ATP-binding cassette G1 membrane transporter-mediated cholesterol efflux capacity influences coronary atherosclerosis and cardiovascular risk in Rheumatoid Arthritis.

OBJECTIVES: Cholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages and reduce the lipid content of atherosclerotic plaques. CEC inversely associated with cardiovascular risk beyond HDL-cholesterol levels. CEC through the ATP-binding-cassette G1 (ABCG1) membrane transporter is impaired in rheumatoid arthritis (RA). We evaluated associations of ABCG1-CEC with coronary atherosclerosis, plaque progression and cardiovascular risk in RA. METHODS: Coronary atherosclerosis (noncalcified, partially, fully-calcified, low-attenuation plaque) was assessed with computed tomography angiography in 140 patients and reevaluated in 99 after 6.9 ± 0.3 years. Cardiovascular events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization and hospitalized heart failure were recorded. ABCG1-CEC was measured in Chinese hamster ovary cells as percentage of effluxed over total intracellular cholesterol. RESULTS: ABCG1-CEC inversely associated with extensive atherosclerosis (≥5 plaques) (adjusted odds ratio 0.50 [95% CI 0.28-0.88]), numbers of partially-calcified (rate ratio [RR] 0.71 [0.53-0.94]) and low-attenuation plaques (RR 0.63 [0.43-0.91] per standard deviation increment). Higher ABCG1-CEC predicted fewer new partially-calcified plaques in patients with lower baseline and time-averaged CRP and fewer new noncalcified and calcified plaques in those receiving higher mean prednisone dose. ABCG1-CEC inversely associated with events in patients with but not without noncalcified plaques, with

Serum cholesterol loading capacity of macrophages is regulated by seropositivity and C-reactive protein in rheumatoid arthritis patients.

OBJECTIVE: Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages. METHODS: In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM. RESULTS: OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)]. CONCLUSION: Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.

Lipoprotein oxidation may underlie the paradoxical association of low cholesterol with coronary atherosclerotic risk in rheumatoid arthritis.

OBJECTIVE: To compare coronary plaque burden, proatherogenic cytokines, oxidized low-density lipoprotein (oxLDL), anti-oxLDL antibodies, lipoprotein(a)-cholesterol, and their relationships in patients with rheumatoid arthritis with low-density lipoprotein cholesterol (LDL-C)<1.8 mmol/L versus ≥1.8 mmol/L. Also, to study differences in inflammation and proprotein convertase subtilisin/kexin type-9 (PCSK9), which impacts LDL clearance, in patients with low versus high LDL-C. METHODS: Computed tomography angiography evaluated coronary plaque (noncalcified, partially calcified, fully calcified, and high-risk plaque) in 150 patients from a single-center observational cohort. Ox-LDL, anti-oxLDL IgG, lipoprotein(a)-cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6, tumor necrosis factor-α (TNF-α) and PCSK9 were measured. Analyses adjusted for Framingham general cardiovascular risk score, statin use, and high-density lipoprotein cholesterol. RESULTS: Patients with LDL-C<1.8 mmol/L versus ≥1.8 mmol/L demonstrated: 1) higher likelihood of per-segment plaque (adjusted-OR = 1.67 [95%CI = 1.10-2.55], p = 0.017) and high-risk plaque presence (adjusted-OR 2.78 [95%CI = 1.06-7.29], p = 0.038); 2) greater anti-oxLDL titers (p = 0.020), which positively associated with TNF-α and likelihood of noncalcified, partially calcified and high-risk plaque presence only in patients with LDL-C<1.8 mmol/L (all p-for-interaction≤0.046); 3) increased lipoprotein(a)-cholesterol content (10.33% [8.11-12.54] versus 6.68% [6.10-7.25], p < 0.001), which positively associated with oxLDL (p < 0.001) and anti-oxLDL (p = 0.036); 4) higher interleukin-6 and PCSK9. No differences in CRP, ESR, or oxLDL were observed. CONCLUSION: RA patients with LDL-C<1.8 mmol/L had more coronary plaque, higher anti-oxLDL titers and anti-oxLDL associated with plaque only in this group. It is possible the observed paradoxical association of low LDL-C with greater atherosclerosis may be related to higher production of the oxidation-prone lipoprotein(a)-cholesterol and anti-oxLDL antibodies, resulting in increased vascular LDL uptake and plaque formation.

