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1.  Comparison of MR-based attenuation correction vs. CT-based attenuation correction of Whole Body PET/MR imaging 
The objective of this paper was to evaluate the performance of the built-in MR-based attenuation correction method (MRAC) included in the combined whole-body Ingenuity TF PET/MR scanner and compare it to the gold standard CT-based attenuation correction (CTAC).
Twenty-six patients undergoing clinical whole body FDG-PET/CT imaging were subsequently scanned on the PET/MR (mean delay 100min). Patients were separated in two groups: alpha group (N=14) with no MR coils during PET/MR imaging and beta group (N=12) including MR coils (Neuro-Vascular, Spine, Cardiac or Torso coils). All images were coregistered to the same space (PET/MR). Voxel- and region-based (10 regions of interest, ROIs) comparisons were made between the 2 PET images from PET/MR: using MRAC and CTAC. Additional comparison of lesions performed by an experienced clinician was also reported.
Body mass index (BMI) and lung density showed significant differences between alpha and beta groups. Right vs. left lung density was also significantly different within each group. Overall the beta group (with coils) presented higher MRAC PET values than the alpha group when compared to the CTAC (alpha: −0.2±33.6%, R2=0.98, p<0.001, beta: 10.31±69.86%, R2=0.97, p<0.001).
In comparison to CTAC, PET values with MRAC method were underestimated by less than 10% on average, although some ROIs and lesions do differ by more (such as spine, lung or heart). The beta group (with coils) showed increased overall PET quantification as well as increased variability when compared to the alpha group (no coils). PET reconstructed with MRAC showed some differences when compared to PET reconstructed with CTAC, mostly due to air pockets, metallic implants and attenuation differences in big bone areas (such as pelvis and spine) due to the segmentation limitation of the MRAC method.
PMCID: PMC4090355  PMID: 24652234
PET/MR; attenuation correction; MRAC; CTAC
2.  Targeted Molecular Probes for Imaging Atherosclerotic Lesions With Magnetic Resonance Using Antibodies That Recognize Oxidation-Specific Epitopes 
Circulation  2008;117(25):3206-3215.
Oxidized low-density lipoprotein plays a key role in the initiation, progression, and destabilization of atherosclerotic plaques and is present in macrophages and the lipid pool. The aim of this study was to assess the feasibility of magnetic resonance imaging of atherosclerotic lesions in mice using micelles containing gadolinium and murine (MDA2 and E06) or human (IK17) antibodies that bind unique oxidation-specific epitopes.
Methods and Results
MDA2 micelles, E06 micelles, IK17 micelles, nonspecific IgG micelles, and untargeted micelles (no antibody) were prepared and characterized with respect to pharmacokinetics and biodistribution in wild-type and atherosclerotic apolipoprotein E–deficient (apoE−/−) mice. Magnetic resonance imaging was performed at 9.4 T over a 96-hour time interval after the administration of 0.075–mmol Gd/kg micelles. MDA2, E06, and IK17 micelles exhibited a longer plasma half-life than IgG or untargeted micelles in apoE−/− but not wild-type mice. In apoE−/− mice, MDA2 and IK17 micelles showed maximal arterial wall uptake at 72 hours and E06 micelles at 96 hours, manifested by 125% to 231% enhancement in magnetic resonance signal compared with adjacent muscle. Confocal microscopy revealed that MDA2, IK17, and E06 micelles accumulated within atherosclerotic lesions and specifically within macrophages. Intravenous injection of free MDA2 before imaging with MDA2 micelles resulted in significantly diminished magnetic resonance signal enhancement. IgG micelles and untargeted micelles showed minimal enhancement in apoE−/− mice. There was no significant signal enhancement with all micelles in wild-type mice.
Magnetic resonance imaging with micelles containing gadolinium and oxidation-specific antibodies demonstrates specific targeting and excellent image quality of oxidation-rich atherosclerotic lesions.
