Safety and Immunogenicity of the mRNA-1273 Coronavirus Disease 2019 Vaccine in Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at high risk for severe COVID-19. METHODS: This open-label, phase 3b trial evaluated mRNA-1273 in 137 kidney and 77 liver SOTRs and 20 immunocompetent participants. In part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received 2 doses. In part B, an additional 100-µg dose was offered ≥4 months after the primary series. Here, we report interim trial results. RESULTS: mRNA-1273 was well-tolerated in SOTRs. Four serious adverse events were considered vaccine related by the investigator in 3 SOTRs with preexisting comorbidities. No vaccine-related biopsy-proven organ rejection events or deaths were reported. mRNA-1273 elicited modest neutralizing antibody responses after dose 2 and improved responses after dose 3 in SOTRs. Post-dose 3 responses among liver SOTRs were comparable to post-dose 2 responses in immunocompetent participants. Post-additional dose responses were increased in SOTRs, regardless of primary series vaccination. In liver SOTRs, post-additional dose responses were ∼3-fold higher versus post-dose 2 but lower than immunocompetent participant responses. Most kidney SOTRs received multiple immunosuppressants and had reduced antibody responses versus liver SOTRs. CONCLUSIONS: mRNA-1273 was well-tolerated, and dose 3 and the additional dose improved antibody responses among SOTRs. CLINICAL TRIALS REGISTRATION: NCT04860297.

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk.

AIMS: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. CONCLUSION: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. TRIAL REGISTRATION NUMBER: NCT03385239.

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.

AIMS: Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS AND RESULTS: This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild. CONCLUSION: Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study.

BACKGROUND: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. METHODS: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent 18F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. FINDINGS: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210). INTERPRETATION: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. FUNDING: None.

Safety and durability of mRNA-1273-induced SARS-CoV-2 immune responses in adolescents: results from the phase 2/3 TeenCOVE trial.

Background: Longitudinal changes in vaccination-induced immune response remain inadequately characterized in adolescents. We present long-term safety, immunogenicity, and COVID-19 incidence following a 2-dose mRNA-1273 100-µg primary series, and immunogenicity following a single dose of mRNA-1273 50 µg in vaccine-naïve adolescents. Methods: TeenCOVE (NCT04649151) Part 1 randomized adolescents (12-17 years) to 2-dose mRNA-1273 100 µg (n = 2490) or placebo (n = 1243) 28 days apart. Subsequently, placebo recipients (n = 91) could receive open-label mRNA-1273. Primary objectives included prespecified adverse events through 12 months; secondary objectives were COVID-19 incidence and neutralizing and spike-binding antibodies (nAbs/bAbs) against SARS-CoV-2 (ancestral/variants) through 12 months (study period: December 2020-January 2022). In Part 2, vaccine-naïve adolescents (n = 52) received up to 2 doses of mRNA-1273 50 µg; interim analysis included Day 28 (D28) nAbs post-injection 1 in SARS-CoV-2-baseline-positive participants (serologic/virologic evidence of prior infection). Findings: In SARS-CoV-2-baseline-negative adolescents (N = 369), mRNA-1273 induced robust nAb responses versus baseline (geometric mean concentration [GMC] = 11; 95% CI, 11-12) at D28 (1868 [1759-1985]), 6 months (625 [583-670]) and 12 months (550 [490-618]) post-injection 2. Similar bAb responses were observed to alpha/beta/delta/gamma variants; nAb/bAb responses were similar in SARS-CoV-2-baseline-positive adolescents. The 2-dose mRNA-1273 100-µg primary series was generally well-tolerated; one case of nonserious, moderate, probable acute myocarditis resolved by 8 days from symptom onset. A single dose of mRNA-1273 50 µg in SARS-CoV-2-baseline-positive adolescents induced higher D28 nAb GMCs against ancestral SARS-CoV-2 than 2-dose mRNA-1273 100 µg in young adults (geometric mean ratio = 4.322 [3.274-5.707]). Interpretation: The overall risk-benefit profile of mRNA-1273 remains favorable in adolescents, with durable 12-month immune responses against SARS-CoV-2 (ancestral/variants). A single mRNA-1273 50-µg injection in vaccine-naïve adolescents elicited robust immune responses against SARS-CoV-2. Funding: This project has been funded in whole or in part with federal funds by the Department of Health and Human Services, United States; Administration for Strategic Preparedness and Response, United States; Biomedical Advanced Research and Development Authority, United States, under Contract No. 75A50120C00034. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.

