Introduction: Allostatic load (AL) is a composite measure of multisystem physiological dysregulation. Elevated AL has been identified as a precursor to cardiovascular and metabolic diseases in older adults, but its role in young adults remains unclear. Methods: In this cross-sectional study, we examined the association between AL and three markers of subclinical atherosclerosis among 304 young adults (mean age=25.1 years) participating in the MetaAir2 study from 2018 to 2025. AL score was generated from 14 biomarkers representing four physiological domains: 1) HPA axis and sympathetic nervous system: cortisol, epinephrine, norepinephrine; 2) Inflammatory system: C-reactive protein, interleukin-6; 3) Metabolic system: BMI, total cholesterol, HDL, HbA1c, glucose, insulin; and 4) Cardiovascular system: systolic and diastolic blood pressure, heart rate. Each biomarker was dichotomized as 1 (high risk; exceeding clinical cut points) or 0 (low risk). System-specific scores were calculated as the mean of dichotomized biomarkers within each system. The four system-specific scores were then summed to generate a total AL score (range: 0–4), with higher values indicating greater physiological dysregulation. Subclinical atherosclerosis was assessed using 3 measures obtained from carotid artery ultrasonography: intima-media thickness (IMT), arterial stiffness (distensibility), and gray-scale median of the intima-media complex (IM-GSM). Associations between AL and subclinical atherosclerosis were evaluated using multivariable linear regression, adjusting for age, sex, race, ethnicity, physical activity, and parental education. Results: Higher overall allostatic load (AL) scores were significantly associated with greater IMT (β=25.5, 95% CI: 8.7, 39.6), lower arterial distensibility (β=-3.9, 95% CI: -5.7, -2.1), and lower IM-GSM (β=-3.8, 95% CI: -7.4, -0.3), indicating that increased physiological wear and tear is linked to thicker arterial walls, reduced elasticity, and greater lipid deposition—characteristics of early atherosclerosis. Further, system-specific analysis indicated that the inflammatory system score was significantly associated with IMT and IM-GSM, the metabolic system was associated with all three markers, and the cardiovascular system was associated with arterial distensibility only. Conclusion: Higher AL scores across multiple physiological systems are associated with greater risk of specific components of subclinical atherosclerosis in young adults.

Introduction: Extensive research has shown an association between BMI and subclinical atherosclerosis in children. However, BMI is a time-varying risk factor, which changes substantially during childhood. To date, no study has investigated how BMI at different developmental stages contributes to subclinical atherosclerosis. The Bayesian Relevant Life Course Model (BRLM) is an ideal tool for evaluating how a time-varying exposure affects health outcomes later in life. In this study, we applied this novel approach to examine the association between life course BMI from early childhood to young adulthood and subclinical atherosclerosis in young adulthood. Method: Data were from Southern California’s Children’s Health Study and its follow-up assessment, MetaAir2 (2003 to 2025). Indicators of subclinical atherosclerosis were evaluated by ultrasound at a mean age of 25 years including carotid artery intima-media thickness (IMT), distensibility, and lipid deposition (determined by gray-- scale median of intima media, IM-GSM). BMI was obtained at mean ages 6.5 (early childhood), 11 (mid-childhood), 15 (adolescence), and 25 years (young adulthood). We used BRLM to investigate: 1) the overall association of BMI measured across 19 years with subclinical atherosclerosis, and 2) the distribution of BMI-atherosclerosis association across the 4 stages. Analyses were adjusted for age, sex, race, ethnicity, adult physical activity level, and parental education level. Results: Among 324 participants, the lifetime effect of BMI on IMT had a posterior mean of 4.4mm (95% CrI: 2.7, 6.4), providing strong evidence of a positive association. The contributions of each life stage were 9.7%, 15.3%, 34.3%, and 40.7% for early childhood, mid-childhood, adolescence, and young adulthood, respectively, supporting a sensitive-period hypothesis, in which all stages contributed to IMT, but young adulthood contributed greater weights. For IM-GSM, the posterior mean association with BMI was –1.19 (95% CrI: –1.54, –0.87). Stage contributions were 8.3%, 8.4%, 10.9%, and 72.4%, suggesting a critical-period effect for arterial wall lipid deposition dominated by young adulthood. The results for distensibility were similar to IM-GSM. Conclusion: Life course BMI significantly impacts measures of subclinical atherosclerosis in early adulthood. Current BMI impacts lipid deposition and distensibility, while BMI’s impact on thickness is more cumulative, with slightly stronger effects from young adulthood.

