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).
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.
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.
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.
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.
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.
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.
Myocardial infarction; Reperfusion injury; Beta-blockers; MRI; Cardioprotection; Myocardial salvage
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).
Cardiac valve calcification has been associated with left ventricular hypertrophy (LVH), which portends cardiovascular events. However, this relationship and its mediators are poorly understood.
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.
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.
Within the MESA cohort, LVH was associated with prevalence, severity, and incidence of valve calcification independent of hypertension and other identified confounders.
aortic valve; calcification; left ventricular mass; mitral valve annulus
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.
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.
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.
computed tomography; gold nanoparticles; contrast agents; iodine
The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945.
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.
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.
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).
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.
atherosclerosis; dynamic contrast-enhanced cardiac magnetic resonance; 18F-FDG–PET/CT; LXR agonist
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.
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.
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.
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.
FDG-PET; Inflammation; Atherosclerosis; Diabetes; Carotid Arteries
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.
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.
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.
cardiac myocyte regeneration; gene transfer; myocardial infarction; stem cell factor
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.
Endothelium; epithelium; development; transition
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.
Lymphocytes; Atherosclerosis; Adventitia; Imaging
In the United States alone, more than 400,000 Americans die annually from coronary artery disease and more than 1,000,000 suffer acute coronary events, i.e., myocardial infarction and sudden cardiac death.1 Considering the aging of our population and increasing incidence of diabetes and obesity, the morbidity from coronary artery disease, and its associated costs, will place an increasing, substantial burden on our society.2 Between 2010 and 2030, total direct medical costs spent in the US for cardiovascular diseases are projected to triple from 273 to 818 billion dollars.2 Although effective treatments are available and considerable efforts are ongoing to identify new strategies for the prevention of coronary events, predicting such events in an individual has been challenging.3 In hopes of improving our ability to determine the risk of coronary events, it is prudent to review our knowledge of factors that lead to acute coronary events.
 Acute coronary syndromes;  Acute myocardial infarction;  Pathophysiology;  Risk Factors
We sought to determine the anti-atherosclerotic properties of pioglitazone using multi-modality non-invasive imaging techniques.
Inflammation is an essential component of vulnerable or high risk atheromas. Pioglitazone, a peroxisome proliferator–activated receptor-gamma (PPAR-γ)agonist possesses potent anti-inflammatory properties. We aimed to non-invasively to quantify the anti-inflammatory effects of pioglitazone on atheroma using 18F-fluorodeoxyglucose (18F-FDG)-PET/CT and dynamic contrast enhanced MRI (DCE-MRI).
Atherosclerotic plaques were induced in the aorta of fifteen New Zealand White (NZW) rabbits by a combination of hyperlipidemic diet and two balloon endothelial denudations. Nine rabbits continued the same diet whereas six received pioglitazone (10mg/kg orally) in addition to the diet. Twelve animals underwent 18F-FDG-PET/CT and fifteen animals underwent DCE-MRI at baseline, one and three months after treatment initiation. Concomitantly, serum metabolic parameters were monitored. After imaging was completed aortic histological analysis and correlation analysis was performed.
18F-FDG-PET/CT detected an increase in average standardized uptake value (SUV) in the control group (p<0.01), indicating progressive inflammation, while stable SUV values were observed in the treatment group, indicating no progression. DCE-MRI detected a significant decrease in area under the curve (AUC) for the pioglitazone group (p<0.01). Immunohistology of the aortas demonstrated a significant decrease in macrophage and oxidized phospholipid immunoreactivity in the pioglitazone group (p=0.04 and p=0.01, respectively) with respect to control animals, underlining the imaging results. Serum metabolic parameters showed no difference between groups. A strong positive correlation between SUV and macrophage density and AUC and neovessels was detected ( r2=0.86, p<0.0001 and r2=0.66, p=0.004, respectively).
