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The longitudinal impact of perceived stress on the risk of cardiometabolic disease has not been comprehensively evaluated among children and young adults. We hypothesized that patterns of perceived stress from childhood to adulthood may predict cardiometabolic risk in early adulthood. As part of the Southern California Children’s Health Study (CHS), we examined perceived stress score (PSS) in adolescence (mean age, 13.3 years) and young adulthood (mean age, 23.6 years) among 276 participants. Based on PSS in adolescence and young adulthood, participants were categorized into 4 stress pattern groups: consistently high (n = 85), decreasing (n = 49), increasing (n = 59), and consistently low (n = 65). CHS participants were assessed for seven measures of cardiometabolic disease risk, namely carotid artery intima-media thickness (CIMT), systolic and diastolic blood pressure (SBP and DBP), obesity, percent body fat, android/gynoid ratio, and elevated HbA1c in their young adulthood. An overall cardiometabolic risk score was generated by summing the number of clinically elevated measures to indicate cumulative cardiometabolic risk. Using multivariate linear and logistic regression models, we examined PSS measured at single time points and change in PSS score across adolescence to young adulthood in relation to cardiometabolic disease risk. Results indicated that PSS in adulthood had significant positive associations with overall cardiometabolic risk score (Beta, 0.12: 95% CI, 0.01-0.22; p =0.031), CIMT (Beta, 0.01; 95% CI, 0.00-0.02; p =0.043), SBP (Beta, 1.27, 95% CI, 0.09-2.45; p =0.035), and DBP (Beta, 0.94; 95% CI, 0.13-1.76; p =0.024). Further, analyses of PSS patterns suggested that individuals with consistently high PSS had higher cardiometabolic risk scores (Beta, 0.26; 95% CI, -0.02-0.54; p =0.066), as well as significantly higher android/gynoid ratio (Beta, 0.09; 95% CI, 0.03-0.14; p =0.002), percent body fat (Beta, 0.96; 95% CI, 0.51-5.41; p =0.018), and greater odds of obesity (OR, 5.73; 95% CI, 1.96-16.78; p = 0.001), compared to individuals with consistently low PSS. Our work suggests that perceived stress from adolescence to adulthood may contribute to cardiometabolic disease risk in adulthood. Interventions to reduce stress earlier in life (e.g., in adolescence) should be investigated for their potential to reduce cardiometabolic disease risk factors in young adulthood.

Cardiovascular disease (CVD) is the leading cause of death in women, who have a notable increase in the risk for this disease after menopause and typically develop coronary heart disease several years later than men. This observation led to the hypothesis that the menopause transition (MT) contributes to the increase in coronary heart disease risk. Over the past 20 years, longitudinal studies of women traversing menopause have contributed significantly to our understanding of the relationship between the MT and CVD risk. By following women over this period, researchers have been able to disentangle chronological and ovarian aging with respect to CVD risk. These studies have documented distinct patterns of sex hormone changes, as well as adverse alterations in body composition, lipids and lipoproteins, and measures of vascular health over the MT, which can increase a woman’s risk of developing CVD postmenopausally. The reported findings underline the significance of the MT as a time of accelerating CVD risk, thereby emphasizing the importance of monitoring women’s health during midlife, a critical window for implementing early intervention strategies to reduce CVD risk. Notably, the 2011 American Heart Association guidelines for CVD prevention in women (the latest sex-specific guidelines to date) did not include information now available about the contribution of the MT to increased CVD in women. Therefore, there is a crucial need to discuss the contemporary literature on menopause and CVD risk with the intent of increasing awareness of the significant adverse cardiometabolic health–related changes accompanying midlife and the MT. This scientific statement provides an up-to-date synthesis of the existing data on the MT and how it relates to CVD.

Introduction: Obstructive sleep apnea (OSA) is associated with increased rates of atrial fibrillation (AF). Recent randomized data suggest that traditional scoring of OSA needs to evolve to improve cardiovascular outcomes. Traditional scoring of OSA does not fully reflect pathophysiological links between OSA and AF, particularly regarding OSA-induced prolongation of p-wave duration (PWD), which is the most powerful predictor of AF occurrence. Hypothesis: We hypothesized that OSA episodes that closely follow each other (serially stacked apneas, ssOSA) exert greater effect on PWD compared to isolated OSA (iOSA) episodes. Methods: Sleeping patients (adults with mild-moderate OSA and presence of both iOSA and ssOSA, but without other cardiovascular comorbidities) undergoing diagnostic polysomnography were recorded by continuous 8-lead ECG. iOSA was defined as OSA episodes with no other episode within 30 seconds. ssOSA consisted of ≥3 consecutive apneas with inter-OSA intervals Results: We analyzed 208 OSA episodes (51.0% iOSA, 49.0% ssOSA) which occurred in 12 patients (7 women; age 63.1±11.5 years; apnea hypopnea index 16.8±5.4). PWD was longer during ssOSA compared to iOSA (median 117.7ms vs 109.6ms; p Conclusions: The impact of OSA on atrial conduction delay is exacerbated by the phenomenon of OSA stacking, which seems independent of oxygen desaturation and heart rate. Stacking of OSA episodes may be an underused and cost-efficient variable in evaluating the severity of OSA and the effectiveness of OSA treatments with the ultimate goal of reducing occurrence of AF.

