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1.  Optimization of dual-saturation single bolus acquisition for quantitative cardiac perfusion and myocardial blood flow maps 
Background
In-vivo quantification of cardiac perfusion is of great research and clinical value. The dual-bolus strategy is universally used in clinical protocols but has known limitations. The dual-saturation acquisition strategy has been proposed as a more accurate alternative, but has not been validated across the wide range of perfusion rates encountered clinically. Dual-saturation acquisition also lacks a clinically-applicable procedure for optimizing parameter selection. Here we present a comprehensive validation study of dual-saturation strategy in vitro and in vivo.
Methods
The impact of saturation time and profile ordering in acquisitions was systematically analyzed in a phantom consisting of 15 tubes containing different concentrations of contrast agent. In-vivo experiments in healthy pigs were conducted to evaluate the effect of R2* on the definition of the arterial input function (AIF) and to evaluate the relationship between R2* and R1 variations during first-pass of the contrast agent. Quantification by dual-saturation perfusion was compared with the reference-standard dual-bolus strategy in 11 pigs with different grades of myocardial perfusion.
Results
Adequate flow estimation by the dual-saturation strategy is achieved with myocardial tissue saturation times around 100 ms (always <30 ms of AIF), with the lowest echo time, and following a signal model for contrast conversion that takes into account the residual R2* effect and profile ordering. There was a good correlation and agreement between myocardial perfusion quantitation by dual-saturation and dual-bolus techniques (R2 = 0.92, mean difference of 0.1 ml/min/g; myocardial perfusion ranges between 0.18 and 3.93 ml/min/g).
Conclusions
The dual-saturation acquisition strategy produces accurate estimates of absolute myocardial perfusion in vivo. The procedure presented here can be applied with minimal interference in standard clinical procedures.
doi:10.1186/s12968-015-0116-2
PMCID: PMC4332925
Dual saturation acquisition strategy; Absolute quantitative cardiac perfusion; Cardiovascular magnetic resonance
2.  Macrophages Transmit Potent Proangiogenic Effects of oxLDL In Vitro and In Vivo Involving HIF-1α Activation: a Novel Aspect of Angiogenesis in Atherosclerosis 
Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1α) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF). Oxidized low-density lipoprotein (oxLDL) is generated in lipid-rich plaque by oxidative stress. It triggers an inflammatory response and was traditionally thought to inhibit endothelial cells. New data, however, suggest that oxLDL can activate HIF-1α in monocytes in a hypoxia-independent fashion. We hypothesized that HIF-1α activation in monocyte-macrophages could transmit proangiogenic effects of oxLDL linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. First, we examined the effect of oxLDL on HIF-1α and VEGF expression in monocyte-macrophages and on their proangiogenic effect on endothelial cells in vitro in a monocyte-macrophage/endothelial co-culture model. OxLDL strongly induced HIF-1α and VEGF in monocyte-macrophages and significantly increased tube formation in co-cultured endothelial cells. HIF-1α inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1α inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1α and VEGF expression. The administration of low-lipid diet significantly reduced the expression of both HIF-1α and VEGF, resulting in decreased plaque neovascularization. Our data point to oxLDL as a proangiogenic agent linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. This effect is dependent on macrophages and, at least in part, on the induction of the HIF-1α pathway.
doi:10.1007/s12265-013-9469-9
PMCID: PMC4334467  PMID: 23661177
Atherosclerosis; Lipids; Angiogenesis; Inflammation
4.  Considerations for pre-clinical models and clinical trials of pluripotent stem cell-derived cardiomyocytes 
Pluripotent stem cells (PSCs) represent an appealing source from which to develop cell replacement therapies. Different initiatives have been launched to promote their development toward clinical applications. This article will review the main questions that should be considered before translating PSC-derived cardiomyocytes into clinical investigations, including the development of good manufacturing practice-level PSC lines, the development of efficient protocols to generate pure populations of cardiac myocytes, and the development of techniques to improve the retention and survival rate of transplanted cells.
doi:10.1186/scrt390
PMCID: PMC4055070  PMID: 24405778
5.  Nurse Management of Hypertension in Rural Western Kenya: Implementation Research to Optimize Delivery 
Annals of global health  2013;80(1):5-12.
Background
Hypertension is the leading global risk factor for mortality. Hypertension treatment and control rates are low worldwide, and insufficient human resource capacity is among the contributing factors. Thus, a critical component of hypertension management is to develop novel and effective solutions to the human resources challenge. One potential solution is task redistribution and nurse management of hypertension in these settings.