Safety and immunogenicity of a single-dose omicron-containing COVID-19 vaccination in adolescents: an open-label, single-arm, phase 2/3 trial.

BACKGROUND: Most individuals show immunity to SARS-CoV-2 from vaccination or infection, or both. We aimed to determine the safety and immunogenicity of an omicron-containing COVID-19 vaccine (mRNA-1273.222) in vaccine-naive adolescents who were SARS-CoV-2 positive. METHODS: Part 3 of the phase 2/3 TeenCOVE trial was a phase 3, open-label, single-arm part done in the USA and the Dominican Republic that enrolled healthy, vaccine-naive adolescents (aged 12-17 years) to receive two 50 µg doses of mRNA-1273.222 (ancestral strain Wuhan-Hu-1 and omicron subvariants BA.4 and BA.5), 6 months apart. Primary reactogenicity and safety outcomes included assessment of solicited local or systemic adverse reactions 7 days after vaccination, and unsolicited and prespecified adverse events throughout study participation. Inferred effectiveness (primary immunogenicity outcome) was established by comparing neutralising antibody responses 28 days after dose 1 of mRNA-1273.222 in SARS-CoV-2-positive adolescents with responses 28 days after dose 2 of mRNA-1273 100 µg primary series in SARS-CoV-2-negative young adults (aged 18-25 years) from the COVE trial. This study is registered with ClinicalTrials.gov (NCT04649151). FINDINGS: Between Dec 21, 2022, and June 5, 2023, 379 adolescents (378 of whom were SARS-CoV-2 positive) received at least one mRNA-1273.222 dose and were included in the safety analysis set. The reactogenicity profile was favourable compared with the mRNA-1273 primary series, with no new safety concerns identified. Unsolicited adverse events were reported in 49 (13%) of 379 participants; no deaths or adverse events leading to study discontinuation were reported. The immunogenicity set included 245 adolescents from the per-protocol immunogenicity subset who were SARS-CoV-2 positive at baseline and 296 young adults who were SARS-CoV-2 negative. Compared with the mRNA-1273 primary series in SARS-CoV-2-negative young adults, a single dose of mRNA-1273.222 induced superior (geometric mean ratio [GMR] 95% CI lower bound >1) neutralising antibody responses against omicron BA.4 and BA.5 (GMR 48·95 [95% CI 44·21-54·21]) and non-inferior (GMR 95% CI lower bound >0·667) neutralising antibody responses against ancestral SARS-CoV-2 (GMR 4·25 [95% CI 3·69-4·88]) in SARS-CoV-2-positive adolescents. INTERPRETATION: In vaccine-naive, SARS-CoV-2-positive adolescents, single-dose mRNA-1273.222 was effective against COVID-19 based on successful immunobridging to the two-dose mRNA-1273 primary series in young adults. The findings support a simplified single-dose vaccination schedule with variant-containing mRNA vaccines, regardless of previous vaccination status. FUNDING: Moderna.

Immunogenicity and safety of MF59-adjuvanted quadrivalent influenza vaccine versus standard and alternate B strain MF59-adjuvanted trivalent influenza vaccines in older adults.