Objectives: Nonclassical monocytes (NCM) have patrolling functions relevant to atherosclerosis. While NCM have low surface CXCR4 expression in people with concurrent HIV and CVD (Mueller Cardiovasc Res 2019), the extent of CVD-related gene expression and the pathways involved are unknown. We described the gene transcription signature of NCM to provide insight into potential mechanisms of HIV-associated CVD. Methods: We identified transcriptomic changes in circulating NCM among women with and without chronic HIV infection. CVD was defined by plaques found on B-mode carotid artery ultrasound. The study included 23 HIV - CVD - , 21 HIV + CVD - , 20 HIV - CVD + , and 21 HIV + CVD + women, with these four groups matched by age (median = 45), race (95% minority) and smoking (86% ever-smokers). Using cryopreserved cells, we flow-sorted NCM (CD14 dim CD16+) and deep-sequenced their mRNA (average depth >40 million reads) to identify differentially expressed genes (DEG) contrasting HIV alone, CVD alone, and concurrent HIV + CVD + groups, versus HIV - CVD - , based on FDR-adjusted P Results: After filtering to genes with raw counts >10 in >60% of participants, 11,343 protein coding genes were analyzed. HIV alone was associated with 10 DEGs on NCM (Figure). Women affected by both HIV and CVD had 93 DEGs, only six of which were shared by the HIV alone DEG signal. CVD alone was associated only with upregulated CDK18, which was also identified as a DEG in the HIV + CVD + group. Conclusion: Concurrent HIV and CVD (HIV + CVD + ) is associated with altered gene expression in NCMs relative to HIV - CVD - , generating responses that involve interleukins (IL32, IL4R), immune checkpoint inhibition (LAG3), chemokines (CCL4, CCL5) and lipid homeostasis (ABCD2).

Introduction: Cardiovascular disease is a major contributor to morbidity and mortality among women living with HIV (WLWH). We previously found HIV infection to be associated with carotid artery plaque, a marker of subclinical atherosclerosis. Plaque morphology and composition may predict plaque rupture and cardiovascular disease events. We characterized the association of HIV-related factors with carotid plaque echomorphology in the WIHS. Methods: Using B-mode ultrasound, we characterized plaque (focal intima-media thickness >1.5 mm) at 6 locations in the right carotid artery in 1,722 participants (1,230 HIV+, 492 HIV-) of the WIHS, a cohort study of women with or at risk for HIV at 6 US sites. Plaque echomorphologic features included relative echogenicity (>50% of plaque is echolucent vs >50% of plaque is echogenic) and surface morphology (smooth vs irregular, i.e., height variations along contour of plaque). We used multinomial logistic regression to assess the odds of each feature vs no plaque comparing HIV+ and HIV- women, adjusting for demographic (e.g., age, race/ethnicity, socioeconomic status), behavioral (e.g., drug/alcohol use, smoking, HCV infection, smoking), cardiometabolic (e.g., systolic blood pressure, BMI, lipids, diabetes) and HIV-related risk factors (e.g., antiretroviral therapy use, current CD4+ T-cell count, AIDS). We further stratified WLWH by CD4+ count ( Results: Among 1,722 women (median age 40, IQR 33-46, 59% black, 29% Hispanic, 71% HIV+), 160 (9%) had at least one carotid plaque (128 HIV+, 32 HIV-). In unadjusted analyses, WLWH had more echolucent plaque (5.3% vs 2.6%, p=0.02) and plaques with smooth surface (2.7% vs 0.6%, p=0.005) than HIV-negative women. After covariate adjustment, HIV serostatus remained significantly associated with smooth plaque (odds ratio [OR] 3.45, 95% CI 1.12-10.62) but not with echolucent plaque (OR 1.60, 95% CI 0.84-3.05). Stratified by HIV viremia, WLWH with unsuppressed HIV viremia had significantly more smooth plaque (OR 3.34, 95% CI 1.26-8.87) than HIV- women, whereas suppressed WLWH did not (OR 1.79, 95% CI 0.55-5.83). In a dose-response manner, lower CD4+ count among WLWH was associated with smooth plaque (e.g., OR for Conclusions: Unsuppressed viremia and low CD4+ count, which are markers of suboptimal HIV care, were associated with certain echomorphologic features of carotid plaque. Further work should assess whether these features differentially lead to cardiovascular morbidity and mortality in WLWH.