Methods
This study investigates whether nurses can effectively reduce blood pressure in hypertensive patients in rural western Kenya and, by extension, throughout sub-Saharan Africa. An initial phase of qualitative inquiry will assess facilitators and barriers of nurse management of hypertension. In addition, we will perform usability and feasibility testing of a novel, electronic tablet-based integrated decision support and record-keeping tool for the nurses. An impact evaluation of a pilot program for nurse-based management of hypertension will be performed. Finally, a needs-based workforce estimation model will be utilized to estimate the nurse workforce requirements for stable, long-term treatment of hypertension throughout western Kenya.
Results
The primary outcome measure of the impact evaluation will be the change in systolic blood pressure of hypertensive individuals assigned to nurse-based management after one year of follow-up. The workforce estimation modeling output will be full-time equivalents of nurses.
Conclusions
This study will provide evidence regarding the effectiveness of strategies to optimize task redistribution and nurse-based management of hypertension that can be applicable to non-communicable disease management in low- and middle-income countries.
doi:10.1016/j.aogh.2013.12.002
PMCID: PMC4036099  PMID: 24751560
6.  The Complementary Roles of Dynamic Contrast Enhanced MRI and 18F-Fluorodeoxyglucose PET/CT for Imaging of Carotid Atherosclerosis 
European journal of nuclear medicine and molecular imaging  2013;40(12):10.1007/s00259-013-2518-4.
Background
Inflammation and neovascularization in vulnerable atherosclerotic plaques are key risk factors for severe clinical events. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) are two non-invasive imaging techniques capable of quantifying plaque neovascularization and inflammatory infiltrate respectively. However, their mutual role in defining plaque vulnerability and their possible overlap has not been thoroughly investigated. Here, we study the relationship between DCE-MRI and 18F-FDG PET in the carotid arteries of 40 subjects with coronary heart disease (CHD) or CHD equivalent, recruited as a substudy of the dal-PLAQUE trial (NCT00655473).
Methods
The dal-PLAQUE trial was a multicenter study that evaluated dalcetrapib, a cholesteryl ester transfer protein modulator. Subjects underwent anatomical MRI, DCE-MRI and 18F-FDG PET. Only baseline imaging and biomarkers data (before randomization) from dal-PLAQUE were used as part of this substudy. Our primary goal was to evaluate the relationship between DCE-MRI and 18F-FDG PET data. As secondary endpoints, we evaluated the relationship between a) PET data and whole vessel anatomical MRI data, and b) DCE-MRI and matching anatomical MRI data. All correlations were estimated using a mixed linear model.
Results
We found a significant inverse relationship between several perfusion indices by DCE-MRI and 18F-FDG uptake by PET. Regarding our secondary endpoints, there was a significant relationship between plaque burden measured by anatomical MRI with several perfusion indices by DCE-MRI and 18F-FDG uptake by PET. No relationship was found between plaque composition by anatomical MRI with DCEMRI or 18F-FDG PET metrics.
Conclusions
In this study we observed a significant, weak inverse relationship between inflammation measured as 18F-FDG uptake by PET and plaque perfusion by DCE-MRI. Our findings suggest that there may be a complex relationship between plaque inflammation and microvascularization during the different stages of plaque development. 18F-FDG PET and DCE-MRI may have complementary roles in identifying subjects at high risk for cardiovascular events in future clinical practice.
doi:10.1007/s00259-013-2518-4
PMCID: PMC3823642  PMID: 23942908
DCE-MRI; PET/CT; atherosclerosis; inflammation; neovascularization
7.  Promotion of Cardiovascular Health in Preschool Children: 36-Month Cohort Follow-up 
The American journal of medicine  2013;126(12):1122-1126.
BACKGROUND
Educational interventions in preschool children could improve dietary behavior and physical activity, and prevent unhealthy body weights in low- and middle-income countries. Previously, we have reported the beneficial impact of an educational intervention in preschoolers in a 6-month trial. We now report extended results after 36 months.
METHODS
Evaluating the cohort of previously intervened children, baseline measurements were made in May 2009 in 14 preschool facilities in Usaquén (Bogotá, Colombia). Follow-up measurements were performed at 18 and 36 months. The primary outcome was the mean change in children’s knowledge and attitudes scores regarding healthy eating and living an active lifestyle, including habits scores related to physical activity. Secondary outcomes were the change over time of children’s nutritional status and the mean change in parent’s knowledge, attitudes, and habits.
