People with HIV (PWH) have an increased risk of developing cardiovascular disease (CVD). Our recent data demonstrated that the multi-isoform proinflammatory cytokine IL-32 is upregulated in PWH and is associated with arterial stiffness and subclinical atherosclerosis. However, the mechanisms by which IL-32 contributes to the pathogenesis of these diseases remain unclear. Here, we show that while the less expressed IL-32α isoform induces the differentiation of human classical monocytes into the calcium-resorbing osteoclast cells, the dominantly expressed isoforms IL-32β and IL-32γ suppress this function through the inhibition of TGF-β and induce the differentiation of monocytes into the calcium-depositing osteocalcin+ osteoblasts. These results aligned with the increase in plasma levels of osteoprotegerin, a biomarker of vascular calcification, and its association with the presence of coronary artery subclinical atherosclerosis and calcium score in PWH. These findings support a novel role for the proinflammatory cytokine IL-32 in the pathophysiology of CVD by increasing vascular calcification in PWH.

Studies have shown an increased risk of coronary artery disease (CAD) in the human immunodeficiency virus (HIV) population. Epicardial fat (EF) quality may be linked to this increased risk. In our study, we evaluated the associations between EF density, a qualitative characteristic of fat, and inflammatory markers, cardiovascular risk factors, HIV-related parameters, and CAD. Our study was cross-sectional, nested in the Canadian HIV and Aging Cohort Study, a large prospective cohort that includes participants living with HIV (PLHIV) and healthy controls. Participants underwent cardiac computed tomography angiography to measure volume and density of EF, coronary artery calcium score, coronary plaque, and low attenuation plaque volume. Association between EF density, cardiovascular risk factors, HIV parameters, and CAD were evaluated using adjusted regression analysis. A total of 177 PLHIV and 83 healthy controls were included in this study. EF density was similar between the two groups (−77.4 ± 5.6 HU for PLHIV and −77.0 ± 5.6 HU for uninfected controls, P = .162). Multivariable models showed positive association between EF density and coronary calcium score (odds ratio, 1.07, P = .023). Among the soluble biomarkers measured in our study, adjusted analyses showed that IL2Rα, tumor necrosis factor alpha and luteizing hormone were significantly associated with EF density. Our study showed that an increase in EF density was associated with a higher coronary calcium score and with inflammatory markers in a population that includes PLHIV.

We report that people with human immunodeficiency virus (HIV) diagnosed with coronary artery atherosclerotic plaques display higher levels of HIV DNA compared with those without atherosclerotic plaques. In a multivariable prediction model that included 27 traditional and HIV-related risk factors, measures of HIV DNA were among the most important predictors of atherosclerotic plaque formation.

The objective of this study was to evaluate whether adaptive NKG2C+CD57+ natural killer (adapNK) cell frequencies are associated with pre-clinical coronary atherosclerosis in participants of the Canadian HIV and Aging Cohort Study. This cross-sectional study included 194 Canadian HIV and Aging Cohort Study participants aged ≥ 40 years of which 128 were cytomegalovirus (CMV)+ people living with HIV (PLWH), 8 were CMV-PLWH, 37 were CMV mono-infected individuals, and 21 were neither human immunodeficiency virus nor CMV infected. Participants were evaluated for the frequency of their adapNK cells and total plaque volume (TPV). TPV was assessed using cardiac computed tomography. Participants were classified as free of, or having, coronary atherosclerosis if their TPV was "0" and ">0," respectively. The frequency of adapNK cells was categorized as low, intermediate or high if they constituted <4.6%, between ≥4.6% and 20% and >20%, respectively, of the total frequency of CD3-CD56dim NK cells. The association between adapNK cell frequency and TPV was assessed using an adjusted Poisson regression analysis. A greater proportion of CMV+PLWH with TPV = 0 had high adapNK cell frequencies than those with TPV > 0 (61.90% vs 39.53%, P = .03) with a similar non-significant trend for CMV mono-infected participants (46.15% vs 34.78%). The frequency of adapNK cells was negatively correlated with TPV. A high frequency of adapNK cells was associated with a relative risk of 0.75 (95% confidence intervals 0.58, 0.97, P = .03) for presence of coronary atherosclerosis. This observation suggests that adapNK cells play a protective role in the development of coronary atherosclerotic plaques.

Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH.

Purpose: To assess the reproducibility of different epicardial fat measurement and their association with other adiposity measurements in HIV-infected and non-HIV-infected patients. Methods and materials: In this cross-sectional study, 167 HIV-infected and 58 non-HIV-infected consecutive participants (200 males; mean age 56 years) with low/intermediate cardiovascular risk were recruited between 2012 and 2017 from a large prospective cohort and underwent non-contrast cardiac CT. Two independent observers measured epicardial fat volume, area and thickness in all participants. For intra-observer agreement, one observer did a second assessment in a subset of 40 patients. Agreement was assessed with the intraclass correlation coefficient (ICC). Pearson's correlation was estimated to assess the association between epicardial fat, body-mass index (BMI) and dual-energy x-ray absorptiometry (DEXA) derived percentage of body fat. Results: Inter-observer agreement was excellent for epicardial fat volume (ICC 0.75) and area (ICC 0.95) and good for epicardial fat thickness (ICC near the left anterior descending artery (LAD) 0.64, ICC near right coronary artery (RCA) 0.64). Intra-observer agreement was excellent for epicardial fat volume (ICC 0.97), area (ICC 0.99), thickness at LAD (ICC 0.71) and good for epicardial fat thickness at RCA (ICC 0.68). Epicardial fat volume had a better correlation to total body fat (r = 0.28, p < 0.001) and trunk fat (r = 0.37, p < 0.001), in comparison to other epicardial fat indices. Conclusion: Assessment of epicardial fat volume is highly reproducible in both HIV-infected and non-HIV-infected patients and shows a superior correlation with DEXA-based body and trunk fat measurements. Epicardial fat volume should be considered over other CT assessment methods when quantifying epicardial fat in HIV patients.

Background Despite antiretroviral therapy (ART), people with human immunodeficiency virus (PWH) have increased risk of inflammatory comorbidities, including cardiovascular diseases. Gut epithelial damage, and translocation of bacterial lipopolysaccharide (LPS) or fungal beta-d-glucan (BDG) drive inflammation in ART-treated PWH. In this study, we investigated whether markers of gut damage and microbial translocation were associated with cardiovascular risk in asymptomatic ART-treated PWH. Methods We cross-sectionally analyzed plasma from 93 ART-treated PWH and 52 uninfected controls older than 40 years of age from the Canadian HIV and Aging Cohort. Participants were cardiovascular disease free and underwent a cardiac computed tomography (CT) to measure total coronary atherosclerotic plaque volume (TPV). Levels of bacterial LPS and gut damage markers REG3 alpha and I-FABP were measured by enzyme-linked immunosorbent assay. Fungal BDG levels were analyzed using the Fungitell assay. Results beta-d-glucan levels but not LPS were significantly elevated in ART-treated PWH with coronary artery plaque (P = .0007). Moreover, BDG but not LPS levels correlated with TPV (r = 0.26, P = .01). Intestinal fatty acid binding protein (I-FABP) but not REG3 alpha levels correlated with TPV (r = 0.23, P = .03). However, BDG and LPS levels were not elevated in uninfected controls with plaque. In multivariable models, elevated BDG levels were independently associated with the presence of coronary atherosclerosis in PWH but not in uninfected controls. Conclusions Translocation of fungal BDG was associated with coronary atherosclerosis assessed by CT-scan imaging in ART-treated PWH, suggesting a human immunodeficiency virus-specific pathway leading to cardiovascular disease. Further investigation is needed to appraise causality of this association. Translocation of fungal products may represent a therapeutic target to prevent cardiovascular disease in ART-treated PWH. Plasma levels of the fungal product beta-D-Glucan, but not the bacterial product lipopolysaccharide, are associated with the presence and the size of subclinical coronary atherosclerosis plaque in people living with HIV taking antiretroviral therapy, independently of classical cardiovascular risk factors.