Objective: Atherosclerosis, an aging-related disease, may begin developing in childhood. Epigenetic age is known to predict biological aging accurately, and epigenetic gestational age can predict biological maturity at birth. However, the association of biological aging at birth with atherosclerosis in later life remains unknown. We aim to examine the association of epigenetic gestational age with subclinical measures of atherosclerosis at ages 11 to 24 and their changes over time. Methods: In the Southern California Children’s Health Study, DNA methylation from newborn bloodspots of 242 participants was analyzed using the Infinium 450K array. We calculated epigenetic gestational ages with the Knight and Bohlin algorithms. Intrinsic Epigenetic Gestational Age Deceleration (IEGAD), indicating developmental immaturity at birth, was derived by regressing epigenetic age on clinical gestational age, adjusted for cell composition. Subclinical measures of atherosclerosis, including carotid intima-media thickness (CIMT) and carotid distensibility, were obtained from ultrasound images from all participants in childhood (mean age: 11.3 years, SD: 0.6) in 2007, and repeatedly obtained from a subset of 54 participants again in adulthood (mean age: 24.2 years, SD: 1.6) between 2019 and 2022. Associations between each IEGAD and subclinical atherosclerosis measures, including their changes over time, were evaluated using linear regression, adjusting for sex, race, birthweight, age and body mass index at time of ultrasound, maternal age at delivery, and maternal pregnancy complications. Results: Knight IEGAD (mean: -0.05, SD = 1.1) and Bohlin IEGAD (mean: -0.03, SD=0.78) was moderately correlated (Pearson r = 0.67, P<0.001). Each week increase in Bohlin EEGAD was associated with higher adult CIMT (β = 34.9 µm, 95% CI: 1.63, 68.2) and with more CIMT thickening from childhood to adulthood (β = 2.2 µm/year, 95% CI: 0.05, 4.36). Similarly, each week increase in Knight IEGAD was associated with reduced arterial elasticity, as measured by lower carotid distensibility, in both childhood (β = -3.22, 95% CI: -0.78, -5.67) units (10 −6 ×m 2 /Newtons) and adulthood (β = -1.99, 95% CI: -0.36, 4.34), and an annual reduction of 0.40 (-0.14, 0.94) unit/year from childhood to adulthood. Conclusion: Developmental immaturity at birth, as indicated by epigenetic gestational age, is associated with adverse subclinical atherosclerosis markers from childhood to adulthood.