PMCID: PMC4492476  PMID: 18541740
Antibodies; atherosclerosis; inflammation; lipoproteins; magnetic resonance imaging
3.  Acute Coronary Syndromes: Pathology, Diagnosis, Genetics, Prevention and Treatment 
Circulation research  2014;114(12):1847-1851.
PMCID: PMC4076699  PMID: 24824094
Acute coronary syndrome; acute myocardial infarction; unstable angina; atherosclerosis
4.  Global Perspective on Acute Coronary Syndrome: A Burden on the Young and Poor 
Circulation research  2014;114(12):1959-1975.
Ischemic heart disease (IHD) is the greatest single cause of mortality and loss of disability-adjusted life years (DALYs) worldwide, and a substantial portion of this burden falls on low- and middle-income countries (LMICs). Deaths from IHD and acute coronary syndrome (ACS) occur, on average, at younger ages in LMICs than in high-income countries, often at economically productive ages, and likewise frequently affect the poor within LMICs. While data regarding ACS in LMICs are limited, there is a growing literature in this area and the research gaps are being steadily filled. In high-income countries, decades of investigation into the risk factors for ACS and development of behavioral programs, medications, interventional procedures, and guidelines have provided us with the tools to prevent and treat events. Although similar tools can be, and in fact have been, implemented in many LMICs, challenges remain in the development and implementation of cardiovascular health promotion activities across the entire life course, as well as in access to treatment for ACS and IHD. Intersectoral policy initiatives and global coordination are critical elements of ACS and IHD control strategies. Addressing the hurdles and scaling successful health promotion, clinical and policy efforts in LMICs are necessary in order to adequately address the global burden of ACS and IHD.
PMCID: PMC4144436  PMID: 24902978
Acute coronary syndrome; epidemiology; global health; low- and middle-income countries; ischemic heart disease
5.  Arterial and Fat Tissue Inflammation are Highly Correlated - A Prospective 18F-FDG PET/CT Study 
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.
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).
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).
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.
PMCID: PMC4024167  PMID: 24442596
FDG-PET; Inflammation; Atherosclerosis; Fat Tissue; Carotid Arteries; Aorta
6.  Combination Proximal Pulmonary Artery Coiling and Distal Embolization Induces Chronic Elevations in Pulmonary Artery Pressure in Swine 
PLoS ONE  2015;10(4):e0124526.
Pulmonary hypertension (PH) is associated with aberrant vascular remodeling and right ventricular (RV) dysfunction that contribute to early mortality. Large animal models that recapitulate human PH are essential for mechanistic studies and evaluating novel therapies; however, these models are not readily accessible to the field owing to the need for advanced surgical techniques or hypoxia. In this study, we present a novel swine model that develops cardiopulmonary hemodynamics and structural changes characteristic of chronic PH. This percutaneous model was created in swine (n=6) by combining distal embolization of dextran beads with selective coiling of the lobar pulmonary arteries (2 procedures per lung over 4 weeks). As controls, findings from this model were compared with those from a standard weekly distal embolization model (n=6) and sham animals (n=4). Survival with the combined embolization model was 100%. At 8 weeks after the index procedure, combined embolization procedure animals had increased mean pulmonary artery pressure (mPA) and pulmonary vascular resistance (PVR) compared to the controls with no effect on left heart or systemic pressures. RV remodeling and RV dysfunction were also present with a decrease in the RV ejection fraction, increase in the myocardial performance index, impaired longitudinal function, as well as cardiomyocyte hypertrophy, and interstitial fibrosis, which were not present in the controls. Pulmonary vascular remodeling occurred in both embolization models, although only the combination embolization model had a decrease in pulmonary capacitance. Taken together, these cardiopulmonary hemodynamic and structural findings identify the novel combination embolization swine model as a valuable tool for future studies of chronic PH.
PMCID: PMC4414513  PMID: 25923775
7.  Quality of Life after PCI vs. CABG among Patients with Diabetes and Multivessel CAD: Results from the FREEDOM Trial 
JAMA  2013;310(15):1581-1590.
