies.
doi:10.1136/heartjnl-2012-302861
PMCID: PMC3671096  PMID: 23257174
hookah; ischemic heart disease; nass; tobacco; water-pipe
13.  Smoking gun theory: Angiographically “normal” or “mild” coronary plaque as a cause of myocardial infarction 
Circulation  2012;126(25):2918-2920.
doi:10.1161/CIRCULATIONAHA.112.150425
PMCID: PMC3755485  PMID: 23168415
14.  Inverse relationship between body mass index and coronary artery calcification in patients with clinically significant coronary lesions 
Atherosclerosis  2011;221(1):176-182.
Aims
Mounting data support a ‘calcification paradox’, whereby reduced bone mineral density is associated with increased vascular calcification. Furthermore, reduced bone mineral density is prevalent in older persons with lower body mass index (BMI). Therefore, although BMI and coronary artery calcification (CAC) exhibit a positive relationship in younger persons, it is predicted that in older persons and/or those at risk for osteoporosis, an inverse relationship between BMI and CAC may apply. We sought to explore this hypothesis in a large group of patients with coronary artery disease undergoing percutaneous coronary intervention (PCI).
Methods and Results
We accessed our single-center registry for 07/01/1999 to 06/30/2009, extracting data on all patients that underwent PCI. To minimize bias we excluded those at the extremes of age or BMI and non-Black/Hispanic/Caucasians, leaving 9,993 study subjects (age 66.6±9.9 years). Index lesion calcification (ILC) was analyzed with respect to BMI. Comparing index lesions with no angiographic calcification to those with the most severe, mean BMI decreased by 1.11 kg.m−2; a reduction of 3.9% (P<0.0001). By multivariable modeling, BMI was an independent inverse predictor of moderate-severe ILC (m-sILC; Odds Ratio [OR] 0.967, 95%CI 0.953–0.980, P<0.0001). Additional fully adjusted models identified that, compared to those with normal BMI, obese patients had an OR of 0.702 for m-sILC (95%CI 0.596–0.827, P<0.0001).
Conclusions
In a large group of PCI patients, we identified an inverse correlation between BMI and index lesion calcification. These associations are consistent with established paradigms and suggest a complex interrelationship between BMI, body size and vascular calcification.
doi:10.1016/j.atherosclerosis.2011.11.020
PMCID: PMC3753813  PMID: 22204865
15.  Cardiovascular Defense Challenges at the Basic, Clinical and Population Levels 
Cardiovascular disease (CVD) is now the leading cause of mortality worldwide. Particularly in Low and Middle Income Countries, rapid urbanization and secondary factors such as increasing obesity, poor diet and lack of exercise have combined to propel CVD into this position. Given the enormous scope of this problem and the complex cultural, societal and political issues that are involved, and equally sophisticated and multipronged approach is required to combat CVD at the global level. In this review we outline the basic, clinical and population level challenges that we face in defending ourselves against this disease.
doi:10.1111/j.1749-6632.2012.06495.x
PMCID: PMC3752384  PMID: 22548564
16.  The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion 
International journal of cardiology  2009;147(3):428-432.
Background
Myocardial infarct size is a strong predictor of cardiovascular events. Intravenous metoprolol before coronary reperfusion has been shown to reduce infarct size; however, it is unknown whether oral metoprolol initiated early after reperfusion, as clinical guidelines recommend, is similarly cardioprotective. We compared the extent of myocardial salvage associated with intravenous pre-reperfusion-metoprolol administration in comparison with oral post-reperfusion-metoprolol or placebo. We also studied the effect on suspected markers of reperfusion injury.
Methods
Thirty Yorkshire-pigs underwent a reperfused myocardial infarction, being randomized to pre-reperfusion-metoprolol, post-reperfusion-metoprolol or placebo. Cardiac magnetic resonance imaging was performed in eighteen pigs at day 3 for the quantification of salvaged myocardium. The amounts of at-risk and infarcted myocardium were quantified using T2-weighted and post-contrast delayed enhancement imaging, respectively. Twelve animals were sacrificed after 24 h for reperfusion injury analysis.
