Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with ⩾10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-κB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-κB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure.

Background: People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH. Methods: We performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Cross-sectional associations with HIV and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression. Results: Among 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m 2 . Of 2594 analyzed proteins, 439 were associated with HIV serostatus, independent of demographics, hepatitis C virus infection, renal function, and substance use (FDR<0.05). We identified 73 of these proteins as candidate contributors to the independent association between positive HIV serostatus and higher LAVi, enriched in tumor necrosis factor (TNF) signaling and immune checkpoint proteins regulating T cell, B cell, and NK cell activation. We identified one protein cluster associated with LAVi and HIV regardless of HIV viral suppression status, which comprised 42 proteins enriched in TNF signaling, ephrin signaling, and extracellular matrix (ECM) organization. This protein cluster and 30 of 73 individual proteins were associated with incident HF among 2273 older PWOH (age 68±9 years; 52% female; 8.5±1.4 years of follow-up). Conclusion: Proteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.

IgE to common food allergens is associated with cardiovascular mortality in the National Health and Examination Survey and the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: In individuals without symptomatic food allergy, food-specific IgE is considered clinically irrelevant. However, recent studies have suggested that galactose-α-1,3-galactose (alpha-gal) IgE is associated with cardiovascular (CV) disease. OBJECTIVE: We sought to determine whether sensitization to common food allergens is associated with CV mortality. METHODS: The association between IgE sensitization to foods and CV mortality ascertained to 2019 was examined in the National Health and Examination Survey (NHANES) 2005-2006 and the Wake Forest site of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort; MESA enrolled adults without baseline clinical CV diseases between 2000 and 2002. Total and specific IgE was measured to cow's milk, egg, peanut, shrimp, and a panel of aeroallergens (NHANES), and to cow's milk, alpha-gal, peanut, dust mite, and timothy grass (MESA). Cox proportional hazard models were constructed, adjusting for sex, age, race/ethnicity, smoking, education, and asthma. RESULTS: A total of 4414 adults from NHANES (229 CV deaths) and 960 from MESA (56 CV deaths) were included. In NHANES, sensitization to at least 1 food was associated with higher CV mortality (hazard ratio [HR], 1.7 [95% confidence interval (CI), 1.2-2.4], P = .005). Milk sensitization was particularly associated (HR, 2.0 [95% CI, 1.1-3.8], P = .026), a finding replicated in MESA (HR, 3.8 [95% CI, 1.6-9.1], P = .003). Restricting analyses in NHANES to consumers of the relevant allergen strengthened food sensitization relationships, unmasking shrimp and peanut sensitization as additional risk factors for CV mortality. CONCLUSIONS: The finding that food sensitization is associated with increased risk of CV mortality challenges the current paradigm that sensitization without overt allergy is benign. Further research is needed to clarify mechanisms of this association.

Prevalence of Subclinical Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with poorer clinical outcomes. The prevalence of subclinical AF in patients with HFpEF remains unknown. OBJECTIVES: The aim of this study was to determine whether subclinical AF was more prevalent in individuals with HFpEF than in individuals without histories of heart failure (HF). METHODS: Patients with HFpEF with no prior diagnoses of AF were screened for subclinical AF, and the prevalence of subclinical AF was compared with that among control subjects without HF drawn from MESA (Multi-Ethnic Study of Atherosclerosis) who underwent the same electrocardiographic monitoring. Multivariable logistic regression was used to adjust for demographic and clinical comorbidities. RESULTS: Ninety patients with HFpEF and 1,230 MESA participants were included. Patients with HFpEF were younger (median age 69 years [Q1-Q3: 63-76 years] vs 72 years [Q1-Q3: 66-80 years]; P = 0.02), more obese (median body mass index 36 kg/m2 [Q1-Q3: 30-45 kg/m2] vs 27 kg/m2 [Q1-Q3: 24-30 kg/m2]; P < 0.001), and more likely to have diabetes (34% vs 21%; P = 0.01). The prevalence of subclinical AF was 8.9% in patients with HFpEF and 4.1% in non-HF participants. After multivariable adjustment for age, sex, race, body mass index, diabetes, smoking, and total analyzable time on electrocardiographic monitor, there was a significantly higher odds of subclinical AF in patients with HFpEF compared with MESA (OR: 3.01; 95% CI: 1.13-7.99; P = 0.03). CONCLUSIONS: Patients with HFpEF had a higher prevalence of subclinical AF than participants without HF from a community-based study. Screening for atrial arrhythmias may be appropriate among patients with HFpEF for timely initiation of thromboembolic prophylaxis and may identify individuals at greater risk for clinical decompensation.