The FREEDOM trial demonstrated that among patients with diabetes mellitus (DM) and multivessel coronary artery disease (CAD), coronary artery bypass graft (CABG) surgery results in lower rates of death and MI but a higher risk of stroke as compared with percutaneous coronary intervention using drug-eluting stents (DES-PCI). Whether there are benefits in terms of health status as assessed from the patient's perspective is unknown.
To compare the impact of CABG vs. DES-PCI on health status among patients with DM and multivessel CAD.
Design, Setting and Participants
Between 2005 and 2010, 1900 patients from 18 countries with DM and multivessel CAD were randomized to undergo either CABG (n=947) or DES-PCI (n=953) as an initial treatment strategy. Of these, a total of 1880 patients had baseline health status assessed (935 CABG, 945 DES-PCI) and comprised the primary analytic sample.
Initial revascularization with CABG or DES-PCI.
Main Outcome Measure
Health status was assessed using the angina frequency (AF), physical limitations (PL), and quality of life (QOL) domains of the Seattle Angina Questionnaire (SAQ) at baseline, 1, 6, and 12 months, and annually thereafter. For each scale, scores range from 0 to 100 where higher scores represent better health. The effect of CABG vs. DES-PCI was evaluated using longitudinal mixed effect models.
At baseline, mean (± standard deviation) scores were 70.9±25.1, 67.3±24.4 and 47.8±25.0 for the SAQ-AF, SAQ-PL and SAQ-QOL subscales for the CABG group and 71.4±24.7, 69.9±23.2 and 49.2±25.7 for the DES-PCI group. At 2 year follow up, mean scores were 96.0±11.9, 87.8±18.7 and 82.2±18.9 after CABG and 94.7±14.3, 86.0±19.3 and 80.4±19.6 after DES-PCI with significantly greater benefit of CABG on each domain (mean treatment benefit 1.3 [95% CI 0.3 to 2.2], 4.4 [95% CI 2.7 to 6.1], and 2.2 [95% CI 0.7 to 3.8] points, respectively; p<0.01 for each comparison). Beyond 2 years, there were no consistent differences between the 2 revascularization strategies.
For patients with diabetes and multivessel CAD, CABG provides slightly better intermediate term health status and quality of life than DES-PCI—mainly between 6 months and 2 years after initial treatment. However, the magnitude of benefit is small and may not be clinically meaningful.
Trial Registration
PMCID: PMC4370776  PMID: 24129463
8.  Targeting Preschool Children to Promote Cardiovascular Health: Cluster Randomized Trial 
The American journal of medicine  2012;126(1):27-35.e3.
School programs can be effective in modifying knowledge, attitudes, and habits relevant to long-term risk of chronic diseases associated with sedentary lifestyles. As part of a long-term research strategy, we conducted an educational intervention in preschool facilities to assess changes in preschoolers’ knowledge, attitudes, and habits toward healthy eating and living an active lifestyle.
Using a cluster design, we randomly assigned 14 preschool facilities in Bogotá, Colombia to a 5-month educational and playful intervention (7 preschool facilities) or to usual curriculum (7 preschool facilities). A total of 1216 children aged 3–5 years, 928 parents, and 120 teachers participated. A structured survey was used at baseline, at the end of the study, and 12 months later to evaluate changes in knowledge, attitudes, and habits.
Children in the intervention group showed a 10.9% increase in weighted score, compared with 5.3% in controls. The absolute adjusted difference was 3.90 units (95% confidence interval [CI], 1.64–6.16; P <.001). Among parents, the equivalent statistics were 8.9% and 3.1%, respectively (absolute difference 4.08 units; 95% CI, 2.03 to 6.12; P <.001), and among teachers, 9.4% and 2.5%, respectively (absolute difference 5.36 units; 95% CI, −0.29–11.01; P = .06). In the intervened cohort 1 year after the intervention, children still showed a significant increase in weighted score (absolute difference of 6.38 units; P <.001).
A preschool-based intervention aimed at improving knowledge, attitudes, and habits related to healthy diet and active lifestyle is feasible, efficacious, and sustainable in very young children.