The impact of statins on coronary atherosclerosis progression and long-term cardiovascular disease risk in rheumatoid arthritis.

OBJECTIVES: To evaluate whether statins lower cardiovascular disease (CVD) risk in RA and if tentative benefits are related to changes in coronary plaque burden or composition. METHODS: In an observational cohort study, 150 patients without CVD underwent coronary atherosclerosis evaluation (total, noncalcified, partially and fully calcified plaque) with CT angiography. Prespecified cardiovascular events including cardiac death, myocardial infarction, unstable angina, revascularization, stroke, claudication and heart failure were prospectively recorded. Change in plaque burden and composition was re-assessed in 102 patients within 6.9 (0.3) years. RESULTS: Time-varying statin therapy, modeled using inverse probability treatment and censoring weights, did not significantly attenuate CVD risk in RA overall [adjusted odds ratio (OR) = 0.39 (95% CI: 0.15, 1.07), P =0.067]. However, statins associated with lower CVD risk in patients with baseline CRP > 0.5 mg/dl [adjusted OR = 0.09 (95%CI: 0.03, 0.30), P <0.001] but not in those with CRP < 0.5 mg/dl (P-interaction = 0.023), after controlling for Framingham-CVD score and time-varying bDMARD use. In patients treated with statin >50% of follow-up time, CRP did not associate with new plaque formation [adjusted OR = 0.42 (95% CI: 0.09, 1.94)], in contrast to statin-naïve [adjusted OR = 1.89 (95% CI:1.41, 2.54)] and statin-treated <50% time [adjusted-OR = 1.41 (95% CI: 1.03, 1.95), P-interaction = 0.029]. Statin therapy >50% follow-up time predicted dissipation [adjusted-OR = 5.84 (95% CI: 1.29, 26.55)] and calcification of prevalent noncalcified lesions [adjusted-OR = 4.16 (95% CI: 1.11, 15.54)], as well as new calcified plaque formation in segments without baseline plaque [adjusted-OR = 2.84 (95% CI:1.09, 7.41)]. CONCLUSION: Statin therapy associated with lower long-term cardiovascular risk in RA patients with higher inflammation. Moreover, statin therapy modified the impact of inflammation on new coronary plaque formation and predicted both regression and calcification of prevalent noncalcified lesions.

The father-daughter relationship in the wake of maternal death from breast cancer.

OBJECTIVES: This paper examines whether a relationship exists between paternal psychological stability and daughters' symptomatology following the death of a wife/mother from breast cancer. Specifically, is there a relationship between paternal parenting style and the daughters' subsequent capacity to form committed relationships later in life? METHODS: We assessed 68 adult daughters (average age = 23.5 years) since the mother's breast cancer diagnosis by means of a semistructured clinical interview and psychological testing. RESULTS: The daughters were subdivided into three psychiatric risk groups. Those in the highest risk group were most likely to be single and to have high CES-Depression and STAI-Anxiety scores. Daughters in the highest risk group were also most likely to have fathers who abused substances, fathers who had experienced a serious psychiatric event, and families with the most closed communication about the mother's cancer. SIGNIFICANCE OF RESULTS: Psychopathology in fathers correlated with increasing anxiety and depression in adult daughters. Daughters at the highest level of risk had the most severe affective states, the most disturbed father-daughter bonding, and the least ability to create successful interpersonal relationships as adults. We suggest specific interventions for these daughters of the lowest-functioning fathers.

Psychological Factors that Link Socioeconomic Status to Depression/Anxiety in Patients with Systemic Lupus Erythematosus.