CT-derived pectoralis composition and incident pneumonia hospitalization using fully automated deep-learning algorithm: multi-ethnic study of atherosclerosis.

BACKGROUND: Pneumonia-related hospitalization may be associated with advanced skeletal muscle loss due to aging (i.e., sarcopenia) or chronic illnesses (i.e., cachexia). Early detection of muscle loss may now be feasible using deep-learning algorithms applied on conventional chest CT. OBJECTIVES: To implement a fully automated deep-learning algorithm for pectoralis muscle measures from conventional chest CT and investigate longitudinal associations between these measures and incident pneumonia hospitalization according to Chronic Obstructive Pulmonary Disease (COPD) status. MATERIALS AND METHODS: This analysis from the Multi-Ethnic Study of Atherosclerosis included participants with available chest CT examinations between 2010 and 2012. We implemented pectoralis muscle composition measures from a fully automated deep-learning algorithm (Mask R-CNN, built on the Faster Region Proposal Network (R-) Convolutional Neural Network (CNN) with an extension for mask identification) for two-dimensional segmentation. Associations between CT-derived measures and incident pneumonia hospitalizations were evaluated using Cox proportional hazards models adjusted for multiple confounders which include but are not limited to age, sex, race, smoking, BMI, physical activity, and forced-expiratory-volume-at-1 s-to-functional-vital-capacity ratio. Stratification analyses were conducted based on baseline COPD status. RESULTS: This study included 2595 participants (51% female; median age: 68 (IQR: 61, 76)) CT examinations for whom we implemented deep learning-derived measures for longitudinal analyses. Eighty-six incident pneumonia hospitalizations occurred during a median 6.67-year follow-up. Overall, pectoralis muscle composition measures did not predict incident pneumonia. However, in fully-adjusted models, only among participants with COPD (N = 507), CT measures like extramyocellular fat index (hazard ratio: 1.98, 95% CI: 1.22, 3.21, p value: 0.02), were independently associated with incident pneumonia. CONCLUSION: Reliable deep learning-derived pectoralis muscle measures could predict incident pneumonia hospitalization only among participants with known COPD. CLINICAL RELEVANCE STATEMENT: Pectoralis muscle measures obtainable at zero additional cost or radiation exposure from any chest CT may have independent predictive value for clinical outcomes in chronic obstructive pulmonary disease patients. KEY POINTS: •Identification of independent and modifiable risk factors of pneumonia can have important clinical impact on patients with chronic obstructive pulmonary disease. •Opportunistic CT measures of adipose tissue within pectoralis muscles using deep-learning algorithms can be quickly obtainable at zero additional cost or radiation exposure. •Deep learning-derived pectoralis muscle measurements of intermuscular fat and its subcomponents are independently associated with subsequent incident pneumonia hospitalization.

Predictive Value of Deep Learning-derived CT Pectoralis Muscle and Adipose Measurements for Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis.

