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BackgroundUrinary isoprostanes are markers of systemic oxidative stress, which is implicated in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Coronary artery calcium (CAC), thoracic aortic calcium (TAC) and carotid plaque are measure subclinical atherosclerosis and prognosticate ASCVD risk. We examined the associations between urinary isoprostane levels and measures of plaque prevalence, burden, incidence and progression across three vascular beds in a cohort from the Multi-Ethnic Study of Atherosclerosis.MethodsUrinary levels of 8-isoprostane and 2,3-dinor-8-F2-isoprostane were measured in 1089 participants (mean±SD 62±8 years, 48% women) at baseline. Participants underwent computed tomography for CAC and TAC, and duplex ultrasound for carotid plaque. TAC and CAC were reassessed at 2.4 and 10 years, respectively. Regression models were adjusted for CVD risk factors.ResultsIn adjusted models, there were no significant associations between isoprostane levels with CAC prevalence or progression. Highest versus lowest tertile of 8-isoprostane was associated with 28% lower prevalence of descending TAC at baseline [prevalence ratio (PR) 0.72 95% CI (0.56, 0.94)], while 1-SD higher 2,3-dinor-8-F2-isoprostane was associated with 96% higher incident ascending TAC at follow-up [Relative Risk 1.96 (1.24, 3.09)]. Highest versus lowest tertile of isoprostane measures were associated with 22% higher prevalence of carotid plaque [(PR 1.22 (1.04, 1.45)] and 14% difference [3,26] in greater extent of carotid plaque at baseline.ConclusionsHigher urinary isoprostanes were inconsistently associated with some measures of subclinical atherosclerosis by imaging. This suggests a limited role of urinary isoprostane levels as a prognostic marker for the development of ASCVD.Trial registrationThe MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

To summarize the state-of-the-art literature on the epidemiology, disease progression, and mediators of heart failure, tachyarrhythmias, and sudden cardiac death in people living with HIV (PLWH) to inform prevention strategies.Recent studies corroborate the role of HIV as a risk enhancer for heart failure and arrhythmias, which persists despite adjustment for cardiovascular risk factors and unhealthy behaviors. Immune activation and inflammation contribute to the risk. Heart failure occurs more frequently at younger ages, and among women and ethnic minorities living with HIV, highlighting disparities. Prospective outcome studies remain sparse in PLWH limiting prevention approaches. However, subclinical cardiac and electrophysiologic remodeling and dysfunction detected by noninvasive testing are powerful disease surrogates that inform our mechanistic understanding of HIV-associated cardiovascular disease and offer opportunities for early diagnosis.Aggressive control of HIV viremia and cardiac risk factors and abstinence from unhealthy behaviors remain treatment pillars to prevent heart failure and arrhythmic complications. The excess risk among PLWH warrants heightened vigilance for heart failure and arrhythmic symptomatology and earlier testing as subclinical abnormalities are common. Future research needs include identifying novel therapeutic targets to prevent heart failure and arrhythmias and testing of interventions in diverse groups of PLWH.

Background: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection. Methods: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up. Results: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus , were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09–1.64] and 1.24 [1.02–1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines. Conclusions: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

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 (iPF(2α)-III) and 2,3-dinor-8-isoprostane (iPF(2α)-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 iPF(2α)-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 iPF(2α)-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 iPF(2α)-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.