PMCID: PMC4365993  PMID: 23062403
Cardiovascular disease (CVD); Global health; Health education; Noncommunicable disease (NCD); Preschool children
9.  Sudden Cardiac Death in Low- and Middle-Income Countries 
Global heart  2012;7(4):353-360.
Cardiovascular disease, and the incidence of sudden cardiac death (SCD), will increase significantly in low- and middle-income countries (LMIC). Thus, SCD threatens to become a global public health problem. We present a summary of the current research that has investigated the epidemiology of SCD in LMIC. Few studies of SCD in LMIC exist, and they are of variable methodological quality. Risk factors for SCD are described, taking into account recent global burden of disease and risk factor statistics. We describe 1 proposal for a community-based, prospective, multiple-source methodology for SCD monitoring and surveillance that can be implemented in LMIC. Further research into the epidemiology of SCD in LMIC, using standardized methodology, would allow investigators and policy makers to determine the regions, communities, and individuals most at need for SCD prevention. Focusing on SCD and its prevention in LMIC should be a priority for the global health community.
PMCID: PMC4363741  PMID: 25689944
10.  Cardiovascular Risk Surveillance to Develop a Nationwide Health Promotion Strategy 
Global heart  2012;7(2):87-94.
The Grenada Heart Project aims to study the clinical, biological, and psychosocial determinants of the cardiovascular health in Grenada in order to develop and implement a nationwide cardiovascular health promotion program.
We recruited 2,827 adults randomly selected from the national electronic voter list. The main outcome measures were self-reported cardiovascular disease and behavioral risk factors, anthropometric measures, blood pressure, point-of-care testing for glucose and lipids, and ankle-brachial index. Risk factors were also compared with the U.S. National Health and Nutritional Survey data.
Prevalence of cardiovascular disease risk factors were: overweight and obesity—57.7% of the population, physical inactivity—23.4%, diabetes—13.3%, hypertension—29.7%, hypercholesterolemia—8.6%, and smoking—7%. Subjects who were physically active had a significantly lower 10-year Framingham risk score (p < 0.001). Compared with the U.S. National Health and Nutrition Survey data, Grenadian women had higher rates of adiposity, diabetes, hypertension, and elevated low-density lipoprotein cholesterol, whereas Grenadian men had a higher rate of diabetes, a similar rate of hypertension, and lower rates of the other risk factors. Prevalence of peripheral arterial disease was 7.6%; stroke and coronary heart disease were equally prevalent at ~2%.
This randomly selected adult sample in Grenada reveals prevalence rates of obesity, hypertension, and diabetes significantly exceeding those seen in the United States. The contrasting, paradoxically low levels of prevalent cardiovascular disease support the concept that Grenada is experiencing an obesity-related “risk transition.” These data form the basis for the implementation of a pilot intervention program based on the Institute of Medicine recommendations and may serve as a model for other low- and middle-income countries.
PMCID: PMC4362689  PMID: 25691303
11.  Optimization of dual-saturation single bolus acquisition for quantitative cardiac perfusion and myocardial blood flow maps 
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.
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.
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).
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.
PMCID: PMC4332925  PMID: 25880970
Dual saturation acquisition strategy; Absolute quantitative cardiac perfusion; Cardiovascular magnetic resonance
12.  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.
PMCID: PMC4334467  PMID: 23661177
Atherosclerosis; Lipids; Angiogenesis; Inflammation
14.  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.
PMCID: PMC4055070  PMID: 24405778
15.  Nurse Management of Hypertension in Rural Western Kenya: Implementation Research to Optimize Delivery 
Annals of global health  2013;80(1):5-12.
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.
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.
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.
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.
PMCID: PMC4036099  PMID: 24751560
16.  Impact of Left Ventricular Hypertrophy on Troponin Release During Acute Myocardial Infarction: New Insights From a Comprehensive Translational Study 
Biomarkers are frequently used to estimate infarct size (IS) as an endpoint in experimental and clinical studies. Here, we prospectively studied the impact of left ventricular (LV) hypertrophy (LVH) on biomarker release in clinical and experimental myocardial infarction (MI).
