Coronary Flow Assessment Using Accelerated 4D Flow MRI With Respiratory Motion Correction.

Magnetic resonance imaging (MRI) can potentially be used for non-invasive screening of patients with stable angina pectoris to identify probable obstructive coronary artery disease. MRI-based coronary blood flow quantification has to date only been performed in a 2D fashion, limiting its clinical applicability. In this study, we propose a framework for coronary blood flow quantification using accelerated 4D flow MRI with respiratory motion correction and compressed sensing image reconstruction. We investigate its feasibility and repeatability in healthy subjects at rest. Fourteen healthy subjects received 8 times-accelerated 4D flow MRI covering the left coronary artery (LCA) with an isotropic spatial resolution of 1.0 mm3. Respiratory motion correction was performed based on 1) lung-liver navigator signal, 2) real-time monitoring of foot-head motion of the liver and LCA by a separate acquisition, and 3) rigid image registration to correct for anterior-posterior motion. Time-averaged diastolic LCA flow was determined, as well as time-averaged diastolic maximal velocity (VMAX) and diastolic peak velocity (VPEAK). 2D flow MRI scans of the LCA were acquired for reference. Scan-rescan repeatability and agreement between 4D flow MRI and 2D flow MRI were assessed in terms of concordance correlation coefficient (CCC) and coefficient of variation (CV). The protocol resulted in good visibility of the LCA in 11 out of 14 subjects (six female, five male, aged 28 ± 4 years). The other 3 subjects were excluded from analysis. Time-averaged diastolic LCA flow measured by 4D flow MRI was 1.30 ± 0.39 ml/s and demonstrated good scan-rescan repeatability (CCC/CV = 0.79/20.4%). Time-averaged diastolic VMAX (17.2 ± 3.0 cm/s) and diastolic VPEAK (24.4 ± 6.5 cm/s) demonstrated moderate repeatability (CCC/CV = 0.52/19.0% and 0.68/23.0%, respectively). 4D flow- and 2D flow-based diastolic LCA flow agreed well (CCC/CV = 0.75/20.1%). Agreement between 4D flow MRI and 2D flow MRI was moderate for both diastolic VMAX and VPEAK (CCC/CV = 0.68/20.3% and 0.53/27.0%, respectively). In conclusion, the proposed framework of accelerated 4D flow MRI equipped with respiratory motion correction and compressed sensing image reconstruction enables repeatable diastolic LCA flow quantification that agrees well with 2D flow MRI.

Manual versus Automated Carotid Artery Plaque Component Segmentation in High and Lower Quality 3.0 Tesla MRI Scans.

PURPOSE: To study the interscan reproducibility of manual versus automated segmentation of carotid artery plaque components, and the agreement between both methods, in high and lower quality MRI scans. METHODS: 24 patients with 30-70% carotid artery stenosis were planned for 3T carotid MRI, followed by a rescan within 1 month. A multicontrast protocol (T1w,T2w, PDw and TOF sequences) was used. After co-registration and delineation of the lumen and outer wall, segmentation of plaque components (lipid-rich necrotic cores (LRNC) and calcifications) was performed both manually and automated. Scan quality was assessed using a visual quality scale. RESULTS: Agreement for the detection of LRNC (Cohen's kappa (k) is 0.04) and calcification (k = 0.41) between both manual and automated segmentation methods was poor. In the high-quality scans (visual quality score ≥ 3), the agreement between manual and automated segmentation increased to k = 0.55 and k = 0.58 for, respectively, the detection of LRNC and calcification larger than 1 mm2. Both manual and automated analysis showed good interscan reproducibility for the quantification of LRNC (intraclass correlation coefficient (ICC) of 0.94 and 0.80 respectively) and calcified plaque area (ICC of 0.95 and 0.77, respectively). CONCLUSION: Agreement between manual and automated segmentation of LRNC and calcifications was poor, despite a good interscan reproducibility of both methods. The agreement between both methods increased to moderate in high quality scans. These findings indicate that image quality is a critical determinant of the performance of both manual and automated segmentation of carotid artery plaque components.

C-Reactive Protein Identifies Low-Risk Metabolically Healthy Obese Persons: The European Prospective Investigation of Cancer-Norfolk Prospective Population Study.