Our analyses examined whether reserve capacity factors would explain the relationship between socioeconomic status (SES) and symptoms of depression/anxiety in patients with systemic lupus erythematosus (SLE). We assessed disease activity, depression/anxiety symptoms, and intrapersonal and interpersonal reserve capacity measures in 128 patients with SLE. Multiple meditational analyses revealed that intrapersonal and interpersonal psychosocial aspects of reserve capacity fully mediated the relationship between SES and depression/anxiety. Lower SES was indirectly associated with higher symptoms of depression and anxiety through the effects of psychosocial resilience. Interventions aimed at improving modifiable reserve capacity variables, such as self-esteem and optimism, may improve anxious/depressive symptomatology in patients with SLE.

Evolution of Emotional Symptoms Over Time Among Daughters of Patients With Breast Cancer.

OBJECTIVE: This study longitudinally profiled anxiety and depressive symptoms of daughters of patients with breast cancer and examined the mother׳s survival status, the daughter׳s age at the time of mother׳s diagnosis, and the style of family communication about breast cancer as moderators of change in symptomatology across participants׳ first 3 appointments at the University of California, Los Angeles Revlon Breast Center High Risk Clinic. METHODS: We evaluated the effects of hypothesized predictors on change in anxiety and depressive symptoms, 3 (symptomatology at first, second, and third clinic visits) × 2 (mother survived or died) × 2 (<20 or ≥20y old at diagnosis) × 2 (open or closed family communication) repeated-measures analyses of variance were employed. RESULTS: There was a main effect for time of diagnosis on state anxiety, demonstrating a significant reduction in anxiety across clinic visits overall (p < 0.001). There were also significant 3-way interactions. For state anxiety, mother׳s survival status moderated the time of diagnosis × age at diagnosis and time of diagnosis × family communication interaction effects. For daughters whose mothers died, decreased anxiety was observed in those who were younger at the time of diagnosis (p = 0.001). For daughters whose mothers survived, anxiety was decreased for those with closed family communication styles (p = 0.001). The time of diagnosis × mother׳s survival × age at diagnosis interaction was also significant for depressive symptoms (p = 0.001). Among daughters whose mothers died, those who were younger showed decreases in symptoms (p = 0.004). CONCLUSION: These daughters appeared to benefit from the high-risk program as demonstrated by decreased symptomatology, particularly daughters whose mothers died who were younger at the time of diagnosis.

Predicting reattendance at a high-risk breast cancer clinic.

OBJECTIVE: The research about follow-up patterns of women attending high-risk breast-cancer clinics is sparse. This study sought to profile daughters of breast-cancer patients who are likely to return versus those unlikely to return for follow-up care in a high-risk clinic. METHOD: Our investigation included 131 patients attending the UCLA Revlon Breast Center High Risk Clinic. Predictor variables included age, computed breast-cancer risk, participants' perceived personal risk, clinically significant depressive symptomatology (CES-D score ≥ 16), current level of anxiety (State-Trait Anxiety Inventory), and survival status of participants' mothers (survived or passed away from breast cancer). RESULTS: A greater likelihood of reattendance was associated with older age (adjusted odds ratio [AOR] = 1.07, p = 0.004), computed breast-cancer risk (AOR = 1.10, p = 0.017), absence of depressive symptomatology (AOR = 0.25, p = 0.009), past psychiatric diagnosis (AOR = 3.14, p = 0.029), and maternal loss to breast cancer (AOR = 2.59, p = 0.034). Also, an interaction was found between mother's survival and perceived risk (p = 0.019), such that reattendance was associated with higher perceived risk among participants whose mothers survived (AOR = 1.04, p = 0.002), but not those whose mothers died (AOR = 0.99, p = 0.685). Furthermore, a nonlinear inverted "U" relationship was observed between state anxiety and reattendance (p = 0.037); participants with moderate anxiety were more likely to reattend than those with low or high anxiety levels. SIGNIFICANCE OF RESULTS: Demographic, medical, and psychosocial factors were found to be independently associated with reattendance to a high-risk breast-cancer clinic. Explication of the profiles of women who may or may not reattend may serve to inform the development and implementation of interventions to increase the likelihood of follow-up care.