Objective: The effect of estradiol therapy (ET) has been evaluated on atherosclerosis progression measured by carotid artery wall thickness. Echogenicity of the arterial wall, a measure of lipid deposition, has not been investigated in relation to ET. Methods: This is a secondary analysis from ELITE. A total of 643 healthy postmenopausal women were randomized within time-since-menopause strata (early (10 years) postmenopause) to daily 1 mg estradiol or placebo. The atherosclerosis outcome for the current analysis is grey scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high resolution ultrasonography of the common carotid arterial wall. Lower GSM values indicate more lipid deposition. GSM and serum concentrations of estradiol (E2) were assessed every 6 months over a median 5-year trial period. Linear mixed effects regression models were used to compare the rate of GSM progression between the randomized groups within time-since-menopause strata. The association of mean on-trial serum E2 levels with GSM progression was also tested using similar mixed effects model. Results: The effect of ET on the annual rate of GSM progression significantly differed between early and late postmenopause strata (p-value for interaction = 0.006). Annual GSM progression rate (95% confidence interval) among women in early postmenopause decreased by -0.30 (-0.63, 0.04) per year among women taking ET compared to -1.41 (-1.77, -1.06) per year among the placebo group (p Conclusion: Compared to placebo, oral ET significantly reduced progression of lipid deposition in the carotid arterial wall among women in early postmenopause. ET had no such beneficial effect in late postmenopause. Associations between serum estradiol levels and lipid deposition validated those findings. Qualitative assessment of subclinical atherosclerosis (GSM) complements the anatomic assessment by carotid artery intima-media thickness.

Objective: Heart fat depots, within [epicardial adipose tissue (EAT)] and outside [paracardial adipose tissue (PAT)] the pericardium, have been linked to carotid atherosclerosis in various populations. Postmenopausal women have greater volumes of heart fat than premenopausal women. Our previous work suggests that lower endogenous estrogen may contribute to heart fat accumulation, although possibly limited to PAT, while postmenopausal oral hormone therapy (HT) may slow its progression. We evaluated the effect modification of HT use over 48 months on associations between heart fat accumulation and carotid artery intima-media thickness (CIMT) progression in recently postmenopausal women. Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multi-center, randomized, double-blind placebo-controlled trial to investigate effects over 48 months of oral conjugated equine estrogens (o-CEE) and transdermal 17β-estradiol (t-E2), both given with cyclic progesterone, compared to placebo, on progression of CIMT in recently postmenopausal women. EAT and PAT volumes, and CIMT were measured at baseline and at 48 months. Associations between the absolute changes in heart fat volumes and CIMT as well as effect modification by HT type were tested using linear regression, adjusting for age, race, study site, employment status, diastolic and systolic blood pressure, anti-hypertensive medications, insulin resistance index, lipids, body-mass index, smoking, alcohol consumption, C-reactive protein, and adipokines. Results: Of 727 randomly assigned women, 467 [mean age (SD): 52.7(2.5); 78.2% Caucasian] had heart fat volumes and CIMT measured at both time points. Overall, changes in EAT and PAT were not associated with CIMT progression; however, assigned treatment significantly modified the association between changes in PAT, but not EAT, and CIMT progression in unadjusted model, P=0.04. In o-CEE group, CIMT progression was 0.028mm (SE:0.01mm) lower, per 1 unit increase in log PAT, than in t-E2 group, P=0.01, and trended 0.017mm (SE:0.01mm) lower than in placebo group, P=0.09. Although adjusted analysis attenuated these findings (P-value for interaction 0.09), differences between o-CEE and t-E2 groups remained significant, P=0.03. Conclusion: HT use modified the association between PAT accumulation, but not EAT, and CIMT progression. Our results suggest a potential beneficial impact of o-CEE (but not transdermal E2) on the relationship between adverse changes in PAT and CIMT. The current findings support the notion that EAT and PAT are distinct fat depots and suggest a complex role of HT in the association between heart fat and CIMT progression in recently postmenopausal women.

Background: Ceramides have been implicated in the pathophysiology of HIV infection and cardiovascular disease. However, no study, to our knowledge, has evaluated circulating ceramide levels in association with subclinical cardiovascular disease risk among HIV-infected individuals. Methods: Plasma levels of 4 ceramide species (C16:0, C22:0, C24:0, and C24:1) were measured among 398 women (73% HIV+) and 339 men (68% HIV+) without carotid artery plaques at baseline from the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. We examined associations between baseline plasma ceramides and risk of carotid artery plaque formation, assessed by repeated B-mode carotid artery ultrasound imaging over a median 7-year follow-up. Results: Plasma levels of C16:0, C22:0, and C24:1 ceramides were significantly higher in HIV-infected individuals compared with those without HIV infection (all P P r =0.70–0.94; all P r =0.42–0.58; all P r =0.24–0.42; all P r =0.30 between C16:0 ceramide and soluble CD14; P + T-cell activation. A total of 112 participants developed carotid artery plaques over 7 years, and higher levels of C16:0 and C24:1 ceramides were significantly associated with increased risk of carotid artery plaques (relative risk [95% CI]=1.55 [1.29, 1.86] and 1.51 [1.26, 1.82] per standard deviation increment, respectively; both P Conclusions: In 2 HIV cohorts, elevated plasma levels of C16:0 and C24:1 ceramides, correlating with immune activation and inflammation, were associated with antiretroviral therapy use and progression of carotid artery atherosclerosis.