RESULTS
We included 1216 children, 3–5 years of age, and 928 parents. After adjusting by sex and age of children, socioeconomic status, age of parents, and age and education level of teachers, we found a significant increase in mean knowledge, attitudes, and habits scores at 36 months, compared with baseline: 87.94 vs 76.15 (P <.001); 86.39 vs 57.03 (P <.001); and 66.29 vs 48.72 (P <.001), respectively. We observed a similar increase in knowledge and attitude scores in parents: 73.45 vs 70.01 (P <.001); and 78.08 vs 74.65 (P <.001). The proportion of eutrophic children increased from 62.1% at baseline to 75.0% at 36 months (P <.0001).
CONCLUSIONS
After 36 months, the educational intervention maintained a beneficial trend toward a healthy lifestyle in children and their parents.
doi:10.1016/j.amjmed.2013.06.021
PMCID: PMC4106297  PMID: 24262725
Cardiovascular disease (CVD); Global health; Health education; Noncommunicable disease (NCD); Preschool children
8.  Gold Nanocrystal Labeling Allows Low Density Lipoprotein Imaging From The Subcellular To Macroscopic Level 
ACS nano  2013;7(11):10.1021/nn403258w.
Low density lipoprotein (LDL) plays a critical role in cholesterol transport and is closely linked to the progression of several diseases. This motivates the development of methods to study LDL behavior from the microscopic to whole-body level. We have developed an approach to efficiently load LDL with a range of diagnostically active nanocrystals or hydrophobic agents. We performed focused experiments on LDL labeled with gold nanocrystals (Au-LDL). The labeling procedure had minimal effect on LDL size, morphology or composition. Biological function was found to be maintained from both in vitro and in vivo experiments. Tumor bearing mice were injected intravenously with LDL, DiR-LDL, Au-LDL or a gold-loaded nanoemulsion. LDL accumulation in the tumors was detected with whole body imaging methods, such as computed tomography (CT), spectral CT and fluorescence imaging. Cellular localization was studied with transmission electron microscopy (TEM) and fluorescence techniques. In conclusion, this LDL labeling procedure should permit the study of lipoprotein biointeractions in unprecedented detail.
doi:10.1021/nn403258w
PMCID: PMC3863599  PMID: 24127782
low density lipoprotein; gold nanoparticles; electron microscopy; computed tomography; fluorescence imaging
9.  The Novel Small Leucine-Rich Repeat Protein Podocan is a Negative Regulator of Migration and Proliferation of Smooth Muscle Cells, Modulates Neointima Formation and is Expressed in Human Atheroma 
Circulation  2013;128(22):2351-2363.
Background
SMC migration and proliferation critically influence the clinical course of vascular disease. We tested the effect of the novel small leucine-rich repeat protein podocan on SMC migration and proliferation using a podocan deficient mouse in combination with a model of arterial injury and aortic explant SMC culture. In addition, we examined the effect of overexpression of the human form of podocan on human SMC and tested for podocan expression in human atherosclerosis. In all these conditions we evaluated concomitantly the Wnt-TCF-pathway.
Methods and Results
Podocan was strongly and selectively expressed in arteries of WT mice after injury. Podocan−/− mice showed increased arterial lesion formation as compared to WT littermates in response to injury (P<0.05). Also, SMC proliferation was increased in arteries of podocan −/− mice compared to WT (P<0.05). In vitro, migration and proliferation were increased in podocan−/− SMC and were normalized by transfection with the WT podocan gene (P<0.05). In addition, upregulation of the Wnt-TCF-pathway was found in SMC of podocan−/− mice both in vitro and in vivo. On the other hand, podocan overexpression in human SMC significantly reduced SMC migration and proliferation inhibiting the Wnt-TCF-pathway. Podocan and a Wnt-TCF-pathway marker were differently expressed in human coronary restenotic versus primary lesions.
Conclusions
Podocan appears to be a potent negative regulator of the migration and proliferation of both murine and human SMC. The lack of podocan results in excessive arterial repair and prolonged SMC proliferation, which likely is mediated by the Wnt-TCF-pathway.
doi:10.1161/CIRCULATIONAHA.113.004634
PMCID: PMC3917564  PMID: 24043300
Extracellular Matrix; Smooth Muscle Cells; Proliferation; Arteries
10.  Risk Factors Associated with the Incidence and Progression of Mitral Annulus Calcification: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2013;166(5):904-912.
Background
Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of participants aged 45–84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression.