Background We investigated how childhood‐to‐adulthood perceived stress patterns predict adult cardiometabolic risk. Methods and Results This study included 276 participants from the Southern California Children's Health Study (2003–2014), and a follow‐up assessment (2018–2021). Perceived stress (Perceived Stress Scale) was initially reported by participants' parents for themselves during early childhood (mean age, 6.3 years), and later self‐reported during adolescence (13.3 years) and young adulthood (23.6 years). Participants were grouped into 4 stress patterns: consistently high, decreasing, increasing, and consistently low. Cardiometabolic risk was assessed in young adulthood by carotid artery intima‐media thickness, systolic and diastolic blood pressure, obesity, percent body fat, android/gynoid ratio, and glycated hemoglobin. A cardiometabolic risk score was generated by summing the clinically abnormal markers. Multivariable linear and logistic regression models were used to (1) examine the associations between Perceived Stress Scale at 3 time points and adult cardiometabolic risk, and (2) assess the impact of stress pattern on adult cardiometabolic risk. Findings suggested that in adulthood, higher Perceived Stress Scale score was associated with increased overall cardiometabolic risk (β=0.12 [95% CI, 0.01–0.22]), carotid artery intima‐media thickness (β=0.01 [95% CI, 0.0003–0.02]), systolic blood pressure (β=1.27 [95% CI, 0.09–2.45]), and diastolic blood pressure (β=0.94 [95% CI, 0.13–1.75]). Individuals with a consistently high adolescence‐to‐adulthood stress pattern had greater overall cardiometabolic risk (β=0.31 [95% CI, 0.02–0.60]), android/gynoid ratio (β=0.07 [95% CI, 0.02–0.13]), percent body fat (β=2.59 [95% CI, 0.01–5.17]), and greater odds of obesity (odds ratio, 5.57 [95% CI, 1.62–19.10]) in adulthood, compared with those with a consistently low Perceived Stress Scale score. Conclusions Consistently high perceived stress from adolescence to adulthood may contribute to greater cardiometabolic risk in young adulthood.

Introduction: Echogenicity of the carotid arterial wall, measured by gray scale median of the intima-media (GSM-IM), is a unitless measure that reflects lipid deposition in the arterial wall, with lower values indicating greater lipid deposition and atherosclerosis. Due to the relative novelty of GSM-IM, its progression and associated risk factors are incompletely understood. This study investigated the GSM profile in childhood and young adulthood using a longitudinal cohort of individuals followed over time, and conducted a priori analysis on the behavioral, psychosocial, and health risk factors for GSM. Methods: Data were collected as part of the Meta-Air2 follow-up study of participants enrolled in the Southern California Children’s Health Study. A total of 240 study participants underwent a carotid artery ultrasound examination in 2008 (mean age±standard deviation [ SD] : 11.2±0.6 years), and again between 2018 and 2023 (24.2±1.6 years) to assess changes in carotid artery health, including GSM-IM, carotid artery intima-media thickness (CIMT), and carotid artery distensibility. Participants self-reported lifestyle behaviors, psychosocial health, and underwent anthropometric and blood pressure measures at both time points. Mixed effects models were used to predict GSM-IM changes with repeated measurements of lifestyle behaviors, perceived stress, BMI, and blood pressure. Results: Means and SDs of GSM-IM were 110.0±27.4 in childhood, and 75.6±15.8 in adulthood, with an annual change rate of -2.6 per year. Individuals of Hispanic ethnicity, and those with lower parental education levels had significantly lower GSM-IM in both childhood and adulthood. GSM-IM was significantly correlated with other measures of carotid artery atherosclerosis, including CIMT (r=0.28; p <0.001) and carotid artery distensibility (r=0.36; p <0.001). Results of mixed effects models adjusting for covariates, indicated that higher BMI (β=-1.35; 95% confidence interval [CI], -1.70, -0.99; p <0.001) and systolic blood pressure (β=-0.32, 95% CI, -0.55, -0.09; p=0.007) were significantly associated with lower GSM-IM. A significant interaction between BMI and age (β difference=0.14; 95% CI, 0.09, 0.20; p <0.001) suggested that a per-unit change in BMI has a greater effect on GSM-IM among adolescents compared to young adults. Health compromising behaviors, including less sleeping time, smoking, drug use, and higher perceived stress were significantly associated with lower GSM-IM in unadjusted models. However, these associations were attenuated after adjustment for covariates. Conclusion: Our study highlights the influence of BMI, particularly during childhood, blood pressure and lifestyle behaviors on adverse changes in GSM-IM, indicative of greater lipid deposition. These risk factors may be key targets for early prevention for atherosclerosis.