18F-FDG-PET/CT and DCE-MRI demonstrate non-invasively the anti-inflammatory effects of pioglitazone on atheroma. Both imaging modalities appear suited to monitor inflammation in atherosclerosis.
pioglitazone; atherosclerosis; inflammation; 18F-FDG-PET/CT; dynamic contrast enhanced MRI
To evaluate the relationship between atherosclerotic plaque inflammation, as assessed by FDG-Positron Emission Tomography/Computed Tomography (FDG-PET/CT), and plaque morphology and composition, as assessed by magnetic resonance imaging (MRI), in the carotid and femoral arteries.
Materials and methods
Sixteen patients underwent FDG-PET/CT and MRI (T2 weighted (T2W) and Proton density weighted (PDW)) of the carotid and femoral arteries. For every image slice, two observers determined the corresponding regions of the FDG-PET/CT and MRI image sets by matching CT and T2W axial images. Each plaque was then classified into one of three groups according to the CT appearance and T2W/PDW signal: 1) collagen, 2) lipid-necrotic core and 3) calcium.
Arterial FDG uptake was measured for each plaque and normalized to vein FDG activity to produce a blood-normalized artery activity called the target to background ratio (TBR). The vessel wall thickness (VWT), the vessel wall area and the total vessel wall area were measured from the T2W MR images.
The TBR value was higher in the lipid-necrotic core group compared to the collagen and calcium groups, (p < 0.001). The lipid-necrotic core group demonstrated a significant TBR variation according to the median of the VWT (TBR = 1.26 ± 0.25 vs. TBR = 1.50 ± 0.12). There was no correlation with other morphological MR parameters.
This study demonstrates the complementary value of non-invasive FDG-PET/CT and MR imaging for the evaluation of atherosclerotic plaque composition and activity. Lipid-rich plaques are more inflamed than either calcified or collagen-rich plaques.
Osteoporosis trials suggest raloxifene decreased cardiovascular events in women with preexisting atherosclerosis. We assessed the hypothesis that selective estrogen receptor modulation induces plaque stability in “menopausal” animals.
Methods and Results
Atherosclerosis was induced in 42 ovariectomized New Zealand White rabbits by cholesterol feeding and mechanical injury. Animals were imaged by magnetic resonance (MRI) for baseline atherosclerosis, and randomized to control (OVX, n=12), raloxifene 35–60 mg/kg/day by diet admixture (RLX, n=24), or immediate sacrifice (n=6) for immunohistopathologic correlation of MRI. Six months later, rabbits underwent repeat MRI then sacrifice for micro-computed tomography (μCT) and molecular analysis. Unlike OVX, RLX reduced atheroma volume. Analysis for lesion inflammation revealed reductions in COX-2, MMP-1, MCP-1 expression and macrophage infiltration in RLX vs. OVX with concomitant upregulation of estrogen receptor α. μCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63 ± 7° vs. 33 ± 6° in OVX), the predicted result of a 53% increase in BMP-2.
Raloxifene treatment results in reduced lesion volume, enhanced mechanical stability of vascular calcification, and less inflamed lesions characterized by less macrophage infiltration and reduced COX-2, MMP-1 and MCP-1 expression.
Atherosclerosis; Inflammation; Osteoporosis; Selective Estrogen Receptor Modulator (SERM); Vascular Calcification
P947 is a gadolinium-based magnetic resonance imaging (MRI) contrast agent with high affinity for several matrix metalloproteinases (MMPs) involved in arterial wall remodelling. We tested whether the intensity of enhancement detected in vivo in the arterial wall with P947 and MRI correlates with actual tissue MMP-related enzymatic activity measured in a rabbit atherosclerotic model subjected to dietary manipulations.
