18Fluoride-based molecular imaging of coronary atherosclerosis in HIV infected patients.

BACKGROUND AND AIMS: Molecular imaging with 18Fluorodeoxyglucose (FDG) and 18F-sodium-fluoride (NaF) captures arterial inflammation and micro-calcification and can reveal potentially unstable atherosclerotic plaques. METHODS: We performed FDG and NaF PET/CT imaging in two clinically similar cohorts of patients living with HIV (PLWH) with no symptomatic cardiovascular disease. The prevalence and intensity of coronary artery uptake of each tracer, measured as target-to-background ratio (TBR), were assessed in patients at low and high cardiovascular risk. RESULTS: Ninety-three PLWH were submitted to PET/CT imaging with FDG (N = 43) and NaF (N = 50); 42% were at low and 58% at high cardiovascular risk. The intensity of uptake and multivessel coronary artery uptake were significantly higher with NaF than FDG both in low and high-risk patients. When each 18F-tracer was tested in low and high-risk patients, an equal proportion of subjects showed no vessel, single and multivessel NaF uptake; the same was true for no and single vessel uptake of FDG (no multivessel FDG uptake was noted). Waist circumference, CRP, D-dimer, HIV duration and treatment with nucleoside reverse transcriptase inhibitors were associated with high NaF uptake in univariable analyses; D-dimer remained significant in multivariable analyses (OR = 1.05; p=0.02). There were no significant associations with FDG uptake. CONCLUSIONS: The prevalence of coronary artery uptake was higher with NaF compared to FDG both in high and low risk patients, hence microcalcification imaging may be a more sensitive tool to detect coronary atherosclerosis than inflammation imaging. However, the uptake of each 18Fluoride tracer was similar between low and high-risk subjects, and this underscores the discordance between clinical and imaging based risk assessment. Future investigation should address the prognostic significance of NaF coronary artery uptake.

Thymus Imaging Detection and Size Is Inversely Associated With Metabolic Syndrome and Frailty in People With HIV.

BACKGROUND: People with HIV (PWH) may experience accentuating aging in relation to immuno-activation. Little is known regarding thymus (THY) involution in this process. We sought to investigate the relationship between THY imaging detection/size and clinically relevant aging outcomes such as metabolic syndrome (MetS), multimorbidity (MM), and frailty in PWH. METHODS: This was a cross-sectional observational study including 665 HIV patients (81% males; median age, 53 years) attending Modena HIV Metabolic Clinic from 2014 to 2017. They underwent thoracic computed tomography scan as part of the medical assessment for cardiovascular disease, in which THY detection and size were reported using a semiquantitative score. Outcome measures were MetS, MM, and frailty. RESULTS: THY was detected in 27.0% of subjects; 71.1% showed THY size of grade 1-2, and 28.9% exhibited grade ≥3. Covariates that inversely correlated with THY detection were age, male gender, body mass index (BMI), and HIV duration. Covariates that inversely correlated with MetS were age, HIV duration, BMI, and THY grade 1-2. Covariates that inversely correlated with MM were age, HIV duration, and CD4 nadir. Covariates that inversely correlated with frailty were age, HIV duration, CD4 nadir, BMI, and THY detection. CONCLUSIONS: THY is inversely associated with MetS and frailty in PWH.

Molecular Imaging of Vascular Calcification with 18F-Sodium-Fluoride in Patients Infected with Human Immunodeficiency Virus.