Confirmatory factor analysis of the Pittsburgh Sleep Quality Index in rheumatoid arthritis patients.

The purpose of this research was to evaluate the factor structure of the Pittsburgh Sleep Quality Index (PSQI) in rheumatoid arthritis (RA). The sample included 107 patients with RA, 88 females and seven males, with an average age of 56.09 years, recruited from the greater Southern California area. Confirmatory factor analysis evaluated single, two- and three-factor models. The single factor solution yielded a poor fit to the data. While the three-factor solution had the best fit, the two-factor solution, comprised of sleep efficiency and perceived sleep quality factors, was optimal because it had very good fit, and acceptable reliability for its individual factors. Clinical indices were consistently correlated with the sleep quality factor, but not with the sleep efficiency factor.

Information-seeking in cancer survivors: application of the Comprehensive Model of Information Seeking to HINTS 2007 data.

Despite health care providers' best efforts, many cancer survivors have unmet informational and support needs. As a result, cancer survivors often have to meet these needs themselves, and how they approach this process is poorly understood. The authors aimed to validate and extend the Comprehensive Model of Information Seeking to examine information-seeking behaviors across a variety of channels of information delivery and to explore the impact of health-related factors on levels of information seeking. The data of 459 cancer survivors were drawn from the National Cancer Institute's 2007 Health Information National Trends Survey. Structural equation modeling was used to evaluate the associations among health-related factors, information-carrier factors, and information-seeking behavior. Results confirmed direct effects of direct experience, salience, and information-carrier characteristics on information-carrier utility. However, the direct impact of demographics and beliefs on information-carrier utility was not confirmed, nor were the effects of information-carrier factors on information-seeking behavior. Contrary to expectations, salience had direct effect on information-seeking behavior and on information-carrier characteristics. These results show that understanding antecedents of information seeking will inform the development and implementation of systems of care that will help providers better meet cancer survivors' needs.

Statins influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis.

Objectives: Cholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-ß HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-ß HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA). Methods: Evaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol. Results: ABCA1-CEC negatively correlated with ABCG1-CEC (r = -0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20-3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65-1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61-0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23-0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18-3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and < 0.001 respectively). Moreover, ABCA1-CEC (per SD) associated with greater partially/fully-calcified plaque progression (adjusted odds ratio 3.07 [95%CI 1.20-7.86]) only in patients not exposed to statins during follow-up (p-for-interaction = 0.009). Conclusion: In patients with RA, higher ABCA1-CEC may reflect a proatherogenic state, associated with enhanced cardiovascular risk. Statin use may unmask the protective impact of ABCA1-mediated cholesterol efflux on plaque formation, progression and cardiovascular risk.

Atherosclerotic Cardiovascular Risk Stratification in the Rheumatic Diseases:: An Integrative, Multiparametric Approach.

Cardiovascular disease (CVD) risk is increased in most inflammatory rheumatic diseases (IRDs), reiterating the role of inflammation in the initiation and progression of atherosclerosis. An inverse association of CVD risk with body weight and lipid levels has been described in IRDs. Coronary artery calcium scores, plaque burden and characteristics, and carotid plaques on ultrasound optimize CVD risk estimate in IRDs. Biomarkers of cardiac injury, autoantibodies, lipid biomarkers, and cytokines also improve risk assessment in IRDs. Machine learning and deep learning algorithms for phenotype and image analysis hold promise to improve CVD risk stratification in IRDs.

Inflammation and immunomodulatory therapies influence the relationship between ATP-binding cassette A1 membrane transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis.

Objectives: High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events. Methods: Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol. Results: Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction ≤ 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027). Conclusion: ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

Culture, emotion, and cancer screening: an integrative framework for investigating health behavior.