Methods and Results
ST‐segment elevation myocardial infarction (STEMI) patients (n=140) were monitored for total creatine kinase (CK) and cardiac troponin I (cTnI) over 72 hours postinfarction and were examined by cardiac magnetic resonance (CMR) at 1 week and 6 months postinfarction. MI was generated in pigs with induced LVH (n=10) and in sham‐operated pigs (n=8), and serial total CK and cTnI measurements were performed and CMR scans conducted at 7 days postinfarction. Regression analysis was used to study the influence of LVH on total CK and cTnI release and IS estimated by CMR (gold standard). Receiver operating characteristic (ROC) curve analysis was performed to study the discriminatory capacity of the area under the curve (AUC) of cTnI and total CK in predicting LV dysfunction. Cardiomyocyte cTnI expression was quantified in myocardial sections from LVH and sham‐operated pigs. In both the clinical and experimental studies, LVH was associated with significantly higher peak and AUC of cTnI, but not with differences in total CK. ROC curves showed that the discriminatory capacity of AUC of cTnI to predict LV dysfunction was significantly worse for patients with LVH. LVH did not affect the capacity of total CK to estimate IS or LV dysfunction. Immunofluorescence analysis revealed significantly higher cTnI content in hypertrophic cardiomyocytes.
Peak and AUC of cTnI both significantly overestimate IS in the presence of LVH, owing to the higher troponin content per cardiomyocyte. In the setting of LVH, cTnI release during STEMI poorly predicts postinfarction LV dysfunction. LV mass should be taken into consideration when IS or LV function are estimated by troponin release.
PMCID: PMC4330053  PMID: 25609414
creatine kinase; hypertrophy; magnetic resonance imaging; myocardial infarction; troponin
17.  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.
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).
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.
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.
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.
PMCID: PMC3823642  PMID: 23942908
DCE-MRI; PET/CT; atherosclerosis; inflammation; neovascularization
18.  Promotion of Cardiovascular Health in Preschool Children: 36-Month Cohort Follow-up 
The American journal of medicine  2013;126(12):1122-1126.
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.
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.
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).
After 36 months, the educational intervention maintained a beneficial trend toward a healthy lifestyle in children and their parents.
PMCID: PMC4106297  PMID: 24262725
Cardiovascular disease (CVD); Global health; Health education; Noncommunicable disease (NCD); Preschool children
19.  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.
PMCID: PMC3863599  PMID: 24127782
low density lipoprotein; gold nanoparticles; electron microscopy; computed tomography; fluorescence imaging
20.  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.
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.
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.
PMCID: PMC3917564  PMID: 24043300
Extracellular Matrix; Smooth Muscle Cells; Proliferation; Arteries
21.  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.
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.
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.
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.
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.
PMCID: PMC3978772  PMID: 24176447
calcification; mitral valve; progression; risk factors; gender
22.  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.
PMCID: PMC4212241  PMID: 25351258
23.  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.
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).
Both plaque inflammation and serum biomarkers of inflammation are associated with atherothrombotic events; however, the relationship between them is unclear.
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.
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.
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.
PMCID: PMC3831277  PMID: 24135322
Inflammatory biomarkers; 18F-Fluorodeoxyglucose Positron Emission Tomography; Atherosclerosis
24.  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.
Intravenous (IV) beta-blockade is currently a Class IIa recommendation in early management of patients with acute coronary syndromes (ACS) without obvious contraindications.
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.
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).
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.
PMCID: PMC4104797  PMID: 23168009
Meta-analysis; Myocardial Infarction; Cardiovascular Pharmacology; Beta-Blocker; IV; Mortality
25.  Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport 
Circulation  2012;125(15):1905-1919.
PMCID: PMC4159082  PMID: 22508840
High density lipoprotein; cholesterol efflux; reverse cholesterol transport; atherosclerosis; cardiovascular disease; vascular imaging

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