Background: Lipid metabolism disruption and excess cardiovascular disease (CVD) risk have been associated with HIV infection, yet plasma lipidomics profile and its relationship with CVD risk has been rarely examined in HIV-infected individuals. Methods: Using liquid chromatography tandem mass spectrometry, 211 plasma lipid species from 13 classes were profiled in 737 women and men aged 35-55 years (520 HIV+, 217 HIV-) from the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. Repeated B-mode carotid artery ultrasound imaging was obtained in 2004-2013. Poisson regression and network analysis were used to examine associations of baseline lipids with incident carotid plaque over 7 years (112 cases, 90 HIV+ and 22 HIV-). Results: Adjusted for demographic and behavioral factors, 120 individual species from 11 lipid classes showed significant associations with incident carotid plaque (all P Figure ). Of note, the Blue module, but not the Pink module, also showed a strong positive association with HIV infection. Most lipids in the Blue module had higher levels in HIV+ compared to HIV- individuals, and were associated with increased risk of carotid plaque ( Figure ). Conclusions: Lipidomics profiling identified that multiple lipids, especially, TAGs, are increased in HIV infection and associated with progression of atherosclerosis. Our data provide new insights into early lipid metabolism alterations preceding the development of CVD in HIV infection.

Introduction: Ceramides, a family of bioactive sphingolipids on plasma membrane, have been implicated in inflammation, immune response, and HIV infection. Recent studies have related plasma ceramides with cardiovascular diseases (CVD), but data are sparse in HIV infected people who have excess CVD risk. Methods: We profiled baseline plasma ceramides C16:0, C22:0, C24:0 and C24:1 in 737 participants aged 35-55 years (520 HIV+, 217 HIV-) from two prospective cohorts (Women’s Interagency HIV Study and Multicenter AIDS Cohort Study) and examined their associations with the risk of incident carotid artery plaque (CAP), assessed by B-mode carotid artery ultrasound imaging over a 7-year period. Plasma levels of ceramides were inverse-normal transformed. We used robust variance estimates from Poisson regression to estimate risk ratios (RRs) on CAP per standard deviation increment in ceramides. We also compared ceramide levels by HIV infection status and antiretroviral therapy (ART) use. Results: Over a 7-year follow-up, 112 individuals developed CAP (90 HIV+, 22 HIV-). After multivariate adjustment, ceramides C16:0 (RR=1.40 [95% CI: 1.09-1.79]; P P Figure ), but there was no significant effect modification by HIV infection status ( P for interaction>0.05). Compared to HIV- group, plasma ceramides C16:0, C22:0 and C24:1 were significantly ( P P < 0.001) higher in people using ART than those not using ART. Conclusions: This study reported that elevated plasma ceramides, especially C16:0, are increased with ART use and associated with HIV-related atherosclerosis. Our data suggest that ceramides might be an intermediate link between HIV infection and CVD risk.

Background— Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated. Methods and Results— The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007 to 2009. Participants attended 1 study visit during which blood pressure, heart rate, and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and sociodemographic characteristics, and a 12-hour fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency's Air Quality System database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (±54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12 years) O 3 exposure was associated with a 7.8-μm (95% confidence interval, −0.3–15.9) or 10.1-μm (95% confidence interval, 1.8–18.5) higher CIMT, respectively. Lifetime exposure to O 3 showed similar but nonsignificant associations. No associations were observed for PM 2.5 , PM 10 , or NO 2 , although adjustment for these pollutants strengthened the childhood O 3 associations. Conclusions— Childhood exposure to O 3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.

Background: We previously found that low CD4+ T-cell counts among HIV-infected (HIV+) women and men were associated with an increased prevalence of carotid artery lesions in a cross-sectional analysis. We now report on the association of HIV infection with progression of subclinical atherosclerosis in the same well-characterized population of HIV+ and HIV-uninfected (HIV-) women and men. We hypothesized that HIV infection would be associated with greater progression over seven years of follow-up. Methods: We examined data from a subset of participants without a history of coronary heart disease in the Women’s Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS) who underwent serial B-mode carotid artery ultrasound imaging between 2004 and 2012 (median follow-up: 7 years). We included individuals with at least two examinations during this period, with a median of 4 exams among women and 3 exams among men. We evaluated changes in common carotid artery intima-media thickness (cIMT, mm) and the development of carotid artery lesions (focal IMT >1.5 mm), defined as an increased number of lesions over the time period, based on regression models with generalized estimated equations to take into account clustering by individual, controlling for demographic factors and smoking status. Models combining women and men, as well as stratified by cohort, are presented. Results: We studied 1011 women (74% HIV+) and 811 men (65% HIV+). The median age was 41 years (IQR 35-47) in women and 49 (IQR 44-55) in men. The unadjusted mean cIMT increased during the period from 0.725 to 0.752 mm in women and from 0.757 to 0.790 mm in men. The prevalence of carotid artery lesions increased from 8% to 15% in women and from 25% to 34% in men during follow-up. In analyses controlling for sex, age, race/ethnicity, study site, and smoking status, progression of carotid artery lesions differed by HIV serostatus. HIV+ persons had a 1.9-fold higher adjusted risk of developing lesions during the follow-up period than HIV- persons (17% with increase in lesions among HIV+ vs. 10% in HIV-; 95% CI 1.29-2.72, p=0.001). This association persisted in models stratified by cohort (in women, adjusted relative risk 1.66, 95% CI 0.96-2.89, p=0.07; in men, 1.92, 95% CI 1.14-3.11, p=0.01), with no evidence of effect modification by cohort (p=0.58). We did not find significant differences in cIMT change over time by HIV serostatus, either in combined or cohort-specific analyses. Conclusion: HIV infection was associated with a greater increase in carotid artery lesions over a seven-year period in both women and men. HIV appears to play a role in focal cIMT thickening in atherosclerosis-prone carotid artery segments, but not a generalized increase in wall thickness in the common carotid artery.