Background People living with HIV (PLWH) have a higher risk of myocardial infarction. Coronary atherosclerotic plaque CT characterization helps to predict cardiovascular risk. Purpose To measure CT characteristics of coronary plaque in PLWH without known cardiovascular disease and healthy volunteers without HIV. Materials and Methods In this prospective study, noncontrast CT (all participants, n = 265) was used for coronary artery calcium (CAC) scoring in asymptomatic PLWH and healthy volunteers without HIV, without known cardiovascular disease, from 2012 to 2019. At coronary CT angiography (n = 233), prevalence, frequency, and volume of calcified, mixed, and noncalcified plaque were measured. Poisson regressions were used with adjustment for cardiovascular risk factors. Results There were 181 PLWH (mean age, 56 years ± 7; 167 men) and 84 healthy volunteers (mean age, 57 years ± 8; 65 men) evaluated by using noncontrast CT. CT angiography was performed in 155 PLWH and 78 healthy volunteers. Median 10-year Framingham risk score was not different between PLWH and healthy volunteers (10% vs 9%, respectively; P = .45), as were CAC score (odds ratio [OR], 1.06; 95% CI: 0.58, 1.94; P = .85) and overall plaque prevalence (prevalence ratio, 1.07; 95% CI: 0.86, 1.32; P = .55) after adjustment for cardiovascular risk. Noncalcified plaque prevalence (prevalence ratio, 2.5; 95% CI: 1.07, 5.67; P = .03) and volume (OR, 2.8; 95% CI: 1.05, 7.40; P = .04) were higher in PLWH. Calcified plaque frequency was reduced in PLWH (OR, 0.6; 95% CI: 0.40, 0.91; P = .02). Treatment with protease inhibitors was associated with higher volume of overall (OR, 1.8; 95% CI: 1.09, 2.85; P = .02) and mixed plaque (OR, 1.6; 95% CI: 1.04, 2.45; P = .03). Conclusion Noncalcified coronary plaque burden at coronary CT angiography was two- to threefold higher in asymptomatic people living with HIV without known cardiovascular disease compared with healthy volunteers without HIV. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lai in this issue.

Background: Despite antiretroviral therapy (ART), people living with HIV (PLWH) have increased risk of inflammatory comorbidities, including cardiovascular diseases. Gut epithelial damage, and translocation of bacterial lipopolysaccharide (LPS) or fungal β-D-Glucan (BDG) drive inflammation in ART-treated PLWH. Herein, we investigated whether markers of gut damage and microbial translocation were associated with cardiovascular risk in asymptomatic ART-treated PLWH. Methods: We cross-sectionally analyzed plasma from 93 ART-treated PLWH and 52 uninfected controls older than 40 years of age from the Canadian HIV and Aging Cohort. Participants were cardiovascular disease free and underwent a cardiac computed tomography to measure total coronary atherosclerotic plaque volume (TPV). Levels of bacterial LPS, and gut damage markers REG3α and I-FABP were measured by ELISA. Fungal BDG levels were analyzed using the Fungitell ® assay. Results: BDG levels but not LPS were significantly elevated in ART-treated PLWH with coronary artery plaque ( p=0.0007 ). Moreover, BDG but not LPS levels correlated with TPV ( r=0.25, p=0.01 ). I-FABP but not REG3α levels correlated with TPV ( r=0.23, p=0.03 ). However, BDG and LPS levels were not elevated in uninfected controls with plaque. In multivariable models, elevated BDG levels were independently associated with the presence of coronary atherosclerosis in PLWH but not in uninfected controls. Conclusion: Translocation of fungal BDG was associated with coronary atherosclerosis assessed by CT-scan imaging in ART-treated PLWH, suggesting a HIV-specific pathway leading to cardiovascular disease. Further investigation is needed to appraise causality of this association. Translocation of fungal products may represent a therapeutic target to prevent cardiovascular disease in ART-treated A total of 145 participants, 93 ART-treated participants and 52 uninfected controls from the cardiovascular imaging sub-study of the Canadian HIV and Aging Cohort Study (CHACS) were included in a transversal study. The study design and protocol of the CHACS study have been reported 21 . Briefly, PLWH over the age of 40 or having lived with HIV for at least 15 years, and HIV-negative controls over the age of 40 were recruited in HIV and sexual transmitted disease clinics, the majority of their population being men who have sex with men (MSM). Participants from the control group have been recruited at the same medical centres as the PLWH participants. CHACS participants who were free of overt cardiovascular disease (had never suffered a myocardial infarction, coronary revascularisation, angina, stroke of peripheral vascular revascularization) and had a 10-year Framingham risk score ranging from 5-20% were invited to participate to the cardiovascular imaging sub-study. Data on all classical cardiovascular risk factors were collected prospectively as part of CHACS study visits. BDG. by likelihood ratio test. significant (p<0.05), we stratus-specific results. TPV as absent (TPV=0) or present (TPV=1). Classical cardiovascular risk factors (age, statin use as a measure of dyslipidemia, hypertension and BMI) were considered confounders of the association and entered into the model were entered into the model sequentially and kept into the model if they modified the association between BDG and TVP by more than 10%. Although potential confounders, sex and diabetes were not included into the final model due to small cell issues, and absence of association with the outcome in our data. GraphPad Prism 8.0 (GraphPad Software) and R-software were used to perform descriptive statistical analyses. T-cell count (cells/µL), and CD4:CD8 ratio of 594 (446-749), 710 (511-1023), and 0.86 (0.56-1.14) respectively. All HIV+ participants were taking for a median of 15 years (12-18) had a suppressed viremia below 50 copies/mL. Plasma levels of I-FABP and REG3α, but not LPS nor BDG, were significantly elevated in PLWH compared to uninfected controls. a reliable marker of microbial translocation 18,30 . We have showed that time of collection mitigates LPS plasma levels in PLWH as those levels displayed a daily variation over 24 hours while BDG did not significantly vary during the same period of time 31 . Furthermore, we have previously shown that glucan rich food and time of food intake do not influence BDG plasma levels in HIV and HCV-infected patients, indicating a gut fungal origin 31,32 . Conversely, circulating LPS has been shown to be rapidly detoxified in the liver and spleen, possibly explaining the absence of association between LPS and CVD 18,33 aging factors (age, smoking, statin use as a measure of dyslipidemia, diabetes, hypertension and BMI>30) were entered into the model sequentially and kept into the model if they modified the association between BDG and TVP by more than 10%. P-value was deemed significant when <5%. HIV+, living with factors (age, smoking, statin use as a measure of dyslipidemia, diabetes, hypertension and BMI>30) were entered into the model sequentially and kept into the model if they modified the association between BDG and TVP by more than 10%. P-value was deemed significant when <5%.