BACKGROUND: Although health disparity research has investigated social structural, cultural, or psychological factors, the interrelations among these factors deserve greater attention. PURPOSE: This study aims to examine cancer screening emotions and their relations to screening fatalism as determinants of breast cancer screening among women from diverse socioeconomic and ethnic backgrounds. METHODS: An integrative conceptual framework was used to test the multivariate relations among socioeconomic status, age, screening fatalism, screening emotions, and clinical breast exam compliance among 281 Latino and Anglo women, using multi-group structural equation causal modeling. RESULTS: Screening emotions and screening fatalism had a negative, direct influence on clinical breast exam compliance for both ethnic groups. Still, ethnicity moderated the indirect effect of screening fatalism on clinical breast exam compliance through screening emotions. CONCLUSIONS: Integrative conceptual frameworks and multivariate methods may shed light on the complex relations among factors influencing health behaviors relevant to disparities. Future research and intervention must recognize this complexity when working with diverse populations.

Healthcare mistreatment and continuity of cancer screening among Latino and Anglo American women in southern california.

The aim of this research was to examine the relation of perceptions of healthcare mistreatment and related emotions to continuity of cancer screening care among women who reported healthcare mistreatment. The structure of relations among cultural beliefs about healthcare professionals, perceptions of mistreatment, mistreatment-related emotions, and continuity of screening was investigated. Participants included 313 Anglo and Latino American women of varying demographic characteristics from southern California who were recruited using multi-stage stratified sampling. Structural equation modeling confirmed the relation of perceptions of mistreatment to continuity of care for both Anglo and Latino American women, with ethnicity moderating this association. For Anglo Americans, greater perceptions of mistreatment were negatively related to continuity of screening. However, for Latinas the relation was indirect, through mistreatment-related anger. While greater perceptions of mistreatment were associated with higher levels of anger for both ethnic groups, anger was negatively related to continuity of care for Latino but not for Anglo women. Furthermore, cultural beliefs about professionals were indirectly related to continuity of screening through perceptions of mistreatment and/or mistreatment-related anger. These findings highlight the importance of the role of cultural and psychological factors in research and interventions aimed at improving patient-professional relations with culturally diverse women.

Beta-2-glycoprotein-I IgA antibodies predict coronary plaque progression in rheumatoid arthritis.

OBJECTIVES: To evaluate whether anti-Beta-2-Glycoprotein-I (anti-ß2GPI) IgA antibodies associate with progression of coronary atherosclerosis and cardiovascular disease (CVD) events in rheumatoid arthritis (RA). METHODS: One hundred-fifty patients underwent plaque evaluation (total, non-calcified, mixed and calcified) with coronary computed tomography angiography; 101 were re-imaged within 6.9±0.3 years to assess progression. The Framingham-D'Agostino score assessed cardiovascular risk. Coronary artery calcium (CAC) and segment involvement score quantified plaque burden. RESULTS: Anti-ß2GPI IgA were seen in 45 (30%) patients. Despite no link to baseline plaque burden, anti-ß2GPI IgA associated with segment involvement score increase (adjusted-RR=1.64 [95%CI 1.02-2.63]), CAC change (adjusted-ß=0.33 [95%CI 0.002-0.656]) and developing new extensive or obstructive plaque at follow-up (adjusted-OR=4.24 [95%CI 1.30-13.87]). Adding anti-ß2GPI IgA to logistic regression models with conventional risk factors predicting plaque progression outcomes increased Area under the receiver-operator curve and improved Net Reclassification and Integrated Discrimination Improvement indices (all P<0.05). In per-segment analyses, anti-ß2GPI IgA predicted mixed plaque formation (adjusted-OR=3.20 [95%CI 1.01-10.09]) and lower likelihood of transition of mixed to calcified plaque (adjusted-OR=0.19 [95%CI 0.04-0.96]). Anti-ß2GPI IgA moderated the effect of C-reactive protein on CAC change such that C-reactive protein associated with CAC change (ß=0.26 [95%CI 0.14-0.38]) and CVD risk (adjusted-HR=1.89 [95%CI 1.02-3.51]) only in anti-ß2GPI IgA positive patients. CONCLUSION: Anti-ß2GPI IgA addition to clinical risk models improved prediction accuracy of CAC, plaque progression and transition to extensive/obstructive disease. They associated with new high-risk mixed plaques and delayed healing to calcified lesions. Anti-ß2GPI IgA further modified the effect of inflammation on plaque progression and CVD events.