We thank Wang et al for their commentary regarding our recently published article relating childhood O3 exposure to carotid intima–media thickness (CIMT) in adulthood.1 The authors suggest that adjustment for additional clinical information may strengthen our conclusion regarding O3 as a novel predictor of CIMT. Specifically, they suggest we include data on childhood dietary patterns, adolescent blood pressure (BP), and glucose tolerance testing. Although we agree that these data are relevant clinical parameters when assessing cardiovascular disease risk and atherosclerosis, it is unlikely that they will act as confounders of our observed association with O3 if they are not related to exposure. First, the evaluation of elementary and lifetime diet, as suggested by the authors, is a daunting task, and one highly susceptible to recall bias. Most food frequency questionnaires are designed to address recall only …

Background There is accumulating experimental, epidemiological, and clinical evidence of an association between antioxidant vitamin intake and reduced risk of coronary heart disease. Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS), we explored the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis. Methods and Results CLAS was an arterial imaging trial in which nonsmoking 40- to 59-year-old men with previous coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet or placebo plus diet. The rate of progression of early preintrusive atherosclerosis was determined in 146 subjects using high-resolution B-mode ultrasound quantification of the distal common carotid artery far wall intima-media thickness (IMT). From the nutritional supplement database, 22 subjects had an on-trial average supplementary vitamin E intake of ≥100 IU per day (high users) and 29 subjects had an average on-trial supplementary vitamin C intake of ≥250 mg per day (high users). Within the placebo group, less carotid IMT progression was found for high supplementary vitamin E users when compared with low vitamin E users (0.008 versus 0.023 mm/y, P =.03). No effect of vitamin E within the drug group was found. No effect of vitamin C within the drug or placebo group was found. Conclusions Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).

Background Local coronary artery enlargement to compensate for atherosclerotic plaques preserves the vessel lumen. The extent to which coronary segments remote from progressing lesions enlarge is unknown. This is clinically relevant since compensatory enlargement may be important in determining whether clinical complications result from progression of coronary artery disease (CAD). Additionally, compensatory change has implications for quantitative coronary angiographic (QCA) trials, since the effect of progression on diameter means may be mitigated by compensatory changes in remote coronary segments when QCA change is averaged over all lesions. Methods and Results Serial QCA data from 78 subjects in the Monitored Atherosclerosis Regression Study were used to demonstrate compensatory changes in coronary segments remote from progressing or regressing lesions. Coronary segments were first classified as progressing (regressing) if percent diameter stenosis (PS) increased or decreased by >10 with a concurrent decrease or increase in minimum lumen diameter (MLD) of either >0.32 mm or >10% of the normal baseline reference diameter (DNORM). Segments not meeting these criteria were labeled stenosis stable. Stenosis-stable segments opposite progressing lesions showed increases in MLD ( P =.0006), DNORM ( P =.001), and average diameter ( P =.001). On-trial apolipoprotein (apo) B, apo C-III, and blood pressure levels inversely correlated with these compensatory changes. Conclusions Lesion progression in one coronary segment is associated with significant increases in segmental diameter of remote parts of the coronary tree. We hypothesize these increases to be vascular compensatory changes in response to progression of CAD. Vascular compensatory change is enhanced by LDL cholesterol and triglyceride-rich lipoprotein reduction and appears to be part of the treatment effect itself.

Introduction: Physical activity is presumed to improve cardiovascular disease (CVD), of which carotid artery intima-media thickness (CIMT) is a common indicator. Individuals with spinal cord injury (SCI) have limited mobility and therefore an expected increased risk for CVD. The purpose of this study was to determine which CVD risk factors predict CIMT among women with SCI, with the ultimate goal of targeting therapy to improve CVD in this population. Methods: One hundred twenty-two women with SCI who attended an outpatient SCI clinic and met inclusion and exclusion criteria participated in this study. SCI was categorized into 1 of 4 categories: complete tetraplegia, incomplete tetraplegia, complete paraplegia, and incomplete paraplegia. Maximum heart rate and VO2 max were obtained using bicycle ergometry with ventilatory gas exchange and continuous electrocardiogram. Hierarchical regression was used to predict CIMT, with the first block including demographic variables (age, race, smoking status) and the second block including physiologic variables (total cholesterol, heart rate, VO2 max, BMI, fasting serum glucose, hemoglobin A1c, and blood pressure). Results: Similar findings were observed for left and right CIMT, therefore only results from right CIMT are reported. The overall model was significant, F(16,46)=8.53, p=.000. Adjusted R square was .54 for the first block of variables and increased significantly (p=.006) to .66 when the second block of variables was added. Significant predictors at alpha=.05 included age (beta=.51, t=4.79, p=.000) and max/peak heart rate (beta=−.336, t=−2.39, p=.02). At alpha=.10, A1c was significant (beta=.187, t=1.99, p=.053). Conclusions: Although low aerobic conditioning is a purported CVD risk factor, quantitative measurements of such lack a demonstrable relationship with subclinical atherosclerosis (CIMT), perhaps because of its reduced importance relative to other CVD risk factors in a mobile population. We found expected relationships with CIMT in our SCI population (i.e., age), however we also found a quantitative measure of aerobic conditioning (max/peak heart rate) to be associated with CIMT. Our data indicate that SCI individuals may bear a greater CVD burden from cardiac de-conditioning than the general population and that investigation of a cohort with mobility limitation may provide a unique opportunity to study the impact of physical conditioning on CVD risk.

