Erin Corsini

Arterial inflammation in patients with HIV

CONTEXT Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown. OBJECTIVE To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls). MAIN OUTCOME MEASURE Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). RESULTS Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV. CONCLUSION Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

The C5a Receptor (C5aR) C5L2 Is a Modulator of C5aR-mediated Signal Transduction

The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and β-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the β-arrestin pathway. Association of C5L2 with β-arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the β-arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.

Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location A Longitudinal FDG-PET/CT Study

Background— Arterial calcium (Ca) deposition has been identified as an active inflammatory process. We sought to test the hypothesis that local vascular inflammation predisposes to subsequent arterial calcium deposition in humans. Methods and Results— From a hospital database, we identified 137 patients (age, 61±13 years; 48.1% men) who underwent serial positron-emission tomography/computed tomography (1–5 years apart). Focal arterial inflammation was prospectively determined by measuring 18F-flourodeoxyglucose uptake (using baseline positron-emission tomography) within predetermined locations of the thoracic aortic wall and was reported as a standardized uptake value. A separate, blinded investigator evaluated calcium deposition (on the baseline and follow-up computed tomographic scans) along the same standardized sections of the aorta. New calcification was prospectively defined using square root–transformed difference of calcium volume score, with a cutoff value of 2.5. Accordingly, vascular segment was classified as either with or without subsequent calcification. Overall, 67 (9%) of aortic segments demonstrated subsequent calcification. Baseline median (interquartile range) standardized uptake value was higher in segments with versus without subsequent calcification (2.09 [1.84–2.44] versus 1.92 [1.72–2.20], P=0.002). This was also true in the subset of segments with Ca present at baseline (2.08 [1.81–2.40] versus 1.86 [1.66–2.09], P=0.02), as well as those without (2.17 [1.87–2.51] versus 1.93 [1.73–2.20], P=0.04). Furthermore, across all patients, subsequent Ca deposition was associated with the underlying 18F-flourodeoxyglucose uptake (inflammatory signal), measured as standardized uptake value (odds ratio [95% confidence interval]=2.94 [1.27–6.89], P=0.01) or target-to-background ratio (2.59 [1.18–5.70], P=0.02), after adjusting for traditional cardiovascular risk factors. Conclusions— Here, we provide first-in-man evidence that arterial inflammation precedes subsequent Ca deposition, a marker of plaque progression, within the underlying location in the artery wall.

Evolution of Coronary Computed Tomography Radiation Dose Reduction at a Tertiary Referral Center

PURPOSE We aimed to assess the temporal change in radiation doses from coronary computed tomography angiography (CCTA) during a 6-year period. High CCTA radiation doses have been reduced by multiple technologies that, if used appropriately, can decrease exposures significantly. METHODS A total of 1277 examinations performed from 2005 to 2010 were included. Univariate and multivariable regression analysis of patient- and scan-related variables was performed with estimated radiation dose as the main outcome measure. RESULTS Median doses decreased by 74.8% (P<.001), from 13.1 millisieverts (mSv) (interquartile range 9.3-14.7) in period 1 to 3.3 mSv (1.8-6.7) in period 4. Factors associated with greatest dose reductions (P<.001) were all most frequently applied in period 4: axial-sequential acquisition (univariate: -8.0 mSv [-9.7 to -7.9]), high-pitch helical acquisition (univariate: -8.8 mSv [-9.3 to -7.9]), reduced tube voltage (100 vs 120 kV) (univariate: -6.4 mSv [-7.4 to -5.4]), and use of automatic exposure control (univariate: -5.3 mSv [-6.2 to -4.4]). CONCLUSIONS CCTA radiation doses were reduced 74.8% through increasing use of dose-saving measures and evolving scanner technology.

Periaortic Adipose Tissue and Aortic Dimensions in the Framingham Heart Study

Background Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described. Methods and Results A total of 3001 individuals (mean age 50±10 years, 49% women) from the Framingham Offspring and Third Generation cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [SD] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (β coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm; P<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations. Conclusions Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted.

Prevalence, Distribution, and Risk Factor Correlates of High Thoracic Periaortic Fat in the Framingham Heart Study

Background Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT. Methods and Results Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (P=0.005). Conclusions Individuals in our community‐based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.

Thoracic Periaortic and Visceral Adipose Tissue and Their Cross-sectional Associations with Measures of Vascular Function

Objective: Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) were associated with vascular function.

Relation of Vascular Growth Factors with CT-Derived Measures of Body Fat Distribution: The Framingham Heart Study

BACKGROUND Visceral adiposity is associated with metabolic risk. Given that angiogenesis is a key feature of adipogenesis, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the systemic pathogenicity of regional fat depots. METHODS AND RESULTS Four body fat compartments [visceral adipose tissue (VAT), sc adipose tissue (SAT), thoracic periaortic fat, and pericardial fat] derived from computed tomography were related to serum concentrations of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (fms-like tyrosine kinase-1), hepatocyte growth factor (HGF), and angiopoietin-2 and its soluble receptor (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2 sTie-2) in 1806 Framingham Heart Study participants (mean age 44.9 yr, 44.5% women). In multivariable models, we observed positive associations between several fat compartments and VEGF and HGF levels. The magnitude of the associations were similar for VAT, SAT, and periaortic fat. We observed effect modification by sex. A stronger association was observed between VAT and HGF levels in women; higher VAT and periaortic fat were jointly associated with higher HGF concentrations (P=0.02 and P=0.051, respectively). In women within the highest tertile of VAT, HGF levels significantly increased with higher periaortic fat (P=0.0005). CONCLUSIONS In our large community-based sample, greater adiposity was associated with higher circulating growth factor levels in general. Additional studies are warranted to confirm the stronger association of VAT and periaortic fat with HGF in women and to examine its potential contribution to the sex-related differences in cardiometabolic risk.

SUBSEQUENT ARTERIAL CALCIFICATION IS PRECEDED BY FOCAL INFLAMMATION: A LONGITUDINAL FDG-PET/CT STUDY

Vascular calcium (Ca) deposition is an actively regulated inflammatory process. Here we test the hypothesis that vascular inflammation predisposes to subsequent deposition of Ca. 137 patients (age 61±13, 48.1pMale, without active cancer or inflammatory disease) underwent 2 PET/CT