18F-Sodium Fluoride (NaF) accumulates in areas of active hydroxyapatite deposition and potentially unstable atherosclerotic plaques. We assessed the presence of atherosclerotic plaques in 50 adult patients with HIV (HIV+) who had undergone two cardiac computed tomography scans to measure coronary artery calcium (CAC) progression. CAC and its progression are predictive of an unfavorable prognosis. Tracer uptake was quantified in six arterial territories: aortic arch, innominate carotid artery, right and left internal carotid arteries, left coronary (anterior descending and circumflex) and right coronary artery. Thirty-one patients showed CAC progression and 19 did not. At least one territory with high NaF uptake was observed in 150 (50%) of 300 arterial territories. High NaF uptake was detected more often in non-calcified than calcified areas (68% vs. 32%), and in patients without than in those with prior CAC progression (68% vs. 32%). There was no correlation between clinical and demographic variables and NaF uptake. In clinically stable HIV+ patients, half of the arterial territories showed a high NaF uptake, often in the absence of macroscopic calcification. NaF uptake at one time point did not correlate with prior progression of CAC. Prospective studies will demonstrate the prognostic significance of high NaF uptake in HIV+ patients.

Emphysema Distribution and Diffusion Capacity Predict Emphysema Progression in Human Immunodeficiency Virus Infection.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and emphysema are common amongst patients with human immunodeficiency virus (HIV). We sought to determine the clinical factors that are associated with emphysema progression in HIV. METHODS: 345 HIV-infected patients enrolled in an outpatient HIV metabolic clinic with ≥2 chest computed tomography scans made up the study cohort. Images were qualitatively scored for emphysema based on percentage involvement of the lung. Emphysema progression was defined as any increase in emphysema score over the study period. Univariate analyses of clinical, respiratory, and laboratory data, as well as multivariable logistic regression models, were performed to determine clinical features significantly associated with emphysema progression. RESULTS: 17.4% of the cohort were emphysema progressors. Emphysema progression was most strongly associated with having a low baseline diffusion capacity of carbon monoxide (DLCO) and having combination centrilobular and paraseptal emphysema distribution. In adjusted models, the odds ratio (OR) for emphysema progression for every 10% increase in DLCO percent predicted was 0.58 (95% confidence interval [CI] 0.41-0.81). The equivalent OR (95% CI) for centrilobular and paraseptal emphysema distribution was 10.60 (2.93-48.98). Together, these variables had an area under the curve (AUC) statistic of 0.85 for predicting emphysema progression. This was an improvement over the performance of spirometry (forced expiratory volume in 1 second to forced vital capacity ratio), which predicted emphysema progression with an AUC of only 0.65. CONCLUSION: Combined paraseptal and centrilobular emphysema distribution and low DLCO could identify HIV patients who may experience emphysema progression.

Lung and Heart Diseases Are Better Predicted by Pack-Years than by Smoking Status or Duration of Smoking Cessation in HIV Patients.

BACKGROUND: The objective of this study was to assess the relationship of pack-years smoking and time since smoking cessation with risk of lung and heart disease. METHODS: We investigated the history of lung and heart disease in 903 HIV-infected patients who had undergone thoracic computed tomography (CT) imaging stratified by smoking history. Multimorbidity lung and heart disease (MLHD) was defined as the presence of ≥ 2 clinical or subclinical lung abnormalities and at least one heart abnormality. RESULTS: Among 903 patients, 23.7% had never smoked, 28.7% were former smokers and 47.6% were current smokers. Spirometry indicated chronic obstructive pulmonary disease in 11.4% of patients and MLHD was present in 53.6%. Age, male sex, greater pack-years smoking history and smoking cessation less than 5 years earlier vs. more than 10 years earlier (OR 2.59, 95% CI 1.27-5.29, p = 0.009) were independently associated with CT detected subclinical lung and heart disease. Pack-years smoking history was more strongly associated with MLHD than smoking status (p<0.001). CONCLUSIONS: MLHD is common even among HIV-infected patients who never smoked and pack- years smoking history is a stronger predictor than current smoking status of MLHD. A detailed pack-years smoking history should be routinely obtained and smoking cessation strategies implemented.

Epicardial adipose tissue and coronary artery calcium predict incident myocardial infarction and death in HIV-infected patients.