Results
The pre-reperfusion-metoprolol group had significantly larger salvaged myocardium than the post-reperfusion-metoprolol or the placebo groups (31±4%, 13±6%, and 7±3% of myocardium at-risk respectively). Post-mortem analyses suggest lesser myocardial reperfusion injury in the pre-reperfusion-metoprolol in comparison with the other 2 groups (lower neutrophil infiltration, decreased myocardial apoptosis, and higher activation of the salvage-kinase phospho-Akt). Salvaged myocardium and reperfusion injury pair wise comparisons proved there were significant differences between the pre-reperfusion-metoprolol and the other 2 groups, but not among the latter two.
Conclusions
The intravenous administration of metoprolol before coronary reperfusion results in larger myocardial salvage than its oral administration initiated early after reperfusion. If confirmed in the clinical setting, the timing and route of β-blocker initiation could be revisited.
doi:10.1016/j.ijcard.2009.09.551
PMCID: PMC3746967  PMID: 19913314
Myocardial infarction; Reperfusion injury; Beta-blockers; MRI; Cardioprotection; Myocardial salvage
18.  Associations of Left Ventricular Hypertrophy with Prevalent and Incident Valve Calcification: The Multi-Ethnic Study of Atherosclerosis 
JACC. Cardiovascular imaging  2012;5(8):781-788.
Objectives
We aim to evaluate the relationship between percent of predicted left ventricular mass (%PredLVM) and valve calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Background
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
Methods
MESA is a longitudinal cohort study of men and women aged 45-84 years without clinical cardiovascular disease in whom serial cardiac magnetic resonance and computed tomography imaging were performed. The relationships between baseline %PredLVM and the prevalence, severity, and incidence of aortic valve (AVC) and mitral annulus calcification (MAC) were determined by regression modeling.
Results
Prevalent AVC was observed in 630 and MAC in 442 of 5,042 subjects (median 55.9 and 71.1 Agatston units, respectively). After adjustment for age, gender, body mass index, ethnicity, socioeconomic status, physical activity, diabetes, cholesterol levels, blood pressure, smoking, kidney function, serum lipids, and antihypertensive and statin medications, %PredLVM was associated with prevalent AVC (OR=1.18 per SD increase in %PredLVM [95%CI 1.08 – 1.30]; p=0.0004) and MAC (OR=1.18 [95%CI 1.06 – 1.32]; p=0.002). Similarly, %PredLVM was associated with increased severity of prevalent AVC (risk difference = 0.26 [95%CI 0.15 – 0.38]; p<0.0001) and MAC (risk difference = 0.20 [95%CI 0.03 – 0.37]; p=0.02). During follow-up (mean 2.4±0.9 years), 153 subjects (4%) developed AVC and 198 (5%) MAC. %PredLVM was associated with incident AVC (OR=1.24 [95%CI 1.04 – 1.47]; p=0.02) and MAC (OR=1.18 [1.01-1.40]; p=0.04). Further adjustment for inflammatory markers and coronary artery calcification did not attenuate these associations. Specifically, concentric LVH most strongly predicted incident valve calcification.
Conclusions
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
doi:10.1016/j.jcmg.2011.12.025
PMCID: PMC3426868  PMID: 22897991
aortic valve; calcification; left ventricular mass; mitral valve annulus
19.  Effect of computed tomography scanning parameters on gold nanoparticle and iodine contrast 
Investigative radiology  2012;47(8):475-481.
Purpose
Gold nanoparticles (gold-NP) have lately been proposed as alternative contrast agents to iodine-based contrast agents (iodine-CA) for computed tomography angiography. The aims of this study were to confirm an appropriate environment in which to evaluate such novel contrast agents, to investigate the comparative contrast of iodine-CA versus gold-NP and to determine optimal scanning parameters for gold-NP.
Materials and methods
Three different clinical scanners were used to acquire CT images. A range of concentrations (10 mM to 1.5 M) of gold-NP and iodine-CA were scanned with varying X-ray tube voltages and currents, reconstruction kernels, protocols and scanner models. The different environments investigated were air, water and water with a bone simulant (Ca3(PO4)2). Regression coefficients were derived from the attenuation values plotted against concentration and compared for statistical significance using t-values.
Results
As expected, contrast was linearly related to concentration up to 500-1000 mM, depending on the conditions used, whereupon a plateau of 3000 HU was reached. Attenuation was significantly different depending on the environment used (air, water or water and bone simulant). Contrast is dependent on the X-ray tube voltage used, with the contrast produced from iodine-CA sharply declining with increasing voltage, while the contrast of gold-NP varied less with tube voltage, but was maximal at 120 kV in water with bone simulant. Current, reconstruction kernels, protocols and scanner model had less effect on contrast.