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.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Background Alterations in gut microbiota have been implicated in HIV infection and cardiovascular disease. However, how gut microbial alterations relate to host inflammation and metabolite profiles, and their relationships with atherosclerosis, have not been well-studied, especially in the context of HIV infection. Here, we examined associations of gut microbial species and functional components measured by shotgun metagenomics with carotid artery plaque assessed by B-mode carotid artery ultrasound in 320 women with or at high risk of HIV (65% HIV +) from the Women’s Interagency HIV Study. We further integrated plaque-associated microbial features with serum proteomics (74 inflammatory markers measured by the proximity extension assay) and plasma metabolomics (378 metabolites measured by liquid chromatography tandem mass spectrometry) in relation to carotid artery plaque in up to 433 women. Results Fusobacterium nucleatum, a potentially pathogenic bacteria, was positively associated with carotid artery plaque, while five microbial species (Roseburia hominis, Roseburia inulinivorans, Johnsonella ignava, Odoribacter splanchnicus, Clostridium saccharolyticum) were inversely associated with plaque. Results were consistent between women with and without HIV. Fusobacterium nucleatum was positively associated with several serum proteomic inflammatory markers (e.g., CXCL9), and the other plaque-related species were inversely associated with proteomic inflammatory markers (e.g., CX3CL1). These microbial-associated proteomic inflammatory markers were also positively associated with plaque. Associations between bacterial species (especially Fusobacterium nucleatum) and plaque were attenuated after further adjustment for proteomic inflammatory markers. Plaque-associated species were correlated with several plasma metabolites, including the microbial metabolite imidazole-propionate (ImP), which was positively associated with plaque and several pro-inflammatory markers. Further analysis identified additional bacterial species and bacterial hutH gene (encoding enzyme histidine ammonia-lyase in ImP production) associated with plasma ImP levels. A gut microbiota score based on these ImP-associated species was positively associated with plaque and several pro-inflammatory markers. Conclusion Among women living with or at risk of HIV, we identified several gut bacterial species and a microbial metabolite ImP associated with carotid artery atherosclerosis, which might be related to host immune activation and inflammation.

ImportanceCoronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts.ObjectiveTo evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor–based model.Design, Setting, and ParticipantsTwo observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands.ExposureTraditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score.Main Outcomes and MeasuresModel discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed.ResultsThe median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, −0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2Conclusions and RelevanceIn 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.

Background: Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variations to the QT interval in the population. Methods: We performed a genome-wide association study of the QTc in 84 630 UK Biobank participants and created a polygenic risk score (PRS). Among 26 976 participants with whole-genome sequencing and ECG data in the TOPMed (Trans-Omics for Precision Medicine) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Results: Fifty-four independent loci were identified by genome-wide association study in the UK Biobank. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS composed of 1 110 494 common variants was significantly associated with the QTc in TOPMed (ΔQTc /decile of PRS =1.4 ms [95% CI, 1.3 to 1.5]; P =1.1×10 -196 ). Carriers of putative pathogenic rare variants had longer QTc than noncarriers (ΔQTc=10.9 ms [95% CI, 7.4 to 14.4]). Of individuals with QTc>480 ms, 23.7% carried either a monogenic rare variant or had a PRS in the top decile (3.4% monogenic, 21% top decile of PRS). Conclusions: QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

BackgroundThe perturbation of tryptophan (TRP)-kynurenine (KYN) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and atherosclerosis has not yet been fully understood in the context of HIV infection.MethodsWe included 361 women (241 HIV+, 120 HIV-) with carotid artery plaque assessments from the Women’s Interagency HIV Study, measured ten plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolites related gut microbial features were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. The associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression.ResultsWhile plasma kynurenic acid (KYNA) (odds ratio [OR]=1.93[1.12, 3.32] per one SD increase,P=0.02) and KYNA/TRP (OR=1.83[1.08, 3.09],P=0.02) were positively associated with plaque, indole-3-propionate (IPA) (OR=0.62 [0.40, 0.98],P=0.03) and IPA/KYNA (OR=0.51[0.33, 0.80],PRoseburia sp.,Eubacterium sp.,Lachnospira sp., andCoprobacter sp.; but no bacterial genera were found to be associated with KYNA. Furthermore, an IPA-associated-bacteria score was inversely associated with plaque (OR=0.47[0.28, 0.79],PConclusionsIn a cohort of women living with and without HIV infection, plasma IPA levels and related gut bacteria were inversely associated with carotid artery plaque, suggesting a potential beneficial role of IPA and its gut bacterial producers in atherosclerosis and CVD.

BackgroundSubclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores.MethodsThe Multi-Ethnic Study of Atherosclerosis (MESA) followed 6,814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supine blood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together and adjustment for conventional risk scores for global CVD, stroke, and dementia.ResultsAfter factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, arteriosclerosis, atherosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of arteriosclerosis and atherosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups.ConclusionsSubclinical vascular composites of arteriosclerosis and atherosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.

Supplementary table 1. Findings of multivariable linear regressions analyzing genetic associations between candidate gene SNPs and lipid profiles in exemestane-treated participants complementary to statistically significant findings in letrozole-treated participants. Supplementary table 2. Findings of multivariable linear regressions analyzing genetic associations between candidate gene SNPs and lipid profiles in only Caucasian women taking both letrozole and exemestane complementary to statistically significant findings in letrozole-treated participants. *new significant finding (in letrozole only), and corresponding data for exemestane (additive rs1062033 and dominant rs1062033 models were not included due to number of homozygotes

Supplementary Figure 1a. Manhattan plots demonstrating associations between variants in the CYP19A1 gene and absolute changes HDL-C using dominant (A) and additive (B) in letrozole treated participants taking lipid lowering medication.

Purpose: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors.Experimental Design: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models.Results: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053).Conclusions: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy. Clin Cancer Res; 22(6); 1395–402. ©2015 AACR.

Supplementary Movie 1 from Hydrophilic Agarose Macrobead Cultures Select for Outgrowth of Carcinoma Cell Populations That Can Restrict Tumor Growth

Cancer cells and their associated tumors have long been considered to exhibit unregulated proliferation or growth. However, a substantial body of evidence indicates that tumor growth is subject to both positive and negative regulatory controls. Here, we describe a novel property of tumor growth regulation that is neither species nor tumor-type specific. This property, functionally a type of feedback control, is triggered by the encapsulation of neoplastic cells in a growth-restricting hydrogel composed of an agarose matrix with a second coating of agarose to form 6- to 8-mm diameter macrobeads. In a mouse cell model of renal adenocarcinoma (RENCA cells), this process resulted in selection for a stem cell–like subpopulation which together with at least one other cell subpopulation drove colony formation in the macrobeads. Cells in these colonies produced diffusible substances that markedly inhibited in vitro and in vivo proliferation of epithelial-derived tumor cells outside the macrobeads. RENCA cells in monolayer culture that were exposed to RENCA macrobead-conditioned media exhibited cell-cycle accumulation in S phase due to activation of a G2/M checkpoint. At least 10 proteins with known tumor suppression functions were identified by analysis of RENCA macrobead-conditioned media, the properties of which offer opportunities to further dissect the molecular basis for tumor growth control. More generally, macrobead culture may permit the isolation of cancer stem cells and other cells of the stem cell niche, perhaps providing strategies to define more effective biologically based clinical approaches to treat neoplastic disease. Cancer Res; 71(3); 725–35. ©2011 AACR.

Aims To evaluate whether myocardial fibrosis predicts cardiovascular events (CVEs) and mortality in the Multi-Ethnic Study of Atherosclerosis. Methods and results Cardiac magnetic resonance (CMR) T1 mapping with gadolinium administration for assessment of extracellular volume fraction (ECV) was performed in 1326 participants, in whom myocardial scar was assessed by late gadolinium enhancement (LGE). The clinical outcomes were defined as all-cause mortality, atherosclerotic CVEs, and incident heart failure (HF) during an average of 8 years of follow-up after the scan. Participants’ mean native T1 time was 971 ms [standard deviation (SD) 45.5], ECV was 27 (SD 2.9), and 117 (8.8%) of them had LGE. At the time of the CMR exam, participant age was 68 years (SD 9) and 48% of them were women. Ideal cut-offs were identified using classification and regression trees accounting for time-to-event outcomes for ECV (30%) and native T1 time (954 ms). Over the follow-up period, 106 participants died, 78 developed CVE, and 23 developed HF. After adjustment for risk factors, ECV >30% was associated with death [hazard ratio (HR): 1.67, P < 0.05], incident CVE (HR: 2.02, P < 0.05), and incident HF (HR: 2.85, P < 0.05). After adjustments, native T1 >954 ms was associated with incident CVE (HR: 2.09, P < 0.05). Myocardial scar by LGE was not predictive of clinical outcomes after adjustments. Conclusion ECV is an independent prognostic marker of incident HF, atherosclerotic CVEs, and all-cause mortality. ECV, with its ability to characterize both diffuse and focal fibrosis processes, better predicted incident events than regional myocardial abnormalities as visualized by LGE imaging in a large multi-ethnic population.