BACKGROUND: Epicardial adipose tissue (EAT) and coronary artery calcium (CAC) have been associated with incident coronary artery disease (CAD) and all-cause mortality in the general population. Their prognostic impact in HIV is unknown. METHODS: Observational study of 843 consecutive HIV-infected patients receiving antiretroviral therapy for at least 6 months. Risk stratification was performed with coronary artery calcium (CAC) scoring and EAT screening. Patients were followed for CAD and all-cause mortality for a median of 2.8 years accounting for a total of 2572 patient-year follow-up. RESULTS: Mean patient age was 50 ± 8 years and 69% were men. At baseline EAT was associated with male gender, age, waist circumference, visceral adipose tissue, and lipodystrophy, while CAC score ≥ 100 was associated with male gender, age and total cholesterol. During follow-up 33 patients suffered an event (15 incident myocardial infarctions and 18 deaths); the EAT volume was larger and the CAC score was higher in patients with events (p = 0.038 and p = 0.001 respectively). Multivariable regression analyses demonstrated that the upper tertile of EAT (≥ 93 cc; OR 2.15, 95% CI 1.06 - 4.39, p = 0.034), and CAC score ≥ 100 (OR 3.37, 95% CI 1.49 - 7.60, p = 0.003) were independent predictors of events after adjusting for age and sex. CONCLUSIONS: In this observational cohort of HIV patients, EAT and CAC were independent predictors of hard outcomes after a median follow-up of approximately 3 years.

Predictors of emphysema progression in HIV-positive patients.

INTRODUCTION: The aim of the study was to find factors associated with emphysema progression (EP), assessed on sequential thoracic CT scans, in a large cohort of HIV-positive patients. MATERIALS AND METHODS: This was an observational, prospective study of 448 consecutive HIV-positive patients on antiretroviral therapy who underwent two sequential ECG-gated coronary artery calcium scoring CT scans. Images were reviewed by three radiologists by consensus to assess lung emphysema using a visual semi-quantitative score (0 to 4) for each of six lobes. EP was defined as an increase in emphysema score. Heavy smoking habit was defined as a self-reported number of cigarettes per day smoked greater than 10. Immune reconstitution was defined as the change in CD4 cell count between first CT scan and CD4 nadir and it was divided into tertiles. Progressors and non-progressors were compared using X2-test for categorical variables and T-test of Mann-Whitney U test for continuous variables where appropriate. Factors independently associated with EP were explored using multivariable logistic regression analyses. A p-value <.05 was considered statistically significant. RESULTS: The mean age of the included patients was 47,9±7,7 years, 24,1% of them were females and 39,3% were smokers. The median interval between the two CT scans was 2,4 years (interquartile range 0,69-5,9 years). EP was significantly associated with HIV-infection duration (p=0,056), smoking (p=0,007) and in particular heavy smoking habit (p=0,015) and time interval between the two scans (p=0,021), while the highest tertile of immune reconstitution was borderline in significance (p=0,075). Age and sex were not significantly related to EP and were not included in further analyses. HIV infection duration (OR=1,01; p=0,013), time interval between the two scans (OR=1,51; p=0,032) and heavy smoking habit (OR=3,36; p=0,041) remained independently associated with EP in multivariate analysis. CONCLUSIONS: In this large cohort of HIV positive patients on antiretroviral therapy, HIV infection duration, time between CT scans and continued heavy cigarette smoking were independently associated with EP.

The burden of image based emphysema and bronchiolitis in HIV-infected individuals on antiretroviral therapy.