Background This study investigated the association of American Heart Association's cardiovascular health guidelines Life's Essential 8 (LE8) and Life's Simple 7 (LS7) with carotid artery outcomes among young adults. Methods and Results This cross‐sectional study included 240 young adults (age 24.2±1.6 years) who underwent a carotid ultrasound between 2018 and 2022. LE8 score was calculated from 4 health factors (body mass index, non–high‐density lipoprotein cholesterol, fasting glucose, and blood pressure), and 4 health behaviors (dietary intake, physical activity, tobacco use, and sleep). LS7 was calculated from 7 metrics (all LE8 metrics, except for sleep) with a simpler algorithm. Higher LE8 and LS7 scores both indicate better health and better adherence to American Heart Association guidelines. Carotid artery outcomes included carotid artery intima‐media thickness, arterial stiffness (eg, distensibility), and echogenicity determined by grayscale median of the intima media complex. Results of linear regression analyses, adjusting for age, sex, ethnicity, and parents' highest degree, indicated that a 1‐SD increase in LE8 score was associated with 12.14 μm lower carotid artery intima‐media thickness (95% CI, −20.93 to 3.35), 1.17 (10 −6 ×m 2 /N) greater distensibility (95% CI, 0.09–2.24), suggesting less arterial stiffness, and 2.66 μm greater grayscale median of the intima media complex (95% CI, 0.58–4.75), suggesting less lipid deposition. Analyses using LS7 score demonstrated comparable findings. Health factor metrics demonstrated stronger association with carotid artery outcomes, as compared with behavior metrics. Conclusions Greater adherence to the American Heart Association's cardiovascular health guidelines is associated with lower risk for subclinical atherosclerosis in young adults. LE8 and LS7 demonstrated comparable associations with carotid artery outcomes.

Background: In 2022, the American Heart Association (AHA) published a new set of cardiovascular health (CVH) guidelines, named Life's Essential 8 (LE8), as an update to the AHA’s previous definition of ideal CVH, Life’s Simple 7 (LS7). This study used both LE8 and LS7 scores to investigate associations between CVH and carotid markers among young adults. Methods: This cross-sectional study included 240 young adults (age 24.2±1.6) who underwent a carotid ultrasound between 2018 to 2022. LE8 score was calculated from 8 metrics including four health factors (body mass index (BMI), non-high density lipid (non-HDL) levels, fasting glucose, and blood pressure), and four health behaviors (physical activity, dietary pattern, tobacco use, and sleep). LS7 was calculated from 7 metrics (all LE8 metrics, except for sleep) with a simpler algorithm. Higher LE8 and LS7 scores both indicate better adherence to CVH guidelines. Carotid artery intima-media thickness (CIMT), arterial stiffness (CAS), and lipid deposition (determined by gray scale median, GSM) were evaluated by carotid ultrasound. Linear regression analyses were conducted to assess the association of LE8 and LS7 with carotid markers, adjusting for age, sex, race/ethnicity, and parents’ highest degree. Results: After adjusting for covariates, a one standard deviation (SD) increase in LE8 score was associated with 11.11μm lower CIMT (95% confidence interval[ CI] , -19.91 -2.30; p , 0.014), 1.20 (10 -6 xm 2 /N) greater distensibility (95% CI , 0.12 2.29; p 0.030), and 2.62 greater GSM (95% CI , 0.51 4.73; p 0.015). Analyses using LS7 score demonstrated consistent findings. Individual health factor metrics demonstrated stronger association with carotid markers, as compared to individual behavior metrics. One-SD increase in LE8 BMI score was associated with 19.37μm lower CIMT (95% CI , -27.66 -11.07; p <0.001), 2.33 greater distensibility (95% CI , 1.31 3.35; p 0.001), and 6.10 greater GSM (95% CI, 4.18 8.03; p <0.001). Similar trends were observed for LE8 scores for lipids and blood pressure with carotid measures. Conclusion: Greater adherence to CVH guidelines is associated with better carotid arterial health in young adults, evidenced by lower CIMT, less arterial stiffness, and less lipid deposition. LE8 and LS7 demonstrated comparable associations with carotid markers, with LE8 displaying a slightly stronger association with CIMT.