Purpose: To develop a deep learning algorithm capable of extracting pectoralis muscle and adipose measurements and to longitudinally investigate associations between these measurements and incident heart failure (HF) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Materials and Methods: MESA is a prospective study of subclinical cardiovascular disease characteristics and risk factors for progression to clinically overt disease approved by institutional review boards of six participating centers (ClinicalTrials.gov identifier: NCT00005487). All participants with adequate imaging and clinical data from the fifth examination of MESA were included in this study. Hence, in this secondary analysis, manual segmentations of 600 chest CT examinations (between the years 2010 and 2012) were used to train and validate a convolutional neural network, which subsequently extracted pectoralis muscle and adipose (intermuscular adipose tissue (IMAT), perimuscular adipose tissue (PAT), extramyocellular lipids and subcutaneous adipose tissue) area measurements from 3031 CT examinations using individualized thresholds for adipose segmentation. Next, 1781 participants without baseline HF were longitudinally investigated for associations between baseline pectoralis muscle and adipose measurements and incident HF using crude and adjusted Cox proportional hazards models. The full models were adjusted for variables in categories of demographic (age, race, sex, income), clinical/laboratory (including physical activity, BMI, and smoking), CT (coronary artery calcium score), and cardiac MRI (left ventricular ejection fraction and mass (% of predicted)) data. Results: In 1781 participants (median age, 68 (IQR,61, 75) years; 907 [51%] females), 41 incident HF events occurred over a median 6.5-year follow-up. IMAT predicted incident HF in unadjusted (hazard ratio [HR]:1.14; 95% CI: 1.03-1.26) and fully adjusted (HR:1.16, 95% CI: 1.03-1.31) models. PAT also predicted incident HF in crude (HR:1.19; 95% CI: 1.06-1.35) and fully adjusted (HR:1.25; 95% CI: 1.07-1.46) models. Conclusion: The study demonstrates that fast and reliable deep learning-derived pectoralis muscle and adipose measurements are obtainable from conventional chest CT, which may be predictive of incident HF.©RSNA, 2023.

Plasma Glycomic Markers of Accelerated Biological Aging During Chronic HIV Infection.

People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.

Oxidative Stress and Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Introduction-Oxidative stress is linked to cardiovascular diseases (CVD) and is suggested to vary by sex. However, few population-level studies have explored these associations and the majority comprise populations with advanced CVD. We assessed urinary isoprostane concentrations, a standard measure of oxidative stress, in a relatively young and healthy cohort, hypothesizing that higher oxidative stress is associated with an adverse cardiometabolic profile and female sex. Methods-Oxidative stress was measured in 475 women and 266 men, aged 48-55 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study using urinary 8-isoprostane (IsoP) and 2,3-dinor-8-isoprostane (IsoP-M). Multivariable-adjusted regression was used to evaluate cross-sectional associations. As secondary analysis, previously measured plasma F2-isoprostanes (plasma IsoP) from another CARDIA subset was similarly analyzed. Results-Mean (SD) ages for men and women were 52.1(2.3) and 52.2(2.2) years, respectively (p = 0.46), and 39% of the participants self-identified as Black (vs. White). Before adjustments, female sex was associated with higher median urinary IsoP (880 vs. 704 ng/g creatinine in men; p < 0.01) and IsoP m (1675 vs. 1284 ng/g creatinine in men; p < 0.01). Higher body mass index (BMI), high-density cholesterol (HDL-C), and triglycerides, current smoking, and less physical activity were associated with higher oxidative stress. Diabetes was not associated with urinary IsoP but was associated with lower IsoP m and plasma IsoP. Higher serum creatinine showed diverging associations with higher plasma and lower urinary isoprostane concentrations. Conclusions-Different isoprostane entities exhibit varying association patterns with CVD risk factors, and therefore are complementary, rather than interchangeable, in assessment of oxidative stress. Still, consistently higher isoprostanes among women, smokers, less active persons, and those with higher BMI and plasma triglycerides could reflect higher oxidative stress among these groups. While urinary isoprostanes are indexed to urinary creatinine due to variations in concentration, caution should be exercised when comparing groups with differing serum creatinine.

Cardiovascular health trajectories and subsequent cardiovascular disease and mortality: The multi-ethnic study of atherosclerosis (MESA).