Rationale: The impact of the COVID-19 pandemic on tobacco use patterns remains incompletely understood. We aimed to examine changes in cigarette smoking patterns over the first 2 years of the COVID-19 pandemic (2020-22) in a large, multiethnic, US community-based sample. Methods: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) ascertained the impact of the COVID-19 pandemic on participants from 14 longitudinal NIH-funded cohorts via 2 waves of standardized questionnaires conducted 2020-22. The C4R questionnaire collected data on cigarette use patterns for the current and immediate pre-pandemic periods (January-March 2020). These data were used to define pandemic-era smoking initiation, smoking cessation, and changes in smoking intensity. Multivariable logistic regression models were adjusted for centrally harmonized pre-pandemic data on sociodemographic characteristics, remote smoking history, and co-morbidities and pandemic-era psychological health, insomnia, and SARS-CoV-2 infection history ascertained through C4R questionnaires. Multiple imputation by chained equations was used to account for missing covariate data. Results: Of 17179 participants completing C4R questions on pandemic-era smoking behaviors, 1899 (11%) participants reported current smoking in the immediate pre-pandemic period (mean age 70 years, 59% women, 31% African American, 2% Hispanic, 1% Asian, 22% American Indian/Alaskan Native [AIAN]). Of these 181 (10%) self-reported quitting during the pandemic. Among 1718 (90%) who continued smoking, smoking intensity increased in 17% and decreased in 26%. Among 15093 participants who were not smoking prior to March 2020, 135 (0.9%) initiated smoking during the pandemic period, including 120 (89%) with a remote history of smoking and 15 (11%) with no history of smoking. Pandemic-era smoking cessation was associated with older age(80+ years vs Conclusion: Greater odds of smoking initiation and/or increased smoking intensity were observed in minoritized groups and participants reporting depressive symptoms. Majority of those who initiated smoking during pandemic-era were relapsers. Smoking cessation programs remain important to improving public health and reducing health disparities.

ObjectiveThe aim of this study was to assess the association of cardiovascular disease (CVD) risk scores and coronary artery plaque (CAP) progression in HIV-infected participants.MethodsWe studied men with and without HIV-infection enrolled in the Multicenter AIDS Cohort Study (MACS) CVD study. CAP at baseline and follow-up was assessed with cardiac computed tomography angiography (CCTA). We examined the association between baseline risk scores including pooled cohort equation (PCE), Framingham risk score (FRS), and Data collect of Adverse effects of anti-HIV drugs equation (D:A:D) and CAP progression.ResultsWe studied 495 men (211 HIV-uninfected, 284 HIV-infected). The adjusted odds ratio (aOR) of total plaque volume (TPV) and noncalcified plaque volume (NCPV) progression in the highest relative to lowest tertile was 9.4 [95% confidence interval (95% CI) 2.4-12.1, P