Results
Prevalent MAC was observed in 534 of 5,895 (9%) participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 yrs; 95% CI, 1.97 to 2.58; P<0.0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, −6.7, 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (β-coefficient per 10 AU, 0.88; 95% CI, 0.85 to 0.91; P<0.0001), although ethnicity and smoking status possessed modest influence.
Conclusions
Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames.
doi:10.1016/j.ahj.2013.08.015
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
11.  Noninvasive Molecular Imaging of Cell Death in Myocardial Infarction using 111In-GSAO 
Scientific Reports  2014;4:6826.
Acute insult to the myocardium is associated with substantial loss of cardiomyocytes during the process of myocardial infarction. In this setting, apoptosis (programmed cell death) and necrosis may operate on a continuum. Because the latter is characterized by the loss of sarcolemmal integrity, we propose that an appropriately labeled tracer directed at a ubiquitously present intracellular moiety would allow non-invasive definition of cardiomyocyte necrosis. A trivalent arsenic peptide, GSAO (4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid), is capable of binding to intracellular dithiol molecules such as HSP90 and filamin-A. Since GSAO is membrane impermeable and dithiol molecules abundantly present intracellularly, we propose that myocardial localization would represent sarcolemmal disruption or necrotic cell death. In rabbit and mouse models of myocardial infarction and post-infarct heart failure, we employed In-111-labelled GSAO for noninvasive radionuclide molecular imaging. 111In-GSAO uptake was observed within the regions of apoptosis seeking agent- 99mTc-Annexin A5 uptake, suggesting the colocalization of apoptotic and necrotic cell death processes.
doi:10.1038/srep06826
PMCID: PMC4212241  PMID: 25351258
12.  Serum Inflammatory Biomarkers and Plaque Inflammation Assessed by 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the dal-PLAQUE Study 
JACC. Cardiovascular imaging  2013;6(10):10.1016/j.jcmg.2013.03.009.
OBJECTIVES
To longitudinally investigate the relationship between a broad spectrum of serum inflammatory biomarkers and plaque inflammation assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT).
BACKGROUND
Both plaque inflammation and serum biomarkers of inflammation are associated with atherothrombotic events; however, the relationship between them is unclear.
METHODS
We conducted a post-hoc analysis of the dal-PLAQUE study – a randomized, placebo-controlled study of dalcetrapib, a cholesteryl ester transfer protein inhibitor, in 130 patients with coronary heart disease, or coronary heart disease risk equivalents on stable lipid-lowering therapy. Baseline and change after 3 months’ follow-up in inflammatory biomarker levels, and baseline and change after 3 months’ follow-up in aorta and carotid 18F-FDG PET/CT (mean maximum target to background ratio of the most diseased segment (TBRmds), were analyzed.
RESULTS
Baseline myeloperoxidase (MPO) positively correlated with baseline carotid TBRmds (rho 0.25, p = 0.02). This correlation remained at 3 months’ and was independent of traditional cardiovascular disease risk factors. Baseline lipoprotein-associated phospholipase A2 mass correlated with aorta TBRmds (rho 0.21, p = 0.03). However, this correlation disappeared at 3 months’ and was not independent of cardiovascular disease risk factors. There was no association between change from baseline in MPO or lipoprotein-associated phospholipase A2 mass and change from baseline in aorta and carotid TBRmds. Baseline and change from baseline in high sensitivity C-reactive protein, interleukin 6, soluble P-selectin, soluble E-selectin, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and matrix-metalloproteinase 3 and 9 did not correlate with baseline or change from baseline in carotid or aorta TBRmds.
CONCLUSION
Our data show that, in patients with coronary heart disease or at high risk of coronary heart disease on stable lipid-lowering therapy, circulating MPO levels are associated with carotid plaque inflammation.
doi:10.1016/j.jcmg.2013.03.009
PMCID: PMC3831277  PMID: 24135322
Inflammatory biomarkers; 18F-Fluorodeoxyglucose Positron Emission Tomography; Atherosclerosis
13.  Early intravenous beta-blockers in patients with acute coronary syndrome–A meta-analysis of randomized trials 
International journal of cardiology  2012;168(2):915-921.
Background
Intravenous (IV) beta-blockade is currently a Class IIa recommendation in early management of patients with acute coronary syndromes (ACS) without obvious contraindications.