BACKGROUND: HIV and hepatitis C virus (HCV) are associated with increased risk of carotid artery atherosclerotic plaque and stroke. We examined associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque. METHODS: This cross-sectional study included participants from the MACS (Multicenter AIDS Cohort Study)/WIHS (Women’s Interagency HIV Study) Combined Cohort Study who underwent high-resolution B-mode carotid artery ultrasound. Plaques were characterized from 6 areas of the right carotid artery. Poisson regression controlling for demographic and cardiometabolic risk factors determined adjusted prevalence ratios (aPRs) and 95% CIs for associations of HIV- and HCV-related factors with echomorphologic features. RESULTS: Of 2655 participants (65% women, median age 44 [interquartile range, 37–50] years), 1845 (70%) were living with HIV, 600 (23%) were living with HCV, and 425 (16%) had carotid plaque. There were 191 plaques identified in 129 (11%) women with HIV, 51 plaques in 32 (7%) women without HIV, 248 plaques in 171 (28%) men with HIV, and 139 plaques in 93 (29%) men without HIV. Adjusted analyses showed that people with HIV and current CD4 + count <200 cells/µL had a significantly higher prevalence of predominantly echolucent plaque (aPR, 1.86 [95% CI, 1.08–3.21]) than those without HIV. HCV infection alone (aPR, 1.86 [95% CI, 1.08–3.19]) and HIV-HCV coinfection (aPR, 1.75 [95% CI, 1.10–2.78]) were each associated with higher prevalence of predominantly echogenic plaque. HIV-HCV coinfection was also associated with higher prevalence of smooth surface plaque (aPR, 2.75 [95% CI, 1.03–7.32]) compared with people without HIV and HCV. CONCLUSIONS: HIV with poor immunologic control, as well as HCV infection, either alone or in the presence of HIV, were associated with different echomorphologic phenotypes of carotid artery plaque.

Background Echogenicity of the carotid arterial wall, measured by gray scale median of the intima‐media complex (IM‐GSM), is a novel subclinical atherosclerosis marker with lower values indicating greater lipid deposition. Our longitudinal study investigated IM‐GSM from childhood to adulthood and its associated risk factors. Methods and Results A total of 240 participants from the Southern California CHS (Children's Health Study) underwent carotid artery ultrasounds in 2008 (mean age±SD): (11.2±0.6 years), and again around 2022 (24.2±1.6 years) to assess IM‐GSM, carotid artery intima‐media thickness, and carotid artery distensibility. Questionnaires and anthropometric and blood pressure measurements were completed by participants at both times. Mean and SD of IM‐GSM were 108.2±24.6 in childhood and 75.6±15.8 in adulthood. Each 1‐year increase in age was associated with −2.52 change in IM‐GSM (95% CI, −2.76 to −2.27). Childhood and adulthood IM‐GSMs were highly correlated (β=0.13 [95% CI, 0.05–0.22]). In childhood, Hispanic ethnicity, lower parental education levels and prenatal father smoking were significantly associated with lower IM‐GSM. In adulthood, higher systolic blood pressure, carotid artery intima‐media thickness, hypertension, and lower distensibility were significantly associated with lower IM‐GSM. Weight status exhibited a consistent association with both childhood and adulthood IM‐GSM. During the transition from childhood to adulthood, individuals who shifted from normal weight to overweight/obese or normal blood pressure to hypertension or experienced an increase in carotid artery intima‐media thickness displayed lower levels of IM‐GSM in adulthood. Conclusions IM‐GSM decreases with age. Maintaining healthy weight and blood pressure levels in children could potentially aid in preventing subclinical atherosclerosis.

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.