Objective: Longitudinal trajectories of cardiovascular health (CVH) may reflect vascular risk burden due to prolonged cumulative exposure to non-ideal CVH levels. Identifying individuals who have a higher risk CVH trajectory may facilitate treatment, screening, and prevention. We aimed to characterize 10-year trajectories of CVH and examine the associations between CVH trajectories and subsequent cardiovascular disease (CVD) and mortality. Methods: We analyzed 3674 MESA participants who completed four exams and remained CVD-free from 2000 to 2011. A 12-point CVH score was calculated based on physical activity, smoking status, body mass index, cholesterol, blood pressure, and glucose. Ideal CVH was defined as a score ≥ 9. Group-based trajectory modeling was used to identify trajectories of ideal CVH. Cox models were used to examine the association of CVH trajectories with incident CVD and death from 2011 to 2018, adjusting for age, sex, race/ethnicity, income, education, and marital status. Results: Three trajectories were identified based on the probability of achieving ideal CVH: high (n = 1251), medium (n = 760), and persistently low (n = 1663). Almost half (45.3%) of the participants had a persistently low trajectory. During a median of 7.7 years follow-up, 392 incident CVD events and 459 deaths occurred. Compared with the high CVH group, participants in the persistently low CVH trajectory group had elevated risks for CVD (adjusted hazard ratios 1.49, 95% confidence interval 1.15-1.93) and mortality (1.34, 1.06-1.70), and participants in the medium group had moderate risks for CVD (1.17, 0.86-1.59) and mortality (1.15, 0.87-1.53) (p-value for trend 0.002 for CVD, 0.014 for mortality). Conclusion: Persistently nonideal CVH is a common trajectory. Targeted prevention programs might benefit individuals with persistently nonideal CVH given their elevated risk of subsequent CVD and mortality.

The association between aging-related monocyte transcriptional networks and comorbidity burden: the Multi-Ethnic Study of Atherosclerosis (MESA).

Translating our knowledge of the biological aging from animal models to humans may give rise to novel approaches of targeting multiple aging-related diseases simultaneously and increasing health span. Here, for the first time, we use transcriptomic signatures of monocytes to identify biological aging pathways underlying multiple aging-related diseases in humans. The ordinal logistic regression was used to cross-sectionally investigate transcriptomics of the comorbidity index in 1264 community-based Multi-Ethnic Study of Atherosclerosis (MESA) adults, 47% Caucasian, 32% Hispanic, 21% African American, and 51% female, aged 55-94 years. The comorbidity index was defined as the number of prevalent aging-related diseases including cardiovascular disease, type-2 diabetes, hypertension, cancer, dementia, chronic kidney disease, chronic obstructive pulmonary disease, and hip fracture. We identified 708 gene transcripts associated with the comorbidity index (FDR < 0.05) after adjusting for age, sex, ethnicity, and study site. In a weighted gene co-expression network analysis, as postulated, aging-related declines in apoptosis/autophagy (OR = 1.21 per SD increment, p = 0.0006) and ribosome/mitochondrion (OR = 0.90 per SD increment, p = 0.05) were positively associated with the comorbidity index. After adjusting for multiple comparisons, we identified 10 comorbidity-associated modules (FDR < 0.05), including the module of apoptosis/autophagy. There were three inter-correlated modules of these 10 involved in the complement subcomponent C1q, Fc gamma receptor I, and Fc gamma receptor III of the immune system, respectively. Aging-related upregulation of these three modules was positively associated with the comorbidity index. The odds of comorbidity increased with more of these modules acting together in a dose-response fashion. In conclusion, transcriptomic analysis of human immune cells may identify biomarker panels indicative of comprehensive biological mechanisms, especially immune signaling pathways, contributing to health aging.

"Living like an empty gas tank with a leak": Mixed methods study on post-acute sequelae of COVID-19.