Epicardial Adipose Tissue Volume As a Marker of Subclinical Coronary Atherosclerosis in Rheumatoid Arthritis.

OBJECTIVE: To assess epicardial adipose tissue volume (EATV) and its link to coronary atherosclerosis and plaque morphology in patients with rheumatoid arthritis (RA) and in age- and sex-matched controls. METHODS: Computed tomography angiography was used to evaluate EATV and coronary plaque in 139 RA patients and 139 non-RA controls. All models assessing the effect of EATV on plaque were adjusted for age, sex, hypertension, diabetes, dyslipidemia, smoking status, family history of coronary artery disease, and obesity (body mass index of ≥30 kg/m2 ). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Mean ± SD log-transformed EATV was similar in patients with RA (4.69 ± 0.36) and controls (4.70 ± 0.42). EATV was higher in RA patients with atherosclerosis compared to those without atherosclerosis (P = 0.046). In stratified analyses, EATV was associated with the number of segments with plaque in RA patients (rate ratio 1.20 [95% CI 1.01-1.41] per 1-SD increment of log-unit increase in EATV) but not in controls (P for interaction = 0.089). Likewise, EATV (per 1-SD log-unit increase) was related to the presence of multivessel or obstructive disease (OR 1.63 [95% CI 1.04-2.61]), noncalcified plaque (OR 1.78 [95% CI 1.17-2.70]), and vulnerable plaque (OR 1.77 [95% CI 1.03-3.04]) in RA patients but not in controls (P for interaction ≤ 0.048 for each). Among RA patients, EATV was associated with the number of segments with plaque in those with RA for <10 years who did not develop any cardiovascular risk factors and who were not obese (P for interaction ≤ 0.017). CONCLUSION: Despite similar EATVs in RA patients and controls, EATVs were associated with greater plaque burden and presence of plaques with a noncalcified component and vulnerability features only in RA patients. EAT may be more pathogenic in RA and play a role in early-stage atherosclerosis. Its value as a biomarker of subclinical atherosclerosis and cardiovascular risk in RA warrants further studies.

Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: a review of evidence and mechanistic insights.

Introduction: Cardiovascular disease is a leading comorbidity in rheumatoid arthritis. Timely introduction of biologic therapies in a treat-to-target approach has optimized disease-related outcomes and attenuated accrual of comorbidities, including cardiovascular risk.Areas covered: A literature search in MEDLINE (via PubMed) was performed between January 2009 and November 2020. This manuscript explores recent developments in atherosclerotic cardiovascular risk in RA compared with non-RA individuals; it synopsizes differences in vascular function and inflammation, prevalence, burden, vulnerability, and progression of atherosclerotic plaque and their underlying cellular and molecular mechanisms. Finally, it reviews the recent literature on cardioprotective benefits of biologics and draws mechanistic links with inhibition of new plaque formation, stabilization of high-risk lesions and improvement in endothelial function, arterial stiffness, lipid metabolism, and traditional cardiac risk factors.Expert opinion: Increasing evidence points to a solid cardioprotective influence of earlier, longer, and ongoing use of biologic treatments in RA. Nevertheless, the precise mechanistic effects of plaque progression and remodeling, vascular stiffness, endothelial dysfunction, lipid metabolism, and traditional cardiac risk factors are less rigorously characterized.

Biologics May Prevent Cardiovascular Events in Rheumatoid Arthritis by Inhibiting Coronary Plaque Formation and Stabilizing High-Risk Lesions.