OBJECTIVE: Evaluate whether adjuvanted quadrivalent influenza vaccine (aQIV) elicits a noninferior immune response compared with a licensed adjuvanted trivalent influenza vaccine (aTIV-1; Fluad™) and aTIV-2 containing an alternate B strain, examine whether aQIV had immunological superiority for the B strain absent from aTIV comparators, and evaluate reactogenicity and safety among adults ≥65 years. METHODS: In a multicenter, double-blind, randomized controlled trial, adults ≥65 years were randomized 2:1:1 to vaccination with aQIV (n = 889), aTIV-1 (n = 445), or aTIV-2 (n = 444) during the 2017-2018 influenza season. Immunogenicity was assessed by hemagglutination inhibition (HI) assay conducted on serum samples collected before vaccination and 21 days after vaccination for homologous influenza strains. RESULTS: aQIV met non-inferiority criteria for geometric mean titer ratios (GMT ratios) and seroconversion rate (SCR) differences against aTIV. The upper bounds of the 2-sided 95% confidence interval (CI) for GMT ratios were <1.5 for all 4 strains (A/H1N1 = 1.27, A/H3N2 = 1.09, B-Yamagata = 1.08, B-Victoria = 1.08). The upper bounds of the 95% CI of the SCR differences were <10% for all 4 strains (A/H1N1 = 7.76%, A/H3N2 = 4.96%, B-Yamagata = 3.27%, B-Victoria = 2.55%). aQIV also met superiority criteria (upper bound of 95% CI for GMT ratios <1 and SCR differences <0) for B strain absent from aTIV comparators (B-Yamagata GMT ratio = 0.70, SCR difference = -8.81%; B-Victoria GMT ratio = 0.78, SCR difference = -8.11%). aQIV and aTIV vaccines were immunogenic and well-tolerated. The immunological benefit of aQIV was also demonstrated in age subgroups 65-74 years, 75-84 years, and ≥85 years and in those with high comorbidity risk scores. Reactogenicity profiles were generally comparable. CONCLUSION: aQIV induces a similar immune response as the licensed aTIV vaccine against homologous influenza strains and has a comparable reactogenicity and safety profile. Superior immunogenicity against the additional B strain was observed, indicating that aQIV could provide a broader protection than aTIV against influenza in older adults (NCT03314662).

Relationship Between Measures of Adiposity, Arterial Inflammation, and Subsequent Cardiovascular Events.

BACKGROUND: The objective of this study was to evaluate how different measures of adiposity are related to both arterial inflammation and the risk of subsequent cardiovascular events. METHODS AND RESULTS: We included individuals who underwent (18)F-fluorodeoxyglucose positron emission tomography/computed tomography imaging for oncological evaluation. Subcutaneous adipose tissue (SAT) volume, visceral adipose tissue (VAT) volume, and VAT/SAT ratio were determined. Additionally, body mass index, metabolic syndrome, and aortic (18)F-fluorodeoxyglucose uptake (a measure of arterial inflammation) were determined. Subsequent development of cardiovascular disease (CVD) events was adjudicated. The analysis included 415 patients with a median age of 55 (P25-P75: 45-65) and a median body mass index of 26.4 (P25-P75: 23.4-30.9) kg/m(2). VAT and SAT volume were significantly higher in obese individuals. VAT volume (r=0.290; P<0.001) and VAT/SAT ratio (r=0.208; P<0.001) were positively correlated with arterial inflammation. Thirty-two subjects experienced a CVD event during a median follow-up of 4 years. Cox proportional hazard models showed that VAT volume and VAT/SAT ratio were associated with CVD events (hazard ratio [95% confidence interval]: 1.15 [1.06-1.25]; P<0.001; 3.60 [1.88-6.92]; P<0.001, respectively). Body mass index, metabolic syndrome, and SAT were not predictive of CVD events. CONCLUSIONS: Measures of visceral fat are positively related to arterial inflammation and are independent predictors of subsequent CVD events. Individuals with higher measures of visceral fat as well as elevated arterial inflammation are at highest risk for subsequent CVD events. The findings suggest that arterial inflammation may explain some of the CVD risk associated with adiposity.

Early aortic valve inflammation precedes calcification: a longitudinal FDG-PET/CT study.