BACKGROUND: The burden and presentation of post-acute sequela of SARS-CoV-2 infection (PASC) are a developing major public health concern. OBJECTIVES: To characterize the burden of PASC in community-dwelling individuals and understand the experiences of people living with PASC. METHODS: This mixed-methods study of COVID-19 positive community-dwelling persons involved surveys and in-depth interviews. Main outcome was self-report of possible PASC symptoms 3 weeks or longer after positive COVID-19 test. In-depth interviews were guided by a semi-structured interview guide with open-ended questions and probes based on emerging literature on PASC and the impact of COVID-19. RESULTS: With a survey response rate of 70%, 442 participants were included in this analysis, mean (SD) age 45.4 (16.2) years, 71% female, 12% Black/African American. Compared to those with no PASC symptoms, persons who reported PASC symptoms were more likely to be older (mean age: 46.5 vs. 42; p = 0.013), female (74.3% vs. 61.2%; p = 0.010), to have pre-existing conditions (49.6% vs. 34%; p = 0.005), and to have been hospitalized for COVID-19 (14.2% vs. 2.9%; p = 0.002). About 30% of the participants experienced severe fatigue; the proportion of persons reporting severe fatigue was 7-fold greater in those with PASC symptoms (Adjusted Prevalence Ratio [aPR] 6.73, 95%CI: 2.80-16.18). Persons with PASC symptoms were more likely to report poor quality of life (16% vs. 5%, p<0.001) and worse mental health functioning (Mean difference: -1.87 95%CI: -2.38, -1.37, p<0.001). Themes from in-depth interviews revealed PASC was experienced as debilitating. CONCLUSIONS: In this study, the prevalence of PASC among community-dwelling adults was substantial. Participants reported considerable coping difficulties, restrictions in everyday activities, invisibility of symptoms and experiences, and impediments to getting and receiving PASC care.

Association of HIV infection with clinical features and outcomes of patients with aortic aneurysms.

Data on the characteristics and outcomes of hospitalized patients with aortic aneurysms (AA) and HIV remain scarce. This is a cohort study of hospitalized adult patients with a diagnosis of AA from 2013 to 2019 using the US National Inpatient Readmission Database. Patients with a diagnosis of HIV were identified. Our outcomes included trends in hospitalizations and comparison of clinical characteristics, complications, and mortality in patients with AA and HIV compared to those without HIV. Among 1,905,837 hospitalized patients with AA, 4416 (0.23%) were living with HIV. There was an overall age-adjusted increase in the rate of HIV among patients hospitalized with AA over the years (14-29 per 10,000 person-years; age-adjusted p-trend < 0.001). Patients with AA and HIV were younger than those without HIV (median age: 60 vs 76 years, p < 0.001) and were less likely to have a history of smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Thoracic aortic aneurysms were more prevalent in those with HIV (37.5% vs 26.7%, p < 0.001). On multivariable logistic regression, HIV was not associated with increased risk of aortic rupture (OR: 0.79; 95% CI: 0.61-1.01, p = 0.06), acute aortic dissection (OR: 0.73; 95% CI: 0.51-1.06, p = 0.3), readmissions (OR: 1.04; 95% CI: 0.95-1.13, p = 0.4), or aortic repair (OR: 0.89; 95% CI: 0.79-1.00, p = 0.05). Hospitalized patients with AA and HIV had a lower crude mortality rate compared to those without HIV (OR: 0.75 (0.63-0.91), p = 0.003). Hospitalized patients with AA and HIV likely constitute a distinct group of patients with AA; they are younger, have fewer traditional cardiovascular risk factors, and a higher rate of thoracic aorta involvement. Differences in clinical features may account for the lower mortality rate observed in patients with AA and HIV compared to those without HIV.

Circulating biomarker correlates of left atrial size and myocardial extracellular volume fraction among persons living with and without HIV.