Methods
We searched the PubMed, EMBASE and the Cochrane Register for Controlled Clinical Trials for randomized clinical trials from 1965 through December, 2011, comparing intravenous beta-blockers administered within 12 hours of presentation of ACS with standard medical therapy and/or placebo. The primary outcome assessed was the risk of short-term (in-hospital mortality-with maximum follow up duration of 90 days) all-cause mortality in the intervention group versus the comparator group. The secondary outcomes assessed were ventricular tachyarrhythmias, myocardial reinfarction, cardiogenic shock, and stroke. Pooled treatment effects were estimated using relative risk with Mantel–Haenszel risk ratio, using a random-effects model.
Results
Sixteen studies enrolling 73,396 participants met the inclusion / exclusion criteria. In- hospital mortality was reduced 8% with intravenous beta-blockers, RR=0.92 (95% CI, 0.86–1.00; p=0.04) when compared with controls. Moreover, intravenous beta-blockade reduced the risk of ventricular tachyarrhythmias (RR=0.61; 95 % CI 0.47–0.79; p=0.0003) and myocardial reinfarction (RR=0.73, 95 % CI 0.59–0.91; p=0.004) without increase in the risk of cardiogenic shock, (RR=1.02; 95% CI 0.77–1.35; p=0.91) or stroke (RR=0.58; 95 % CI 0.17–1.98; p=0.38).
Conclusions
Intravenous beta-blockers early in the course of appropriate patients with ACS appears to be associated with significant reduction in the risk of short-term cardiovascular outcomes, including a reduction in the risk of all-cause mortality.
doi:10.1016/j.ijcard.2012.10.050
PMCID: PMC4104797  PMID: 23168009
Meta-analysis; Myocardial Infarction; Cardiovascular Pharmacology; Beta-Blocker; IV; Mortality
14.  Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport 
Circulation  2012;125(15):1905-1919.
doi:10.1161/CIRCULATIONAHA.111.066589
PMCID: PMC4159082  PMID: 22508840
High density lipoprotein; cholesterol efflux; reverse cholesterol transport; atherosclerosis; cardiovascular disease; vascular imaging
15.  Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial 
Lancet  2011;378(9802):1547-1559.
Summary
Background
Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.
Methods
In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and 18F-fluorodeoxyglucose (18F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.
Findings
189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (−7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.
Interpretation
Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed.
Funding
F Hoffmann-La Roche Ltd.
doi:10.1016/S0140-6736(11)61383-4
PMCID: PMC4151875  PMID: 21908036
16.  Prevalence and Risk Factors of Carotid Vessel Wall Inflammation in Coronary Artery Disease Patients 
JACC. Cardiovascular imaging  2011;4(11):1195-1205.
OBJECTIVES
We investigated the prevalence and clinical risk factors of carotid vessel wall inflammation by means of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in a population consisting of coronary artery disease (CAD) patients.
BACKGROUND
The atherosclerotic disease process is characterized by infiltration and retention of oxidized lipids in the artery wall, triggering a disproportionate inflammatory response. Efforts have been made to use noninvasive imaging to quantify this inflammatory response in the vessel wall. Recently, carotid FDG-PET has been shown to reflect the metabolic rate of glucose, a process known to be enhanced in inflamed tissue.
METHODS
Carotid inflammation was quantified in 82 CAD patients (age 62 ± 10 years) as the maximum target-to-background ratio (wholevesselTBRmax). Furthermore, we assessed the maximal standardized uptake value values (wholevesselSUVmax), the single hottest segment (SHS), and the percent active segments (PAS) of the FDG uptake in the artery wall, measured by FDG-PET.
RESULTS
Whole-vessel TBRmax > 1.8 was present in 67%, > 2.0 in 39%, > 2.2 in 23%, and > 2.4 in 12% of the population. Multiple linear regression analysis with backward elimination revealed that body mass index (BMI) ≥ 30 kg/m2 (p < 0.0001), age > 65 years (p = 0.01), smoking (p = 0.02), and hypertension (p = 0.01) were associated with wholevesselTBRmax. The number of components of the metabolic syndrome was also associated with wholevesselTBRmax (p = 0.02). In similar analyses, wholevesselSUVmax was associated with BMI ≥30 kg/m2 (p < 0.0001), age > 65 years (p = 0.004), male gender (p = 0.02), and hypertension (p = 0.04); SHS with BMI ≥30 kg/m2 (p < 0.0001), age >65 years (p = 0.02), smoking (p = 0.04), and hypertension (p = 0.05); PAS with BMI ≥30 kg/m2 (p = 0.001), smoking (p = 0.03), and hypertension (p = 0.01).