Supplemental Digital Content is available in the text Objectives: People with HIV are exposed to a higher risk of coronary artery disease (CAD) compared with the general population. Epicardial fat may play a unique role in promoting coronary atherosclerosis. We measured epicardial fat in participants living with HIV and controls and investigated its association with coronary plaque volume and low attenuation plaque, a marker of plaque vulnerability. Design: This is a cross-sectional study, nested in the Canadian HIV and Aging Cohort Study, a large prospective cohort actively following participants with HIV and controls. Participants with low/intermediate cardiovascular risk without symptoms/history of CAD were invited to undergo cardiac computed tomography (CT). Methods: Volume of epicardial fat, coronary plaque and low attenuation component of the plaque were measured. Association between epicardial fat, coronary plaque volume and low attenuation component was tested using adjusted regression analysis. Results: A total of 169 participants with HIV and 81 controls underwent cardiac CT. Participants with HIV had a greater epicardial fat volume compared with controls (P = 0.019). In participants with HIV, epicardial fat volume was positively associated with duration of nonnucleoside reverse transcriptase inhibitors (NNRTI) (β=2.19, P = 0.004). After adjustment for cardiovascular risk factors, epicardial fat volume was positively associated to noncalcified plaque volume [odds ratio (OR) = 1.09, P = 0.028] and to the low-attenuation plaque component portion (β=0.38, P = 0.026). Conclusion: The association of epicardial fat volume to noncalcified plaque volume and to low attenuation component plaque may suggest a potential mechanism by which epicardial fat could be a silent driver of CAD in the HIV population.