Introduction: Activation of T-lymphocytes, a hallmark of HIV infection, reaches a set point early in HIV infection and persists even after viral suppression with highly active antiretroviral therapy (HAART). Early T-cell activation predicts subsequent CD4 depletion, progression to AIDS and survival. HIV-infected subjects are at high risk for premature atherosclerosis. Little is known regarding the impact of early T cell activation on arterial stiffness. While Kaplan et al. (2011) were the first and only group to show a cross-sectional association, we investigate here if early T cell activation can predict future arterial stiffness. Hypothesis: High early T cell activation will predict increased arterial stiffness, measured 5.5 (IQR=2.5-7.5) years later, in HIV and HCV co-infected women. Methods: A longitudinal study nested within the WIHS, an ongoing prospective cohort study. Percentages of CD4 and CD8 T cell activation, assessed by CD38 and HLA-DR co-expression using 3-color flow cytometry, were measured on average 5.5 years before arterial stiffness assessments (carotid artery distensibility, and Young’s elastic modulus for elasticity) using B-mode carotid ultrasound. Multiple linear regression models evaluated the association between log-transformed T cell activation markers (independent variables) and arterial stiffness (dependent variable). Analyses were stratified by HCV co-infection status and by pre- and post-HAART assessment of T cell activation. Results: A total of 376 HIV+ women (185 HCV+) were included in the analysis. Participants were on average 46(SD=9) years old, 59% Black, and 49% were current smokers. Activation of both CD4 and CD8 T cells significantly univariately predicted reduced distensibility and elasticity among HIV-infected women. CD4 activation continued to significantly predict distensibility (β(SEM)= −3.51(1.30) 10 −6* N −1* m 2 , p=0.01), and elasticity (0.11(0.04)10 5* N * m 2 , p=0.004) with adjustment for age, race, BMI, smoking, ART, CD4 count, and HIV RNA. CD8 activation was no longer associated after adjustment. When stratified by HCV co-infection status, the prediction of arterial stiffness parameters from early CD4 activation was somewhat stronger among the HIV+/HCV+ women compared to HIV+/HCV- women (β(SEM)= −4.44(1.93), p=0.02 vs. −3.04(1.84), p=0.10 for distensibility, and 0.17(0.06), p=0.003 vs. 0.09(0.05), p=0.09 for elasticity); however the test for interaction was not statistically significant. In a subset of 188 women, CD4 activation measured both pre- and post-HAART significantly predicted later arterial stiffness. Conclusions: CD4 activation level predicts future arterial stiffness in HIV-infected women, perhaps more markedly among HCV co-infected women. These data confirm the proinflammatory impact of activated T cells that can cause vascular dysfunction and shed light on the early onset of atherogenesis.

More than 3 decades of clinical research have suggested a relationship between triglycerides and coronary heart disease.1 However, because of the complexity of what is actually measured by a plasma triglyceride determination, establishing a firm relationship between triglycerides and coronary heart disease has been difficult. Triglycerides are carried in virtually all plasma lipoproteins and present a different risk profile in both the fasting and postprandial states, making triglyceride-rich lipoproteins highly heterogenous. This heterogeneity is a major contributing factor to the complexity of the relationship between triglycerides and coronary heart disease. Accumulating evidence indicates that specific triglyceride-rich lipoprotein remnants of differing size and composition, such as VLDL, IDL, lipoprotein B–containing particles (LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E), and markers of triglyceride-rich lipoprotein metabolism such as apolipoprotein C-III (apoC-III), are more related to progression of atherosclerosis than triglycerides per se.2 In this issue of Circulation , Kugiyama et al3 present further evidence for the relationship between coronary heart disease and triglyceride-rich lipoproteins, demonstrating in patients with coronary artery disease that remnant lipoprotein levels in the fasting state predict future clinical coronary events independently of other risk factors. This is an important observation because it is consistent with a previous report that showed that calculated IDL plus estimated remnant VLDL as a measure of triglyceride-rich lipoprotein remnants was significantly correlated with the progression of coronary artery disease and clinical coronary events.4 The assertion by Kugiyama et al3 that fasting remnant lipoproteins may reflect postprandial remnant lipoproteins is consistent with the long circulatory residence time of certain partially delipidized lipoproteins …