BACKGROUND: Infection with human immunodeficiency virus (HIV) is associated with higher risk for myocardial disease despite modern combination antiretroviral therapy (cART). Factors contributing to this excess risk, however, remain poorly characterized. We aimed to assess cross-sectional relationships between elevations of left atrial volume index (LAVI) and myocardial extracellular volume (ECV) fraction that have been reported in persons living with HIV and levels of circulating biomarkers of inflammation, fibrosis, and myocyte stretch among persons living with and without HIV (PLWH, PLWOH). METHODS: Participants from three cohorts of PLWH and PLWOH underwent cardiovascular magnetic resonance imaging for measurement of LAVI and ECV. Levels of circulating proteins (IL-6, sCD14, galectin-3, NT-proBNP, GDF-15, TIMP-2, MMP-2, and hsTnI) were measured using immunoassays. Associations were assessed using logistic and linear regression, adjusting for demographics, substance use, and clinical characteristics. RESULTS: Among 381 participants with and without HIV, median age (IQR) was 55.1 (51.2, 58.4) years, 28% were female, 69% were Black, and 46% were current smokers. Sixty-two percent were PLWH (n = 235), of whom 88% were receiving cART and 72% were virally suppressed. PLWH had higher levels of sCD14 (p = < 0.001), GDF-15 (p = < 0.001), and NT-proBNP (p = 0.03) compared to PLWOH, while levels of other biomarkers did not differ by HIV serostatus, including IL-6 (p = 0.84). Among PLWH, higher sCD14, GDF-15, and NT-proBNP were also associated with lower CD4 + cell count, and higher NT-proBNP was associated with detectable HIV viral load. NT-proBNP was associated with elevated LAVI (OR: 1.79 [95% CI: 1.31, 2.44]; p < 0.001) with no evidence of effect measure modification by HIV serostatus. Other associations between HIV-associated biomarkers and LAVI or ECV were small or imprecise. CONCLUSIONS: Our findings suggest that elevated levels of sCD14, GDF-15, and NT-proBNP among PLWH compared to PLWOH observed in the current cART era may only minimally reflect HIV-associated elevations in LAVI and ECV. Future studies of excess risk of myocardial disease among contemporary cohorts of PLWH should investigate mechanisms other than those connoted by the studied biomarkers.

Higher Soluble CD163 in Blood Is Associated With Significant Depression Symptoms in Men With HIV.

BACKGROUND: People with HIV (PWH) are more likely to experience depression, a highly morbid disease. More evidence is needed to better understand mechanisms of depression in PWH. We evaluated a panel of blood biomarkers in relation to depression symptoms in the Multicenter AIDS Cohort Study (MACS). SETTING: Four sites in the United States. METHODS: A cross-sectional analysis was performed within the MACS, a prospective study of cisgender men with and without HIV. Depression was assessed with the Center for Epidemiological Studies-Depression Scale, and six blood biomarkers were measured: GlycA, high sensitivity C-reactive protein (CRP), interleukin-6, CCL2, soluble CD14 (sCD14), and soluble CD163 (sCD163). Using univariable and multivariable logistic regression, the biomarkers and other factors were evaluated in relation to significant depression symptoms (SDS) by Center for Epidemiological Studies-Depression score ≥16. RESULTS: 784 men were analyzed; most of whom (63%) were PWH. PWH were more likely to have SDS (32% vs. 21%). In univariable analysis, higher GlycA, CRP, and sCD163 concentrations were associated with SDS. In multivariable analysis, however, only higher sCD163 concentration was associated with SDS (odds ratio = 2.30, 95% CI = 1.11 to 4.76). This relationship was driven by the PWH group (odds ratio = 2.72, 95% CI = 1.12 to 6.58) and remained significant when controlling for antidepressant use. Lack of college education was also associated with SDS. CONCLUSIONS: Higher sCD163, a marker of macrophage activation, was significantly associated with significant depression symptoms in the MACS. Further research on this biomarker and macrophage activation in general is warranted to better understand and treat depression in PWH.

Oxidative Stress and Menopausal Status: The Coronary Artery Risk Development in Young Adults Cohort Study.

Background: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. Methods and Results: We examined differences in urinary 8-isoprostane (iPF2α-III) and 2,3-dinor-8-isoprostane (iPF2α-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF2α-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF2α-III-M (95% confidence interval [6.5-47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9-42.6]) and then CVD risk factors (18.8% [0.1-39.6]) led to additional partial attenuation. Menopause was associated with higher iPF2α-III in Black but not White women. Conclusions: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.

Clonal hematopoiesis in men living with HIV and association with subclinical atherosclerosis.