BACKGROUND: With the widespread use of anti-retroviral therapy (ART), individuals infected with human immune deficiency virus (HIV) are increasingly experiencing morbidity and mortality from respiratory disorders. However, the prevalence or the risk factors associated with emphysema and bronchiolitis are largely unknown. METHODS: Thoracic computed tomography (CT) scans were performed in 1,446 patients infected with HIV who were on ART and who attended a tertiary care metabolic clinic (average age 48 years and 29% females). Detailed history and physical examination including anthropometric measurements were performed. Complete pulmonary function tests were performed in a subset of these patients (n = 364). No subjects were acutely ill with a respiratory condition at the time of CT scanning. FINDINGS: Nearly 50% of the subjects had CT evidence for emphysema, bronchiolitis or both with 13% (n = 195) showing bronchiolitis, 19% (n = 274) showing emphysema and 16% (n = 238) revealing both. These phenotypes were synergistically associated with reduced regular physical activity (p for interaction <.0001). The most significant risk factors for both phenotypes were cigarette smoking, intravenous drug use and peripheral leucocytosis. Together, the area-under-the curve statistics was 0.713 (p = 0.0037) for discriminating those with and without these phenotypes. There were no significant changes in lung volumes or flow rates related to these phenotypes, though the carbon monoxide diffusion capacity was reduced for the emphysema phenotype. INTERPRETATION: Emphysema and bronchiolitis are extremely common in HIV-infected patients who are treated with ART and can be identified by use of thoracic CT scanning.

MR quantitative biomarkers of non-alcoholic fatty liver disease: technical evolutions and future trends.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis as the earliest manifestation and hallmark, and ranges from benign fatty liver to non-alcoholic steatohepatitis (NASH). Liver biopsy (LB) is considered the reference standard for NAFLD diagnosis, grading and characterization, but it is limited by its invasiveness and observer-dependence. Among imaging surrogates for the assessment of hepatic steatosis, MR is the most accurate. (1)H MR spectroscopy (MRS) provides a quantitative biomarker of liver fat content (LFC) called proton density fat fraction (PDFF), but it is time-consuming, not widely available and limited in sample size. Several MR imaging (MRI) techniques, in particular fat suppression and in-opposed phase techniques, have been used to quantify hepatic steatosis, mainly estimating LFC from water and fat signal intensities rather than proton densities. Several technical measures have been introduced to minimize the effect of confounding factors, in particular a low flip angle, a multiecho acquisition and a spectral modeling of fat with multipeak reconstruction to address respectively T1 effect, T2* effect, and the multifrequency interference effects of fat protons, allowing to use MRI to estimate LFC based on PDFF. Tang et al. evaluated MRI-estimated PDFF, obtained by applying the above-mentioned technical improvements, in the assessment of hepatic steatosis, using histopathology as the reference standard. The identification of PDFF thresholds, even though to be further explored and validated in larger and more diverse cohorts, is useful to identify steatosis categories based on MRI-based steatosis percentages. MRI, with the new refined techniques which provide a robust quantitative biomarker of hepatic steatosis (PDFF) evaluated on the whole liver parenchyma, is a promising non-invasive alternative to LB as the gold standard for steatosis diagnosis and quantification.

Parallel increase of subclinical atherosclerosis and epicardial adipose tissue in patients with HIV.

BACKGROUND: Epicardial adipose tissue (EAT) may contribute to the development of coronary atherosclerosis via paracrine secretion of inflammatory cytokines. METHODS: This is a prospective, observational study of 240 consecutive HIV-infected patients receiving antiretroviral therapy. All patients underwent 2 sequential chest computed tomographic scans to assess the change in coronary artery calcium (CAC), a marker of subclinical atherosclerosis, and EAT volume. Patients with known cardiovascular disease were excluded. Factors independently associated with EAT change were explored using multivariable linear regression analyses. The association between EAT increase and CAC progression was explored using logistic regression analyses. RESULTS: Two hundred forty patients were included. Patients' mean age was 47.5 ± 8 years, and 68% were men. The median interval between computed tomographic scans was 18.7 months (interquartile range 10-27 months). Men showed a larger increase in EAT (5 ± 14.2 cm(3)) than did women (-0.45 ± 8.8 cm(3), P = .007). Factors independently associated with change in EAT were CD4(+) recovery (ß = 0.43, CI 0.05-0.82) and male gender (ß = 5.65, CI, 1.05-10.26). Change in EAT was independently associated with CAC progression (odds ratio 1.04, 95% CI 1.004-1.88, P = .030) after adjusting for traditional cardiovascular risk factors. CONCLUSIONS: In this cohort of patients with HIV receiving antiretroviral therapy, male gender and CD4(+) were independent predictors of EAT increase, and there was a parallel progression of CAC and EAT. Abnormal immunoreactivity associated with T-lymphocyte recovery should be further studied as a determinant of atherosclerosis progression in HIV-infected patients.