Background: 5-Lipoxygenase (5-LOX) is the rate-limiting enzyme in the biosynthesis of leukotrienes from arachidonic acid (Ara), an n-6 polyunsaturated fatty acid (PUFA). Previous studies suggest that polymorphisms in the number of tandem Sp1 binding sites in the promoter of the 5-LOX gene may have an atherogenic effect due to a heightened inflammatory state when dietary Ara is high and dietary long-chain n-3 PUFAs (eicosapentaenoic acid, EPA, plus docosahexaenoic acid, DHA) are low. Methods: We determined 5-LOX genotypes in 1,663 adults participating in one of five randomized controlled atherosclerosis trials using carotid artery intima-media thickness (CIMT) as the outcome. Baseline data on participant characteristics and clinic and laboratory measurements, including fasting lipids and CIMT, were obtained using the same methods in all trials. Diet was measured using 3-day records and intake of each PUFA was categorized as above or below the median. We used linear regression to examine the cross-sectional associations between 5-LOX genotype, dietary PUFAs, and CIMT. Results: Alleles were classified as wild-type (W, with 5 repeats), deletion (D, with 2– 4 repeats), or addition (A, with 6–9 repeats). The frequencies of the six genotypes were: 60.6% WW, 27.1% WD, 4.9% WA, 4.9% DD, 2.2% DA, and 0.4% AA. Among participants using lipid-lowering medication, mean CIMT was significantly elevated by 79.1 μm (95% CI = 5.3–152.9) in DD individuals compared to WW individuals after adjustment for sex, race, age, trial, and BMI >25 kg/m 2 . High dietary EPA+DHA blunted the gene-CIMT association (p for interaction = 0.007). In contrast, DD genotype was not associated with CIMT among non-users of lipid-lowering medication. Conclusion: The atherogenic effect of the shorter promoter alleles is modulated by dietary intake, especially in individuals using lipid-lowering medication, indicating a complex mechanism involving both inflammation and lipids.

To the Editor: Two articles have appeared in Circulation 1,2 that have cited the Estrogen in the Prevention of Atherosclerosis Trial (EPAT)3 as supportive evidence that hormone replacement therapy (HRT) has no benefit on atherosclerosis in women with established cardiovascular disease (CVD). Citation of EPAT as supportive evidence for such a statement is incorrect on 2 major grounds, as follows: (1) EPAT was a randomized, double-blind, placebo-controlled, 2-year, serial arterial imaging trial conducted in healthy postmenopausal women without preexisting …

Background— Epidemiological studies have demonstrated an inverse relationship between vitamin E intake and cardiovascular disease (CVD) risk. In contrast, randomized controlled trials have reported conflicting results as to whether vitamin E supplementation reduces atherosclerosis progression and CVD events. Methods and Results— The study population consisted of men and women ≥40 years old with an LDL cholesterol level ≥3.37 mmol/L (130 mg/dL) and no clinical signs or symptoms of CVD. Eligible participants were randomized to DL-α-tocopherol 400 IU per day or placebo and followed every 3 months for an average of 3 years. The primary trial end point was the rate of change in the common carotid artery far-wall intima-media thickness (IMT) assessed by computer image-processed B-mode ultrasonograms. A mixed effects model using all determinations of IMT was used to test the hypothesis of treatment differences in IMT change rates. Compared with placebo, α-tocopherol supplementation significantly raised plasma vitamin E levels ( P P =0.03), and reduced LDL oxidative susceptibility ( P Conclusions— The results are consistent with previous randomized controlled trials and extend the null results of vitamin E supplementation to the progression of IMT in healthy men and women at low risk for CVD.

Background —The clustering of hypertension, insulin resistance, and obesity remains unexplained. We tested for genetic and nongenetic influences on the association among these traits in Hispanic families with hypertension. Methods and Results —Blood pressure and body mass index (BMI) were measured in 331 members of 73 Hispanic families in which an index case (proband) had hypertension. Insulin sensitivity (S I ) was measured by euglycemic clamp in 287 probands and their spouses (parents’ generation) or their adult offspring. Correlation analysis examined relationships among traits within and between generations. Path analysis estimated genetic and nongenetic contributions to variability in systolic blood pressure (SBP), S I , and the correlation between them. In the offspring, there was a significant correlation between individuals for each trait, as well as significant correlations within and between individuals for all possible pairs of traits. Between generations, SBP, S I , and BMI in parents correlated with the same traits in their offspring; BMI in parents correlated with S I and SBP in offspring; and S I in parents correlated with SBP in offspring. Path analysis estimated that among offspring, genetic effects unrelated to BMI accounted for 60.8% of the variation in SBP, 36.8% of the variation in S I , and 31.5% of the correlation between SBP and S I after adjustment for age and sex. Heritable effects related to BMI accounted for an additional 14.0% of variation in SBP, 26.8% of variation in S I , and 56.3% of variation in their correlation. Conclusions —Clustering of hypertension and insulin resistance in Hispanic Americans is accounted for in part by heritable factors both associated with and independent of BMI.