BackgroundThere are multiple predictive factors for cardiovascular (CV) mortality measured at, or after heart failure (HF) diagnosis. However, the predictive role of long-term exposure to these predictors prior to HF diagnosis is unknown.ObjectivesWe aim to identify predictive factors of CV mortality in participants with HF, using cumulative exposure to risk factors before HF development.MethodsParticipants of Multi-Ethnic Study of Atherosclerosis (MESA) with incident HF were included. We used stepwise Akaike Information Criterion to select CV mortality predictors among clinical, biochemical, and imaging markers collected prior to HF. Using the AUC of B-spline-corrected curves, we estimated cumulative exposure to predictive factors from baseline to the last exam before HF. The prognostic performance for CV mortality after HF was evaluated using competing risk regression with non-CV mortality as the competing risk.ResultsOverall, 375 participants had new HF events (42.9% female, mean age: 74). Over an average follow-up of 4.7 years, there was no difference in the hazard of CV death for HF with reduced versus preserved ejection fraction (HR = 1.27, p = 0.23). The selected predictors of CV mortality in models with the least prediction error were age, cardiac arrest, myocardial infarction, and diabetes, QRS duration, HDL, cumulative exposure to total cholesterol and glucose, NT-proBNP, left ventricular mass, and statin use. The AUC of the models were 0.72 when including the latest exposure to predictive factors and 0.79 when including cumulative prior exposure to predictive factors (p = 0.20).ConclusionIn HF patients, besides age and diagnosed diabetes or CVD, prior lipid profile, NT-proBNP, LV mass, and QRS duration available at the diagnosis time strongly predict CV mortality. Implementing cumulative exposure to cholesterol and glucose, instead of latest measures, improves predictive accuracy for HF mortality, though not reaching statistical significance.

Both left atrial and left ventricular functional parameters influence the prognosis of patients with cardiovascular diseases. This study aimed to investigate the prognostic value of a novel left atrioventricular coupling index (LACI) in a population without history of cardiovascular diseases at baseline. Participants of the Multi-Ethnic Study of Atherosclerosis who underwent a baseline cardiovascular magnetic resonance study were analyzed. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular end-diastolic volume. Cox proportional hazard models were used to evaluate the association between LACI and atrial fibrillation, heart failure, coronary heart disease death, and hard cardiovascular disease defined by myocardial infarction, resuscitated cardiac arrest, fatal and nonfatal stroke, or coronary heart disease death. Among the 4124 participants (61.5±10.1 years, 47.4% men), 1074 cardiovascular events were observed (mean follow-up, 13.0±3.2 years). Greater LACI was independently associated with atrial fibrillation (hazard ratio, 1.86 [95% CI, 1.69–2.04]), heart failure (hazard ratio, 1.50 [95% CI, 1.38–1.62]), hard cardiovascular disease (1.23 [95% CI, 1.13–1.34]), and coronary heart disease death (hazard ratio, 1.29 [95% CI, 1.15–1.45]; all P

AIMS: Atherosclerotic cardiovascular disease (ASCVD) risk prediction equations apply to older adults. For this study, the Pathobiologic Determinants of Atherosclerosis in Youth (PDAY) risk score, based on post-mortem measurements of atherosclerosis in 15–34-year olds dying accidentally, was used to predict ASCVD events, specifically myocardial infarction and revascularization, in middle age, from risk measured at ≤40 years of age. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults Study (CARDIA) collected longitudinal cardiovascular risk data, coronary artery calcium (CAC) scores, and ASCVD data beginning at age 18 and 30 years with 30-year follow-up. Predictive accuracy for ASCVD of the PDAY risk score, calculated at baseline (mean age 24) and at all six CARDIA examinations up until year 15, was examined. We also examined whether the presence of CAC improved model discrimination. The cohort for this study comprised 5004 Black and White men and women, at baseline and 3558 with data at year 15. Each standard deviation increase in PDAY score, at each examination, was significantly associated with future ASCVD. Hazard ratios (per standard deviation) increased from 1.74 to 2.04 from year 0 to year 15. C-statistics ranged from 0.771 to 0.794. Coronary artery calcium measurement at age 33–45 years improved risk prediction only if the score was 0. Cumulative risk exposure over the first 15 years of the CARDIA study also had high-predictive value (c-statistic 0.798, 95% confidence interval 0.762–0.835). CONCLUSION: The PDAY risk score may be used in young adults, prior to age 40 years to predict ASCVD events.

Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi‐Ethnic Study of Atherosclerosis, 967 participants completed 14‐day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.