Ectopic fat is linked to prior cardiovascular events in men with HIV.

Epicardial Adipose Tissue (EAT) has been associated with adverse cardiovascular events in the general population. We studied the association of general adiposity measures (body mass index, waist circumference) and ectopic adipose tissue [visceral adipose tissue (VAT); liver fat (LF); EAT) with prevalent cardiovascular disease (CVD) (prior myocardial infarction, coronary revascularization, stroke, peripheral vascular disease] in 583 HIV-infected men. VAT, EAT, and LF (liver/spleen attenuation ratio < 1.1) were measured by computed tomography. Patients' mean age was 48.5 ± 8.1 years, prior CVD was present in 33 (5.7%) patients. Factors independently associated with CVD on multivariable analyses were age [incidence-rate ratio (IRR) = 1.07, 95% confidence interval (CI): 1.02 to 1.12], smoking (IRR = 2.70, 95% CI: 1.22 to 6.01), Center for Disease Control group C (IRR = 3.09, 95% CI: 1.41 to 6.76), EAT (IRR = 1.13, 95% CI: 1.04 to 1.24, per 10 cm), LF (IRR = 1.17, 95% CI: 1.04 to 1.32), and VAT (IRR = 1.05, 95% CI: 1.00 to 1.10, per 10 cm). Ectopic fat but not general adiposity measures were associated with prevalent CVD in men with HIV.

Epicardial adipose tissue is an independent marker of cardiovascular risk in HIV-infected patients.

BACKGROUND: Epicardial adipose tissue (EAT) is increased in HIV-infected patients. The aim of this study was to evaluate the association between EAT and coronary artery calcium (CAC) a marker of atherosclerosis; furthermore, we investigated the association of EAT with HIV infection, antiretroviral therapy (ART), and lipodystrophy. METHODS: This was a cross-sectional study of 876 consecutive HIV-infected ART experienced patients. Patients underwent CAC imaging with multidetector computed tomography (CT) for atherosclerosis screening and risk of cardiovascular events (CAC score >100); EAT was measured in the same CT images. Factors independently associated with EAT were explored in a multivariable backward stepwise linear regression analysis. Multivariable logistic regression was used to evaluate the association of EAT and CAC score greater than 100. RESULTS: Patients' mean age was 47.2 ± 8 years, 68% were men. EAT was associated with central fat accumulation and mixed lipodystrophy phenotypes. Factors independently associated with EAT were: age [ß = 0.6, confidence interval (CI) 0.2-1.0], male sex (ß = 6.6, CI 0.5-12.7), visceral adipose tissue (ß = 0.12, CI 0.08-0.17), waist circumference (ß = 0.7, CI 0.04-1.3), current CD4⁺ (ß = 0.6, CI 0.1-1.2, per 50 cells), total cholesterol (ß = 0.1, CI 0.02-0.15), and cumulative exposure to ART (months) (ß = 0.05, CI 0.00-0.11). EAT (per 10 cm³) was associated with CAC greater than 100 (odds ratio = 1.10, CI 1.02-1.19) after adjustment for age, male sex, and diabetes. CONCLUSION: We showed an association between EAT and central fat accumulation and mixed form lipodystrophy phenotypes as well as traditional risk factors for atherosclerosis. EAT may be a useful marker of cardiovascular risk as shown by its association with CAC greater than 100.