OBJECTIVES: People with HIV (PWH) are at increased risk for premature cardiovascular disease (CVD). Clonal hematopoiesis is a common age-related condition that may be associated with increased CVD risk. The goal of this study was to determine the prevalence of clonal hematopoiesis and its association with chronic inflammation and CVD in PWH. DESIGN: Cross-sectional study utilizing archived specimens and data from 118 men (86 PWH and 32 HIV-uninfected) from the Baltimore-Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary computed tomography angiography (CTA) and measurement of 34 serologic inflammatory biomarkers. METHODS: Clonal hematopoiesis was assessed on peripheral blood mononuclear cells utilizing targeted error-corrected next generation sequencing (NGS) focused on 92 genes frequently mutated in hematologic malignancies. Clinical and laboratory data were obtained from the MACS database. RESULTS: Clonal hematopoiesis with a variant allele frequency (VAF) greater than 1% was significantly more common in PWH [20/86 (23.3%)] than in HIV-uninfected men [2/32 (6.3%)] ( P  = 0.035). PWH with clonal hematopoiesis (VAF > 1%) were more likely to have coronary artery stenosis of at least 50% than those without clonal hematopoiesis [6/20 (30%) vs. 6/64 (9%); P  = 0.021]. Presence of clonal hematopoiesis was not significantly associated with serological inflammatory markers, except for significantly lower serum leptin levels; this was not significant after adjustment for abdominal or thigh subcutaneous fat area. CONCLUSION: Clonal hematopoiesis was more common in PWH and among PWH was associated with the extent of coronary artery disease. Larger studies are needed to further examine the biological and clinical consequences of clonal hematopoiesis in PWH.

A Safe Home? A Qualitative Study into the Experiences of Adolescents Growing Up in the Dutch Area Impacted by Earthquakes Induced by Gas Extraction.

For decades, the Netherlands has experienced minor earthquakes due to gas extraction. This study aims to obtain insight into the experiences of adolescents and the impact of these earthquakes on their well-being and living environment. Focus groups were held with 24 adolescents, and interviews were held with 3 adolescents (N = 27; M = 15 years). Through qualitative analysis, we identified six themes. The adolescents shared experiences of anxiety related to the earthquakes and their consequences and considered these to be a normal part of their life. Anxiety and feelings of endangerment not only related to their own experiences but were also connected to the impact of earthquakes on their social environment, such as the restoration of buildings. Several sources of support (e.g., talking, social cohesion) were mentioned to deal with the negative consequences of the earthquakes. A lack of trust in the government was an additional main theme, with adolescents mentioning several needs, potentially relevant to policymakers in the Netherlands. Growing up in the gas extraction area of Groningen had many consequences on the adolescents in the study, who felt inhibited from expressing feelings of anxiety and fear. To support their needs, interventions at the individual, family, educational, societal, and policy levels are recommended.

Association of HIV Serostatus and Inflammation With Ascending Aortic Size.

Background The prevalence and extent of subclinical large vessel vasculopathy is not well defined among people living with HIV. We aimed to evaluate associations between aortic root and ascending aortic sizes measured by 2-dimensional transthoracic echocardiography and HIV serostatus, and to identify risk factors for larger aortic sizes among men with HIV, including levels of circulating inflammatory markers. Methods and Results Using clinical and echocardiographic data from the MACS (Multicenter AIDS Cohort Study), adjusted multivariable linear and logistic regression was performed. Four segments of the proximal aorta were measured: aortic annulus, aortic root at the sinuses of Valsalva, sinotubular junction, and ascending aorta. HIV infection was associated with significantly larger aortic root (0.03 cm [95% CI, 0.002-0.06 cm]) and ascending aorta (0.04 cm [95% CI, 0.01-0.06 cm]) diameters. Higher standardized nadir CD4 (cluster of differentiation 4) T-cell count was significantly associated with smaller aortic root (-0.03 cm [95% CI, -0.05 to -0.01 cm]), sinotubular junction (-0.03 cm [95% CI, -0.05 to -0.01 cm]), and ascending aorta (-0.03 cm [95% CI, -0.05 to -0.004 cm]) diameters. Higher levels of standardized TNF-α (tumor necrosis factor-α) were associated with larger diameters of the aortic annulus (0.02 cm [95% CI, 0.003-0.04 cm]) and sinotubular junction (0.02 cm [95% CI, 0.002-0.04 cm]). There were no other cardiovascular or HIV disease severity-related risk factors associated with the aortic dimensions. Conclusions HIV infection is an independent risk factor for greater ascending aortic sizes. Lower nadir CD4 T-cell count and higher TNF-α levels are associated with larger aortic sizes in men with HIV. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00046280.