We read with interest the meta-analysis of Alhelaly and colleagues in the January 2020 issue of Clinical Imaging [ [1] Alhelaly Mohamed M. Abdelhakimb Ahmed M. Ellotfa Hamed Khaleda Anas Solimana Ahmed M. Attiaa Mahmoud M. Comparative effect of iso-osmolar versus low-osmolar contrast media on vascular attenuation, image quality, and heart rate changes in coronary CT angiography: a systematic review and meta-analysis. Clin Imaging. 2020; 61: 69-79 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar ], which showed no significant differences between iodixanol, an iso-osmolar contrast media (IOCM), in comparison to low-osmolar contrast media (LOCM) agents considered as a group regarding vascular enhancement, image quality, heart rate (HR) variability and patient discomfort. The authors showed a slightly lower HR change of 0.9 beat per minute (bpm) with the use of IOCM (p = 0.04) [ [1] Alhelaly Mohamed M. Abdelhakimb Ahmed M. Ellotfa Hamed Khaleda Anas Solimana Ahmed M. Attiaa Mahmoud M. Comparative effect of iso-osmolar versus low-osmolar contrast media on vascular attenuation, image quality, and heart rate changes in coronary CT angiography: a systematic review and meta-analysis. Clin Imaging. 2020; 61: 69-79 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar ].

The Canadian HIV and Aging Cohort Study (CHACS) is a large, controlled, prospective cohort recruiting participants living with HIV, and participants unexposed to HIV. The CHACS focus on identifying the prevalence, type and determinants of premature cardiovascular disease in HIV+ individuals. The objective of the present cardiovascular imaging substudy nested in the CHACS is to compare subclinical coronary plaque burden and characteristics between HIV+ and HIV- individuals and to evaluate the association of coronary plaque with HIV-related factors. This cross-sectional study was approved by our ethics committee. Participants provided written consent. Consecutive HIV+ and HIV- participants were prospectively recruited for cardiac computed tomography (CT). Eligibility criteria were absence of known coronary artery disease and low/intermediate 10-yr Framingham risk score (FRS, 5-20%). CT was used for calcium scoring and plaque assessment. Assessors were blinded to HIV status. Multivariate regression models were used. A total of 265 participants (181 HIV+ (92% males), 84 HIV- (77 % males)) were included (mean 56 yo), with similar FRS. Smoking (p < 0.001) and dyslipidemias (p ≤ 0.02) were increased in HIV+ participants. All HIV+ participants were on antiretroviral therapy. After adjusting for cardiovascular risk factors, burden of calcium and overall plaque was similar between HIV+ and HIV- participants. However, HIV+ participants had an increased volume (25 and 5 mm3/participant, p=0.03) of noncalcified plaques compared to HIV- participants. Prevalence and volume of calcified (p= 0.12 and 0.29) and mixed (p= 0.18 and 0.17) plaques, as well as ≥ 70% stenosis (p=0.99) were similar between HIV+ and HIV- participants. In HIV participants, total plaque volume, noncalcified plaque volume and mixed plaque volume (p=0.01, 0.03 and 0.006) increased with the use of protease inhibitors; noncalcified plaque volume (p=0.02) increased with the use of nucleoside reverse transcriptase inhibitors. To our knowledge, this is the largest Canadian imaging study of HIV-associated coronary atherosclerosis. In line with previous studies, our results confirm that asymptomatic HIV+ individuals under antiretroviral therapy have increased noncalcified plaque in comparison to HIV- individuals, after adjustment for cardiovascular risk factors. Noncalcified plaques are usually considered vulnerable and this finding could suggest one anatomic substrate for the known increased risk of myocardial infarction in the HIV population. Additionally, our data are intended as a basis for novel correlative analyses (e.g. carotid wall biomechanics, advanced immunological factors, frailty) planned with other teams of the CHACS.

To assess computed tomography pulmonary angiography (CTPA) positive yield rate for pulmonary embolism (PE) in a Canadian academic tertiary center. This one-center retrospective cross-sectional study includes from 5565 (model 1) to 5296 (model 2) patients that were evaluated for suspected PE in 2015, among which 1331 (23.9% (model 1) to 25.1% (model 2)) underwent CTPA. Mean age of CTPA patients was 60.2 ± 16.6 years, of which 575 were males (43.2%). Two hundred eleven CTPA examinations were positive for PE, giving a CTPA positive yield rate of 15.9% (95% CI (13.93–17.87)). One hundred and thirteen (8.1%) CTPA were considered indeterminate, and eleven were considered nondiagnostic (0.8%). Among the 211 CTPA positive for PE, 67 (32%) were proximal emboli, 98 (47%) were segmental emboli and 44 (21%%) were subsegmental emboli. In conclusion, in this retrospective study done in a Canadian academic tertiary center, we report a positive rate of 15.9% for PE detection with CTPA, which is above the generally accepted lower threshold of 10% for the yield of CTPA.