OBJECTIVES: Recent data shows a relationship between aortic valve (AV) inflammation and calcification. However, direct evidence linking early valve inflammation (prior to hemodynamic compromise) to subsequent calcium (Ca) deposition is lacking in humans. We sought to test the hypothesis whether local AV inflammation predisposes to subsequent AV Ca deposition. METHODS: We identified 111 individuals (age 60[49, 68], 50.5% male) without active cancer or aortic stenosis who underwent 2 PET/CT studies 1-5 years apart for cancer surveillance. AV inflammation was determined by measuring FDG uptake (maximum standardized uptake value, SUVmax) within the AV on baseline PET/CT. Subsequent deposition of AV Ca was determined by comparing baseline and follow-up CT scans, determined as an increase in AV Ca volume score (CaVS). Patients were classified as "non-progressors" or "progressors" based on Square Root difference in CaVS (using a pre-determined cut-off value of 2.5). CT and PET measurements were conducted by 2 mutually blinded laboratories. RESULTS: During follow-up, AV Ca increased in 23 patients (20.2%) classified as "progressors", of whom 9 (9.2%) demonstrated subsequent 'incident' AV Ca. The AV SUVmax (mean ± SD) was higher in progressors vs. non-progressors (2.03 ± 0.52 vs.1.74 ± 0.36, p = 0.02) and especially in patients with-vs. without-incident AV Ca (2.28 ± 0.42 vs. 1.73 ± 0.36, p < 0.001). Moreover, AV inflammation (AV SUVmax) independently predicted subsequent calcification after adjusting for cardiovascular risk factors [OR (95%CI): 4.99 (1.30-19.15), p = 0.02]. CONCLUSION: The findings suggest that early AV inflammation may predispose to AV sclerosis. The evaluation of valvular metabolic activity may prove useful for developing a better understanding of calcific valve disease.

Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans.

OBJECTIVES: This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events. BACKGROUND: Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk. METHODS: (18)F-fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. RESULTS: Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio [HR]: 3.3; 95% confidence interval [CI]: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02). CONCLUSIONS: Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.

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], =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.

Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events.

OBJECTIVES: This study sought to determine whether arterial inflammation measured by (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) improves prediction of cardiovascular disease (CVD) beyond traditional risk factors. BACKGROUND: It is unknown whether arterial (18)F-FDG uptake measured with routine PET imaging provides incremental value for predicting CVD events beyond Framingham risk score (FRS). METHODS: We consecutively identified 513 individuals from 6,088 patients who underwent (18)F-FDG-PET and computed tomography (CT) imaging at Massachusetts General Hospital between 2005 and 2008 and who met additional inclusion criteria: ≥30 years of age, no prior CVD, and free of cancer. CVD events were independently adjudicated, while blinded to clinical data, using medical records to determine incident stroke, transient ischemic attack, acute coronary syndrome, revascularization, new-onset angina, peripheral arterial disease, heart failure, or CVD death. FDG uptake was measured in the ascending aorta (as target-to-background-ratio [TBR]), while blinded to clinical data. RESULTS: During follow-up (median 4.2 years), 44 participants developed CVD (2 per 100 person-years at risk). TBR strongly predicted subsequent CVD independent of traditional risk factors (hazard ratio: 4.71; 95% confidence interval [CI]: 1.98 to 11.2; p < 0.001) and (hazard ratio: 4.13; 95% CI: 1.59 to 10.76; p = 0.004) after further adjustment for coronary calcium score. Addition of arterial PET measurement to FRS scores improved the C-statistic (mean ± standard error 0.62 ± 0.03 vs. 0.66 ± 0.03). Further, incorporation of TBR into a model with FRS variables resulted in an integrated discrimination of 5% (95% CI: 0.36 to 9.87). Net reclassification improvements were 27.48% (95% CI: 16.27 to 39.92) and 22.3% (95% CI: 11.54 to 35.42) for the 10% and 6% intermediate-risk cut points, respectively. Moreover, TBR was inversely associated with the timing of CVD (beta -0.096; p < 0.0001). CONCLUSIONS: Arterial FDG uptake, measured from routinely obtained PET/CT images, substantially improved incident CVD prediction beyond FRS among individuals undergoing cancer surveillance and provided information on the potential timing of such events.

Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology.

BACKGROUND: Several high-risk morphological features (HRM) of plaques, especially in combination, are associated with an increased risk of a clinical event. Although plaque inflammation is also associated with atherothrombosis, the relationship between inflammation and number of HRM is not well understood. METHODS AND RESULTS: Thirty-four patients underwent (18)flurodeoxyglucose positron emission tomography (FDG-PET) imaging, and carotid atherosclerotic inflammation was assessed (target-to- BACKGROUND: =0.0003) and increased with the number of HRM observed (P<0.001 for trend). Similarly, inflammation within atherosclerotic specimens (% CD68 staining) was higher in plaques with (versus without) HRM (median [interquartile range]: 10 [0, 19.85] versus 0 [0, 1.55], P=0.01) and increased with the number of HRM observed (P<0.001 for trend). CONCLUSIONS: Inflammation, as assessed by both FDG uptake and histology, is increased in plaques containing HRM and increases with increasing number of HRM. These data support the concept that inflammation accumulates relative to the burden of morphological abnormalities.