CONCLUSIONS
Carotid inflammation as revealed by FDG-PET is highly prevalent in the CAD population and is associated with obesity, age over 65 years, history of hypertension, smoking, and male gender. Artery wall FDG uptake increased when components of the metabolic syndrome clustered.
doi:10.1016/j.jcmg.2011.07.008
PMCID: PMC4120023  PMID: 22093271
atherosclerosis; FDG-PET; inflammation; metabolic syndrome; obesity
17.  Comparison of echocardiographic measurements of left ventricular volumes to full volume magnetic resonance imaging in normal and diseased rats 
Background
Clinical two-dimensional (2D) and clinical three-dimensional (3D) echocardiography are validated against Cardiac Magnetic Resonance imaging (CMR), the gold standard for left ventricle (LV) volumes. In rodents, there is no widely accepted echocardiographic measure of whole LV volumes, and CMR measurements vary between studies. We compared LV volumes by 2D-echocardiography (hemisphere-cylinder (HC) model) to HC and full-volume (FV) CMR in normal and diseased rats to measure the impact of geometric models and imaging modalities.
Methods
Rats (n=27) underwent ascending aortic banding, myocardial infarction induction by either permanent left anterior descending artery (LAD) ligation or ischemia-reperfusion, and sham thoracotomy. Subsequently, we measured end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) using a HC-2D-echocardiography model combining parasternal short-axis and long-axis measurements and compared these to HC and FV-CMR.
Results
Diseased groups showed LV dilatation and dysfunction. HC-echocardiography and FV-CMR measures of EDV, ESV and EF were correlated. On Bland-Altman plots, EDV were concordant between both methods while HC-echocardiography underestimated ESV, resulting in a modest overestimation of EF versus FV-CMR. Other 2D-echocardiographic geometric models offered less concordance with FV-CMR than HC. HC-CMR overestimates LV volumes versus FV-CMR, while HC-echocardiography underestimates HC-CMR volumes. Echocardiography underestimates corresponding LV dimensions by CMR, particularly short-axis.
Conclusions
Concordant measures of LV volume and function were obtained using: (1) a relatively simple HC model of the LV inclusive of two orthogonal 2D-echocardiographic planes, and (2) FV-CMR in normal and diseased rats. The HC model appears to compensate the underestimation of LV dimensions by echocardiography.
doi:10.1016/j.echo.2013.04.016
PMCID: PMC3725209  PMID: 23706342
Echocardiography; magnetic resonance imaging; rat; animal ultrasound; animal models of disease
18.  In vivo characterization of a new abdominal aortic aneurysm mouse model with conventional and molecular MRI 
Objectives
To use non-invasive conventional and molecular magnetic resonance imaging (MRI) to detect and characterize abdominal aortic aneurysms (AAAs) in vivo.
Background
Collagen is an essential constituent of aneurysms. Non-invasive MRI of collagen may represent an opportunity to help detect and better characterize AAA and initiate intervention.
Methods
We used an AAA C57BL/6 mouse model where a combination of angiotensin-II infusion and TGF-β neutralization results in AAA formation with incidence of aortic rupture. High-resolution multi-sequence MRI was performed to characterize the temporal progression of AAA. To allow molecular MRI of collagen, paramagnetic/fluorescent micellar nanoparticles functionalized with a collagen-binding protein (CNA-35) were intravenously administered. In vivo imaging results were corroborated with immunohistochemistry and confocal fluorescence microscopy.
Results
High-resolution multi-sequence MRI allowed the visualization of the primary fibrotic response in the aortic wall. As the aneurysm progressed, the formation of a secondary channel or dissection was detected. Further analysis revealed a dramatic increase of the aortic diameter. Injection of CNA-35 micelles resulted in a significant higher MR signal enhancement in the aneurysmal wall compared to non-specific micelles. Histological studies demonstrated the presence of collagen in regions of MR signal enhancement and confocal microscopy proved the precise colocalization of CNA-35 micelles with collagen-I. In addition, in a proof of concept experiment, we have shown the potential of CNA-35 micelles to discriminate between stable AAA lesions and aneurysms that were likely to rapidly progress/rupture.
Conclusion
Multi-sequence MRI allowed longitudinal monitoring of AAA progression while the presence of collagen was visualized by nanoparticle-enhanced MRI.
doi:10.1016/j.jacc.2011.09.017
PMCID: PMC4095885  PMID: 22133853
MRI; molecular imaging; abdominal aortic aneurysm; collagen
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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