Conclusion
Water with a bone simulant is a preferable environment for evaluating novel cardiac CT contrast agents. Relative iodine-CA vs. gold-NP contrast is dependent on the scanning conditions used. Optimal scanning conditions for gold-NP will likely use an X-ray tube voltage of 120 kV.
doi:10.1097/RLI.0b013e3182562ab9
PMCID: PMC3582405  PMID: 22766909
computed tomography; gold nanoparticles; contrast agents; iodine
20.  Regression of Inflammation in Atherosclerosis by the LXR Agonist R211945 
JACC. Cardiovascular imaging  2012;5(8):819-828.
OBJECTIVES
The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945.
BACKGROUND
R211945 induces reversal cholesterol transport and modulates inflammation in atherosclerotic plaques. We aimed to characterize with 18F-fluorodeoxyglucose (FDG)–positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced cardiac magnetic resonance (DCE-CMR) inflammation and neovascularization, respectively, in atherosclerotic plaques with R211945 treatment compared with atorvastatin treatment and a control.
METHODS
Twenty-one atherosclerotic New Zealand white rabbits were divided into 3 groups (control, R211945 [3 mg/kg orally], and atorvastatin [3 mg/kg orally] groups). All groups underwent 18F-FDG–PET/CT and DCE-CMR at baseline and at 1 and 3 months after treatment initiation. Concomitantly, serum metabolic parameters and histology were assessed. For statistical analysis, continuous DCE-CMR and PET/CT outcomes were modeled as linear functions of time by using a linear mixed model, whereas the histological data, animal characteristics data, and nonlinear regression imaging data were analyzed with a 2-tailed Student t test.
RESULTS
18F-FDG–PET/CT detected a decrease in mean and maximum standard uptake values (SUV) over time in the R211945 group (both p = 0.001), indicating inflammation regression. The atorvastatin group displayed no significant change (p = 0.371 and p = 0.600, respectively), indicating no progression or regression. The control group demonstrated an increase in SUV (p = 0.01 and p = 0.04, respectively), indicating progression. There was a significant interaction between time and group for mean and maximum SUV (p = 0.0003 and p = 0.0016, respectively). DCE-CMR detected a trend toward difference (p = 0.06) in the area under the curve in the atorvastatin group, suggesting a decrease in neovascularization. There was no significant interaction between time and group (p = 0.6350 and p = 0.8011, respectively). Macrophage and apolipoprotein B immunoreactivity decreased in the R211945 and atorvastatin groups (p < 0.0001 and p = 0.0004, respectively), and R211945 decreased oxidized phospholipid immunoreactivity (p = 0.02).
CONCLUSIONS
Noninvasive imaging with 18F-FDG–PET/CT and DCE-CMR and histological analysis demonstrated significant anti-inflammatory effects of the LXR agonist R211945 compared with atorvastatin. The results suggest a possible role for LXR agonists in the treatment of atherosclerosis.
doi:10.1016/j.jcmg.2011.11.025
PMCID: PMC3600612  PMID: 22897996
atherosclerosis; dynamic contrast-enhanced cardiac magnetic resonance; 18F-FDG–PET/CT; LXR agonist
21.  Impact of Non-Insulin Dependent Type-2 Diabetes on Carotid Wall 18F-FDG-PET Uptake 
Objective & Background
Inflammation is a pivotal process in the progression of atherosclerosis, which can be non-invasively imaged by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). In this study, the impact of non-insulin dependent type-2 diabetes on carotid wall FDG uptake in patients with documented or suspected cardiovascular disease was evaluated.
Methods
Carotid artery wall FDG uptake was quantified in 134 patients (age 60.2±9.7 years; diabetic subjects: n=43). The pre-scan glucose (gluc) level corrected mean of the maximum standardized uptake value (SUV) values (meanSUVgluc), mean of the maximum target-to-background ratio (meanTBRgluc), and Single Hottest Segment (SHSgluc) of FDG uptake in the artery wall were calculated. Associations between FDG uptake, the presence of risk factors for atherosclerosis, and diabetes were then assessed by multiple regression analysis with backward elimination.