OBJECTIVE: To evaluate whether biologic disease-modifying antirheumatic drugs (DMARDs) decrease cardiovascular disease (CVD) risk in rheumatoid arthritis (RA) and whether biologic DMARDs might have a beneficial effect on coronary plaque formation or progression. METHODS: In this single-center observational cohort study, 150 patients underwent computed tomographic angiography for evaluation of coronary atherosclerosis (total, noncalcified, mixed/calcified, and low-attenuation plaque); 101 had repeat assessments within a mean ± SD of 6.9 ± 0.3 years to evaluate plaque progression. All CVD events were prospectively recorded, including cardiac death, myocardial infarction, unstable angina, revascularization, stroke, claudication, and hospitalization for heart failure. The Framingham-D'Agostino score was used to assess cardiovascular risk. The segment stenosis score was used to measure plaque burden. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: After adjustment for the segment stenosis score, the Framingham-D'Agostino score, and time-varying Disease Activity Score in 28 joints using the C-reactive protein level using marginal structural models, current biologic DMARD use was associated with lower long-term CVD risk (OR 0.15 [95% CI 0.04-0.60]). Noncalcified and low-attenuation plaque presence moderated the effect of biologic DMARDs on CVD risk; specifically, biologic DMARD use was associated with lower CVD risk in patients with noncalcified or low-attenuation plaque at baseline (OR 0.21 [95% CI 0.04-0.99] and OR 0.08 [95% CI 0.01-0.70], respectively), but not in those without noncalcified or low-attenuation plaque. Per-segment plaque progression analyses showed that biologic DMARD exposure was associated with transition of noncalcified to mixed/calcified plaque (OR 4.00 [95% CI 1.05-15.32]). Biologic DMARD exposure predicted a lower likelihood of new plaque forming in segments without plaque among patients without mixed/calcified plaque in other coronary segments (OR 0.40 [95% CI 0.17-0.93]), but not among those with calcification. Biologic DMARD treatment also predicted low-attenuation plaque loss (P = 0.042). CONCLUSION: Our findings indicate that in RA, biologic DMARD use is associated with reduced CVD risk, protective calcification of noncalcified lesions, and lower likelihood of new plaque formation in patients with early atherosclerosis.

Impact of Cumulative Inflammation, Cardiac Risk Factors, and Medication Exposure on Coronary Atherosclerosis Progression in Rheumatoid Arthritis.

OBJECTIVE: To explore incidence and progression of coronary atherosclerosis and identify determinants in patients with rheumatoid arthritis (RA). We specifically evaluated the impact of inflammation, cardiac risk factors, duration of medication exposure, and their interactions on coronary plaque progression. METHODS: One hundred one participants with baseline coronary computed tomography angiography findings underwent follow-up assessment a mean ± SD of 83 ± 3.6 months after baseline. Plaque burden was reported as the segment involvement score (describing the number of coronary segments with plaque) and the segment stenosis score (characterizing the cumulative plaque stenosis over all evaluable segments). Plaque composition was classified as noncalcified, mixed, or calcified. Coronary artery calcium (CAC) was quantified using the Agatston method. RESULTS: Total plaque increased in 48% of patients, and progression was predicted by older age, higher cumulative inflammation, and total prednisone dose (P < 0.05). CAC progressors were older, more obese, hypertensive, and had higher cumulative inflammation compared to nonprogressors (P < 0.05). Longer exposure to biologics was associated with lower likelihood of noncalcified plaque progression, lesion remodeling, and constrained CAC change in patients without baseline calcification, independent of inflammation, prednisone dose, or statin exposure (all P < 0.05). Longer statin treatment further restricted noncalcified plaque progression and attenuated the effect of inflammation on increased plaque and CAC (P < 0.05). Stringent systolic blood pressure (BP) control further weakened the effect of inflammation on total plaque progression. CONCLUSION: Inflammation was a consistent and independent predictor of coronary atherosclerosis progression in RA. It should therefore be specifically targeted toward mitigating cardiovascular risk. Biologic disease-modifying antirheumatic drugs, statins, and BP control may further constrain plaque progression directly or indirectly.