Association Between the Development of Subclinical Cardiovascular Disease and Human Immunodeficiency Virus (HIV) Reservoir Markers in People With HIV on Suppressive Antiretroviral Therapy.

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.

Prevalence and Characterization of Subclinical Coronary Atherosclerotic Plaque with CT among Individuals with HIV: Results from the Canadian HIV and Aging Cohort Study.

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.

Epicardial fat density, coronary artery disease and inflammation in people living with HIV.

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.

High frequencies of adaptive NK cells are associated with absence of coronary plaque in cytomegalovirus infected people living with HIV.

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.

Quantification of epicardial fat using non contrast cardiac CT in an HIV population: Reproducibility and association with other body fat indices.

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.

Association of epicardial fat with noncalcified coronary plaque volume and with low attenuation plaque in people with HIV.

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) (ß=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 (ß=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.

Circulating ß-d-Glucan as a Marker of Subclinical Coronary Plaque in Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus.

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 ß-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 REG3α and I-FABP were measured by enzyme-linked immunosorbent assay. Fungal BDG levels were analyzed using the Fungitell assay. RESULTS: ß-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 REG3α 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 ß-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.

Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis.

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, ß, 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-1ß 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-1ß 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.

Yield of CT pulmonary angiography in the diagnosis of acute pulmonary embolism: short report.

OBJECTIVE: To assess computed tomography pulmonary angiography (CTPA) positive yield rate for pulmonary embolism (PE) in a Canadian academic tertiary center. RESULTS: 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.