Positron emission tomography measurement of periodontal 18F-fluorodeoxyglucose uptake is associated with histologically determined carotid plaque inflammation.

OBJECTIVES: This study aimed to test the hypothesis that metabolic activity within periodontal tissue (a possible surrogate for periodontal inflammation) predicts inflammation in a remote atherosclerotic vessel, utilizing (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging. BACKGROUND: Several lines of evidence establish periodontal disease as an important risk factor for atherosclerosis. FDG-PET imaging is an established method for measuring metabolic activity in human tissues and blood vessels. METHODS: One hundred twelve patients underwent FDG-PET imaging 92 ± 5 min after FDG administration (13 to 25 mCi). Periodontal FDG uptake was measured by obtaining standardized uptake values from the periodontal tissue of each patient, and the ratio of periodontal to background (blood) activity was determined (TBR). Standardized uptake value measurements were obtained in the carotid and aorta as well as in a venous structure. Localization of periodontal, carotid, and aortic activity was facilitated by PET coregistration with computed tomography or magnetic resonance imaging. A subset of 16 patients underwent carotid endarterectomy within 1 month of PET imaging, during which atherosclerotic plaques were removed and subsequently stained with anti-CD68 antibodies to quantify macrophage infiltration. Periodontal FDG uptake was compared with carotid plaque macrophage infiltration. RESULTS: Periodontal FDG uptake (TBR) is associated with carotid TBR (R = 0.64, p < 0.0001), as well as aortic TBR (R = 0.38; p = 0.029). Moreover, a strong relationship was observed between periodontal TBR and histologically assessed inflammation within excised carotid artery plaques (R = 0.81, p < 0.001). CONCLUSIONS: FDG-PET measurements of metabolic activity within periodontal tissue correlate with macrophage infiltration within carotid plaques. These findings provide direct evidence for an association between periodontal disease and atherosclerotic inflammation.

Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina.

OBJECTIVES: This study tested the hypothesis that fluorodeoxyglucose (FDG) uptake within the ascending aorta and left main coronary artery (LM), measured using positron emission tomography (PET), is greater in patients with recent acute coronary syndrome (ACS) than in patients with stable angina. BACKGROUND: Inflammation is known to play an important role in atherosclerosis. Positron emission tomography imaging with (18)F-FDG provides a measure of plaque inflammation. METHODS: Twenty-five patients (mean age 57.9 +/- 9.8 years, 72% male, 10 ACS, and 15 stable angina) underwent cardiac computed tomographic angiography and PET imaging with (18)F-FDG after invasive angiography. Images were coregistered, and FDG uptake was measured at locations of interest for calculation of target-to-background ratios (TBR). Additionally, FDG uptake was measured at the site of the lesion deemed clinically responsible for the presenting syndrome (culprit) by virtue of locating the stent deployed to treat the syndrome. RESULTS: The FDG uptake was higher in the ACS versus the stable angina groups in the ascending aorta (median [interquartile ranges] TBR 3.30 [2.69 to 4.12] vs. 2.43 [2.00 to 2.86], p = 0.02), as well as the LM (2.48 [2.30 to 2.93] vs. 2.00 [1.71 to 2.44], p = 0.03, respectively). The TBR was greater for culprit lesions associated with ACS than for lesions stented for stable coronary syndromes (2.61 vs. 1.74, p = 0.02). Furthermore, the TBR in the stented lesions (in ACS and stable angina groups) correlated with C-reactive protein (r = 0.58, p = 0.04). CONCLUSIONS: This study shows that in patients with recent ACS, FDG accumulation is increased both within the culprit lesion as well as in the ascending aorta and LM. This observation suggests inflammatory activity within atherosclerotic plaques in acute coronary syndromes and supports intensification of efforts to refine PET methods for molecular imaging of coronary plaques.