Association of Brain Volumes and White Matter Injury With Race, Ethnicity, and Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis.

Background Cardiovascular risk factors are associated with cognitive decline and dementia. Magnetic resonance imaging provides sensitive measurement of brain morphology and vascular brain injury. However, associations of risk factors with brain magnetic resonance imaging findings have largely been studied in White participants. We investigated associations of race, ethnicity, and cardiovascular risk factors with brain morphology and white matter (WM) injury in a diverse population. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, measures were made in 2018 to 2019 of total brain volume, gray matter and WM volume, and WM injury, including WM hyperintensity volume and WM fractional anisotropy. We assessed cross-sectional associations of race and ethnicity and of cardiovascular risk factors with magnetic resonance imaging measures. Magnetic resonance imaging data were complete in 1036 participants; 25% Black, 15% Chinese-American, 19% Hispanic, and 41% White. Mean (SD) age was 72 (8) years and 53% were women. Although WM injury was greater in Black than in White participants in a minimally adjusted model, additional adjustment for cardiovascular risk factors and socioeconomic status each attenuated this association, rendering it nonsignificant. Overall, greater average WM hyperintensity volume was associated with older age and current smoking (69% greater vs never smoking); lower fractional anisotropy was additionally associated with higher diastolic blood pressure, use of antihypertensive medication, and diabetes. Conclusions We found no statistically significant difference in measures of WM injury by race and ethnicity after adjustment for cardiovascular risk factors and socioeconomic status. In all racial and ethnic groups, older age, current smoking, hypertension, and diabetes were strongly associated with WM injury.

Hypertension and Socioeconomic Status in South Central Uganda: A Population-Based Cohort Study.

Background: Limited studies exploring the impact of socioeconomic status (SES) on hypertension in Africa suggest a positive association between higher SES and hypertension. The economic development in sub-Saharan African countries has led to changes in SES and associated changes in lifestyle, diet, and physical activity, which may affect the relationship between hypertension and SES differently compared with higher income countries. This cross-sectional study from a large population-based cohort, the Rakai Community Cohort Study (RCCS), examines SES, hypertension prevalence, and associated risk factors in the rural Rakai Region in south-central Uganda. Methods: Adults aged 30-49 years residing in 41 RCCS fishing, trading, and agrarian communities, were surveyed with biometric data obtained between 2016 and 2018. The primary outcome was hypertension (systolic blood pressure (BP) ≥ 130 mmHg or diastolic BP ≥ 80 mmHg). Modified Poisson regression assessed the adjusted prevalence ratios (PR) of hypertension associated with SES; body mass index (BMI) was explored as a potential mediator. Results: Among 9,654 adults, 20.8% had hypertension (males 21.2%; females 20.4 %). Participants with hypertension were older (39.0 ± 6.0 vs. 37.8 ± 5.0; p < 0.001). Higher SES was associated with overweight or obese BMI categories (p < 0.001). In the multivariable model, hypertension was associated with the highest SES category (aPR 1.23; confidence interval 1.09-1.38; p = 0.001), older age, male sex, alcohol use, and living in fishing communities and inversely associated with smoking and positive HIV serostatus. When BMI was included in the model, there was no association between SES and hypertension (aPR 1.02; CI 0.90-1.15, p = 0.76). Conclusion: Hypertension is common in rural Uganda among individuals with higher SES and appears to be mediated by BMI. Targeted interventions could focus on lifestyle modification among highest-risk groups to optimize public health impact. Key Messages: What is already known about this subject? Hypertension is an important modifiable risk factor for cardiovascular disease.There are few large epidemiological studies that investigate the relationship between hypertension and socioeconomic status in low-income countries. What are the new findings? Hypertension is common among adults in rural South-Central Uganda, particularly among those with higher socioeconomic status.BMI is a mediator of the relationship between hypertension and socioeconomic status. How might it impact on clinical practice in the foreseeable future? These findings suggest that public health interventions and community efforts to prevent chronic cardiovascular disease and hypertension should focus on lifestyle modification by elucidating obesity risk perception and health risk awareness, particularly among those of higher socioeconomic status.