Results
We demonstrated a significant association between diabetes and FDG uptake in the arterial wall (diabetes: meanSUVgluc; β=0.324, meanTBRgluc; β=0.317, and SHSgluc; β=0.298; for all: p<0.0001, respectively). In addition, in diabetic patients, both body mass index (BMI) ≥30 kg/m2 (BMI ≥30 kg/m2: meanSUVgluc; β=0.4, meanTBRgluc; β=0.357, and SHSgluc; β=0.388; for all: p<0.015) and smoking (smoking: meanTBRgluc; β=0.312, SHSgluc; β=0.324; for all: p<0.04) were significantly associated with FDG uptake.
Conclusions
Type-2 diabetes was significantly associated with carotid wall FDG uptake in patients with known or suspected cardiovascular disease. In diabetic patients, obesity and smoking add to the risk of increased FDG uptake values. Furthermore, the degree of carotid wall FDG uptake increases with increments of fasting glucose levels in diabetic patients.
doi:10.1016/j.jacc.2011.11.069
PMCID: PMC3392202  PMID: 22651864
FDG-PET; Inflammation; Atherosclerosis; Diabetes; Carotid Arteries
22.  Stem Cell Factor Gene Transfer Promotes Cardiac Repair After Myocardial Infarction via In Situ Recruitment and Expansion of c-kit+ Cells 
Circulation research  2012;111(11):1434-1445.
Rationale
There is growing evidence that the myocardium responds to injury by recruiting c-kit+ cardiac progenitor cells to the damage tissue. Even though the ability of exogenously introducing c-kit+ cells to injured myocardium has been established, the capability of recruiting these cells through modulation of local signaling pathways by gene transfer has not been tested.
Objective
To determine whether stem cell factor gene transfer mediates cardiac regeneration in a rat myocardial infarction model, through survival and recruitment of c-kit+ progenitors and cell-cycle activation in cardiomyocytes, and explore the mechanisms involved.
Methods and Results
Infarct size, cardiac function, cardiac progenitor cells recruitment, fibrosis, and cardiomyocyte cell-cycle activation were measured at different time points in controls (n=10) and upon stem cell factor gene transfer (n=13) after myocardial infarction. We found a regenerative response because of stem cell factor overexpression characterized by an enhancement in cardiac hemodynamic function: an improvement in survival; a reduction in fibrosis, infarct size and apoptosis; an increase in cardiac c-kit+ progenitor cells recruitment to the injured area; an increase in cardiomyocyte cell-cycle activation; and Wnt/β-catenin pathway induction.
Conclusions
Stem cell factor gene transfer induces c-kit+ stem/progenitor cell expansion in situ and cardiomyocyte proliferation, which may represent a new therapeutic strategy to reverse adverse remodeling after myocardial infarction.
doi:10.1161/CIRCRESAHA.111.263830
PMCID: PMC3651889  PMID: 22931954
cardiac myocyte regeneration; gene transfer; myocardial infarction; stem cell factor
23.  Perspectives and opportunities for nanomedicine in the management of atherosclerosis 
Nature reviews. Drug discovery  2011;10(11):835-852.
The use of nanotechnology for medical purposes — nanomedicine — has grown exponentially over the past few decades. This is exemplified by the US Food and Drug Administration’s approval of several nanotherapies for various conditions, as well as the funding of nanomedical programmes worldwide. Although originally the domain of anticancer therapy, recent advances have illustrated the considerable potential of nanomedicine in the diagnosis and treatment of atherosclerosis. This Review elaborates on nanoparticle-targeting concepts in atherosclerotic disease, provides an overview of the use of nanomedicine in atherosclerosis, and discusses potential future applications and clinical benefits.
doi:10.1038/nrd3578
PMCID: PMC3623275  PMID: 22015921
24.  Epithelial- and Endothelial- to Mesenchymal Transition: from Cardiovascular Development to Disease 
Circulation  2012;125(14):1795-1808.
doi:10.1161/CIRCULATIONAHA.111.040352
PMCID: PMC3333843  PMID: 22492947
Endothelium; epithelium; development; transition
25.  Lymphocytes and the Adventitial Immune Response in Atherosclerosis 
Circulation Research  2012;110(6):889-900.
Though much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue (PVAT). Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature.
doi:10.1161/CIRCRESAHA.111.263186
PMCID: PMC3373006  PMID: 22427326
Lymphocytes; Atherosclerosis; Adventitia; Imaging

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