Methods and results
Aortas of 15 rabbits in which atherosclerotic lesions were induced by balloon angioplasty and 4 months of hypercholesterolaemic diet were imaged at ‘baseline’ with P947-enhanced MRI. Atherosclerotic rabbits were divided into three groups: five rabbits were sacrificed (‘baseline’ group); five rabbits continued to be fed a lipid-supplemented diet (‘high-fat’ group); and five rabbits were switched from atherogenic to a purified chow diet (‘low-fat’ group). Four months later, a second P947-enhanced MRI was acquired in the 10 remaining rabbits. A significantly lower signal was detected in the aortic wall of rabbits from the ‘low-fat’ group as compared with rabbits from the ‘high-fat’ group (21 ± 6 vs. 46 ± 3%, respectively; P = 0.04). Such differences were not detected with the contrast agent P1135, which lacks the MMP-specific peptide sequence. In addition, the intensity of aortic wall enhancement detected with MRI after injection of P947 strongly correlated with actual MMP-2 gelatinolytic activity measured in corresponding aortic segments using zymography (r = 0.87).
P947-enhanced MRI can distinguish dietary-induced variations in MMP-related enzymatic activity within plaques in an experimental atherosclerotic model, supporting its utility as a clinical imaging tool for in vivo detection of arterial wall remodelling.
Atherosclerosis; Magnetic resonance imaging; Matrix metalloproteinases; Vulnerable plaque; Contrast agent
Atherosclerosis is an inflammatory disease causing great morbidity and mortality in the Western world. To increase the anti-inflammatory action and decrease adverse effects of glucocorticoids (PLP), a nanomedicinal liposomal formulation of this drug (L-PLP) was developed and intravenously applied at a dose of 15 mg/kg PLP to a rabbit model of atherosclerosis. Since atherosclerosis is a systemic disease, emerging imaging modalities for assessing atherosclerotic plaque are being developed. 18F-fluoro-deoxy-glucose positron emission tomography and dynamic contrast enhanced magnetic resonance imaging, methods commonly used in oncology, were applied to longitudinally assess therapeutic efficacy. Significant anti-inflammatory effects were observed as early as 2 days that lasted up to at least 7 days after administration of a single dose of L-PLP. No significant changes were found for the free PLP treated animals. These findings were corroborated by immunohistochemical analysis of macrophage density in the vessel wall. In conclusion, this study evaluates a powerful two-pronged strategy for efficient treatment of atherosclerosis that includes nanomedical therapy of atherosclerotic plaques and the application of non-invasive and clinically approved imaging techniques to monitor delivery and therapeutic responses. Importantly, we demonstrate unprecedented rapid anti-inflammatory effects in atherosclerotic lesions after the nanomedical therapy.
MRI; FDG-PET; multifunctional liposomes; atherosclerosis; rabbits; glucocorticoids
This cross sectional study was conducted to test reproducibility of analysis of MRI parameters in carotids and thoracic descending aorta (TOA), evaluate the correlation of plaque burden and associations with subject age and gender.
Three hundred subjects, with cardiovascular risk factors, underwent a black blood MRI of both carotids and TOA. Mean wall area, wall thickness, lumen area, total vessel area and wall area/total vessel area (WA/TVA) ratio were manually measured. Inter-reader and intra-reader-reproducibility was tested on 187 and 20 randomly chosen subjects respectively.
The intra-observer-reproducibility for the analysis was high (Intraclass-Correlation-Coefficients (ICC’s >0.8), except mean WA/TVA ratio of TOA. Similarly, the inter-observer reproducibility was acceptable (ICC’s >0.7 for mean wall area, lumen area and total vessel area). MRI parameters in aorta and carotids increased with age for both sexes (p<0.001). Except for mean wall thickness of TOA and WA/TVA ratio, MRI parameters were significantly higher in males than in females. All MRI measurements except the mean wall thickness and WA/TVA ratio were highly reproducible. There was good correlation for mean wall area between carotids and aorta compatible with the systemic nature of atherosclerosis. Similar to clinical presentation of cardiovascular diseases we found greater values in most MRI parameters (except for WA/TVA ratio) in males than in females and with increasing age.
These data suggest that analysis of most MRI measurements of plaque burden is reproducible and that there is correlation between plaque burden between carotids and aorta validating the systemic distribution of the disease.