Background Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS). Methods and Results MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (S f 0 to 12), IDL (S f 12 to 20), VLDL (S f 20 to 400), and HDL (F 1.20 0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B–containing lipoproteins were measured independently, IDL ( r =.21, P r =−.09, P =.24) or LDL ( r =.09, P =.26) was associated with the progression of carotid artery intima-media thickness. Conclusions These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (S f 12 to 20) that is included within the traditional measurements of LDL-C.

Background Progression of coronary artery disease is assumed to be a surrogate end point for clinical coronary events. Because no single method or measure for a coronary angiographic end point is uniformly accepted as optimal, the utility and validity of surrogate end points for predicting clinical coronary events remain unsettled. Methods and Results The Cholesterol Lowering Atherosclerosis Study randomized 162 nonsmoking, 40- to 59-year-old men with previous coronary artery bypass graft surgery to colestipol/niacin plus diet or placebo plus diet. Atherosclerosis change on 2-year coronary angiograms was evaluated by a consensus panel and by quantitative coronary angiography (average per-subject change in percent diameter stenosis [%S] and minimum lumen diameter [MLD]). With all three end points, the benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported. Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram. Clinical coronary events (need for revascularization, nonfatal acute myocardial infarction, and coronary death) have been documented. Risk of clinical coronary events was positively related to coronary lesion progression for all three surrogate end points ( P P =.02) and progression of mild/moderate lesions (P P Conclusions In this population of nonsmoking men with previous bypass surgery, both the consensus panel– and quantitative coronary angiography–based end points of coronary artery disease progression predict clinical coronary events. Subjects who demonstrate greater coronary artery lesion progression have an increased risk of future clinical coronary events. Design of shorter, smaller trials of antiatherosclerotic agents is justified.

BACKGROUND The Monitored Atherosclerosis Regression Study, a randomized, double-blind, placebo-controlled, 2-year trial of lovastatin monotherapy, found that coronary lesions < 50% diameter stenosis (%S) and coronary lesions > or = 50% S at baseline had different responses to therapy. We now report on clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets. METHODS AND RESULTS Two hundred seventy subjects, 37 to 67 years old, with plasma total cholesterol (TC) 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and total triglyceride < 500 mg/dL (5.65 mmol/L) were randomized to low-fat, low-cholesterol diet and either lovastatin 80 mg/d or placebo. Logistic regression was used to model the association between risk factors and coronary lesion progression in mild/moderate (< 50% S) and severe (> or = 50% S) lesions in 220 angiogram pairs analyzed by computer quantitative coronary angiography. In the placebo group, risk factors (P < .05) for the progression of mild/moderate lesions were triglycerides and TC/high-density lipoprotein cholesterol (HDL-C). Risk factors for the progression of severe lesions were HDL-C (negative), low-density lipoprotein cholesterol (LDL-C)/HDL-C, and TC/HDL-C. TC/HDL-C was the predominant risk factor for both mild/moderate and severe lesions in the multivariate analysis. In the lovastatin group, with aggressive lowering of LDL-C and TC below 85 mg/dL and 156 mg/dL, respectively, risk factors for mild/moderate lesions included triglycerides and very-low-density lipoprotein-LDL-associated apolipoprotein C-III (apo C-III-heparin precipitate), a marker of triglyceride-rich lipoprotein particles. Apo C-III-heparin precipitate was the predominant risk factor in the multivariate analysis. Risk factors for severe lesions were LDL-C, LDL-C/HDL-C, TC/HDL-C, and apo B; LDL-C/HDL-C was the predominant risk factor. CONCLUSIONS These results indicate that triglyceride-rich lipoproteins and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression, respectively. These results add to the growing evidence of the importance of triglyceride-rich lipoproteins as a risk factor for coronary artery disease and the need for treatment in the progression of atherosclerosis.

It has been >55 years since Hahn1 first observed that the intravenous injection of heparin abolished postprandial lipemia in dogs; subsequently, Korn and Quigley2 identified the factor released by intravenous heparin as a triglyceride lipase. Since that time, the putative role of lipoprotein lipase in atherosclerosis has expanded tremendously. Lipoprotein lipase is a key enzyme in the regulation of lipid fuel disposal,3 and it provides fatty acids for tissue utilization by catalyzing the hydrolysis of triacylglycerol circulating in triglyceride-rich lipoproteins. Anchored to the surface of the capillary endothelium by glycosaminoglycans, lipoprotein lipase hydrolyzes plasma chylomicrons and VLDL to remnant particles. As such, lipoprotein lipase is the rate-limiting enzyme responsible for the removal of plasma triglyceride-rich lipoproteins from the circulation. Although expressed in most tissues of the body, in particular, skeletal and heart muscle and adipose tissue, lipoprotein lipase is also expressed and secreted by macrophages. Lipoprotein lipase is important for the transfer of phospholipids and apolipoproteins to HDL and, thus, is critical for the formation of this particle.4 Apolipoprotein C-II is an essential cofactor for the activation of lipoprotein lipase activity, …