BACKGROUND: Conflicting data exist about the cardiovascular risk of metabolically healthy obese persons. The prognostic value of C-reactive protein (CRP) in this intriguing group is unknown. We assessed the association between CRP levels and the risk of coronary heart disease (CHD) in metabolically healthy persons with abdominal obesity. METHODS AND RESULTS: In the European Prospective Investigation of Cancer-Norfolk prospective cohort, CRP levels and information on metabolic syndrome criteria were available for 7279 participants, of whom 825 (11%) developed CHD during a follow-up period of 10.9±1.8 years. There was a trend toward a higher multivariable-adjusted hazard ratio for CHD in metabolically healthy obese participants with CRP levels >2 mg/L compared with <2 mg/L (hazard ratio 1.59, 95% CI 0.97-2.62, P=0.066). Metabolically unhealthy obese participants had significantly higher CHD risk compared with metabolically healthy obese participants with CRP levels <2 mg/L (hazard ratio 1.88, 95% CI 1.20-2.94, P=0.006). Most important, we found that the risk of CHD among metabolically healthy obese persons with CRP levels <2 mg/L was comparable to that of metabolically healthy nonobese persons (hazard ratio 0.91, 95% CI 0.60-1.39, P=0.674). CONCLUSIONS: Among metabolically healthy obese persons, low CRP levels were associated with a CHD risk comparable to that of metabolically healthy nonobese persons. CRP appears to be an easy and widely available method for identifying a low-risk subpopulation among metabolically healthy obese persons.

Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration.

Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. FROM THE CLINICAL EDITOR: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.

Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.

BACKGROUND: Patients with familial hypercholesterolemia (FH) are characterized by elevated atherogenic lipoprotein particles, predominantly low-density lipoprotein cholesterol (LDL-C), which is associated with accelerated atherogenesis and increased cardiovascular risk. OBJECTIVES: This study used (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) to investigate whether arterial inflammation is higher in patients with FH and, moreover, whether lipoprotein apheresis attenuates arterial wall inflammation in FH patients. METHODS: In total, 38 subjects were recruited: 24 FH patients and 14 normolipidemic controls. All subjects underwent FDG-PET imaging at baseline. Twelve FH patients who met the criteria for lipoprotein apheresis underwent apheresis procedures followed by a second FDG-PET imaging 3 days (range 1 to 4 days) after apheresis. Subsequently, the target-to-background ratio (TBR) of FDG uptake within the arterial wall was assessed. RESULTS: In FH patients, the mean arterial TBR was higher compared with healthy controls (2.12 ± 0.27 vs. 1.92 ± 0.19; p = 0.03). A significant correlation was observed between baseline arterial TBR and LDL-C (R = 0.37; p = 0.03) that remained significant after adjusting for statin use (ß = 0.001; p = 0.02) and atherosclerosis risk factors (ß = 0.001; p = 0.03). LDL-C levels were significantly reduced after lipoprotein apheresis (284 ± 118 mg/dl vs. 127 ± 50 mg/dl; p < 0.001). There was a significant reduction of arterial inflammation after lipoprotein apheresis (TBR: 2.05 ± 0.31 vs. 1.91 ± 0.33; p < 0.02). CONCLUSIONS: The arterial wall of FH patients is characterized by increased inflammation, which is markedly reduced after lipoprotein apheresis. This lends support to a causal role of apoprotein B-containing lipoproteins in arterial wall inflammation and supports the concept that lipoprotein-lowering therapies may impart anti-inflammatory effects by reducing atherogenic lipoproteins.

C-reactive protein, fatal and nonfatal coronary artery disease, stroke, and peripheral artery disease in the prospective EPIC-Norfolk cohort study.

OBJECTIVE: Circulating levels of C-reactive protein (CRP) are associated with an increased risk of coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Observational and experimental evidence suggest that CRP might differentially predict fatal and nonfatal cardiovascular events. Here, we sought to determine the predictive value of CRP for fatal and nonfatal CAD, stroke, or PAD. APPROACH AND RESULTS: CRP levels were measured in 18 450 apparently healthy participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. Cox proportional hazards models were used to quantify the association between CRP levels and fatal and nonfatal CAD events, strokes, and PAD events. Bootstrapping was applied to test for significant differences between the risk of fatal and nonfatal events. During 208 485 person-years at risk, 2915 CAD events, 361 strokes, and 657 PAD events occurred. CRP was associated with fatal and nonfatal CAD events and nonfatal PAD events. When adding CRP to predictive risk models for fatal and nonfatal events corrected for known cardiovascular risk factors, the net reclassification index was 2.1% for fatal and 1.9% for nonfatal events. Multivariate adjusted hazard ratios for fatal CAD events (hazard ratio, 1.36; 95% confidence interval, 1.27-1.46) differed significantly (mean difference, 13%; 95% confidence interval, 5.1%-21.9%; P<0.001) from the multivariate adjusted hazard ratio for nonfatal CAD events (hazard ratio, 1.21; 95% confidence interval, 1.15-1.26). CONCLUSIONS: In the EPIC-Norfolk cohort, CRP was associated with fatal and nonfatal CAD events, as well as nonfatal PAD events. Adding CRP to risk stratification models resulted in a small improvement in classification for both fatal and nonfatal events. Importantly, CRP was significantly more strongly associated with fatal CAD events than with nonfatal CAD events.

ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.

AIMS: Low HDL-C is a potent risk factor for cardiovascular disease (CVD). Yet, mutations in ABCA1, a major determinant of circulating HDL-C levels, were previously not associated with CVD risk in cohort studies. To study the consequences of low plasma levels of high-density lipoprotein cholesterol (HDL-C) due to ATP-binding cassette transporter A1 (ABCA1) dysfunction for atherosclerotic vascular disease in the carotid arteries. METHODS AND RESULTS: We performed 3.0 Tesla magnetic resonance imaging (MRI) measurements of the carotid arteries in 36 carriers of high impact functional ABCA1 mutations and 36 normolipidemic controls. Carriers presented with 42% lower HDL-C levels (P < 0.001), a larger mean wall area (18.6 ± 6.0 vs. 15.8 ± 4.3 mm(2); P = 0.02), a larger mean wall thickness (0.82 ± 0.21 vs. 0.70 ± 0.14 mm; P = 0.005), and a higher normalized wall index (0.37 ± 0.06 vs. 0.33 ± 0.04; P = 0.005) compared with controls, retaining significance after adjustment for smoking, alcohol consumption, systolic blood pressure, diabetes, body mass index, history of CVD, LDL-C, and statin use (P = 0.002). CONCLUSION: Carriers of loss of function ABCA1 mutations display a larger atherosclerotic burden compared with age and sex-matched controls, implying a higher risk for CVD. Further studies are needed to elucidate the full function of ABCA1 in the protection against atherosclerosis. These data support the development of strategies to up-regulate ABCA1 in patients with established CVD.

Reduction of monocyte chemoattractant protein 1 and macrophage migration inhibitory factor by a polyphenol-rich extract in subjects with clustered cardiometabolic risk factors.

Inflammation is a hallmark of the metabolic syndrome, which also contributes to a pro-atherogenic state. NF-κB activation, a critical step in regulating inflammatory reactions, can be inhibited by polyphenol (PF) extracts, at least in vitro. In the present study, we set out to study whether a PF-rich extract could attenuate the chronic inflammatory state and/or an acute immune response in vivo in subjects with clustered metabolic risk factors. A commercially available, PF-rich extract (500 mg daily) or placebo was administered for 4 weeks to thirty-four subjects with two or more metabolic risk factors using a randomised, double-blind, cross-over design. During the final study visit, an acute inflammatory challenge (lipopolysaccharide (LPS) 1 ng/kg body weight) was administered to a random subgroup of subjects (PF-rich extract (n 12) and placebo (n 12)). The PF-rich extract modestly reduced the inflammatory chemokines monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor (MIF) (MCP-1 - 6.5 % (PF, median 116 (interquartile range 97-136) pg/ml v. placebo, median 124 (interquartile range 105-153) pg/ml; P < 0.05); MIF - 10.8 % (PF, median 2512 (interquartile range 1898-3972) pg/ml v. placebo, median 2814.5 (interquartile range 2296-3852) pg/ml; P < 0.05); however, other measured markers of inflammation and cardiometabolic disease, such as C-reactive protein, IL-6, HDL-cholesterol, adiponectin and oxidised LDL, remained unaffected. Following the LPS challenge, we found a statistically significant 48 % reduction of MCP-1 production in the PF-rich extract group (n 12) v. placebo (n 12) over 6 h (PF 766 (sd 155) v. placebo 1466 (sd 989) ng/ml; P < 0.05, area under the curve). In conclusion, short-term oral administration of the PF-rich extract caused a modest anti-inflammatory effect in subjects with clustered metabolic risk factors. Further dose-ranging studies are needed to evaluate whether and to what extent PF-rich extracts can be used to reduce the pro-inflammatory state in subjects with metabolic diseases at increased cardiovascular risk.