Objectives Although carotid artery intima media thickness (CIMT) is a widely used determinant of subclinical atherosclerosis, gray‐scale median of the intima‐media complex (IM‐GSM) of the common carotid artery is a relatively novel measure of echogenicity reflecting composition of the arterial wall. It is important to compare cardiovascular disease (CVD) risk factor correlates across CIMT and IM‐GSM to determine whether these measures reflect distinct aspects of atherosclerosis. Methods Baseline information from a completed randomized clinical trial of 643 healthy postmenopausal women without clinically apparent CVD was included in this cross‐sectional study. The women were on average ± SD 61 ± 7 years old, and predominantly non‐Hispanic White. CIMT and IM‐GSM were measured by high‐resolution B‐mode ultrasonogram in the far wall of the right common carotid artery. CVD risk factors including age, race, body mass index (BMI), smoking, weekly hours of physical activity, systolic (SBP) and diastolic blood pressure (DBP), lipids, glucose, and inflammatory markers were measured at baseline. Linear regression models were used to assess associations of CVD risk factors with CIMT and IM‐GSM. Multivariable models included groups of risk factors added one at a time with and withoutbasic demographic factors (age, race, BMI, physical activity) with model R 2 values compared between CIMT and IM‐GSM. Results In multivariable analysis, age, Black race, BMI, SBP, and DBP were associated with CIMT (all P < .05), whereas age, Hispanic race, BMI, SBP, physical activity, LDL‐cholesterol, and leptin were correlates of IM‐GSM (all P < .05). Adjusted for age, race, BMI, and physical activity, the R 2 value for SBP was greater for CIMT association, whereas R 2 values for lipids, glucose, inflammatory markers, and adipokines were greater for IM‐GSM associations. Conclusions CIMT and IM‐GSM assess different attributes of subclinical atherosclerosis. Integrating both measures may provide improved assessment of atherosclerosis in asymptomatic individuals.

Objective: To evaluate the effect of hormone therapy (HT) on arterial wall composition by ultrasound. Background: The effect of HT on the progression of subclinical atherosclerosis has been well-described using measurements of common carotid artery (CCA) wall thickness. However, it is unknown whether the change in arterial wall anatomic structure is accompanied by an effect of HT on arterial wall composition. Methods: A total of 643 healthy postmenopausal women divided into two strata according to the time since menopause (< 6 years, the early-postmenopause group; or > 10 years, the late-postmenopause group) were randomized to receive either active treatment or placebo. For hysterectomized women, the active treatment was oral micronized 17 beta-estradiol 1 mg/day; for women with a uterus, 4% vaginal micronized progesterone gel 45 mg/day for 10 days each month was added to the estradiol regimen. Gray-scale median of the CCA intima-media complex (IM-GSM), a (unitless) measurement of arterial wall composition based on echogenicity, was determined by high-resolution B-mode ultrasonography. Lower IM-GSM, or less echogenicity, indicates more atherosclerosis. IM-GSM and serum estradiol (E2) concentration were assessed every 6 months over a median 4.8-year trial period. Linear mixed effects regression models were used for all analyses. Results: Overall, IM-GSM progression/year had a negative trajectory, reflecting reduction in echogenicity over time (worsening atherosclerosis). HT effects on IM-GSM progression/year differed by postmenopause strata (interaction p-value = 0.02). IM-GSM progression/year (95% CI) in the early postmenopause group randomized to HT was-0.50 (-0.82,-0.18)/year compared with-1.47 (-1.81,-1.13)/year among those randomized to placebo (p-value < 0.0001). In the late postmenopause group, the annual IM-GSM progression rate did not significantly differ between HT and placebo (p = 0.28). Higher mean on-trial E2 (pg/ml) levels were associated with higher IM-GSM progression, indicating less atherosclerosis progression in all women (beta (95% CI) = 0.006 (0.0003, 0.01), p = 0.04). For each pg/dl E2, IM-GSM progression/year was 0.007 ((-0.0002, 0.01), p = 0.056) in the early and 0.003 ((-0.006, 0.01), p = 0.50) in the late postmenopause group (interaction p-value = 0.51). CIMT progression rate (mu m/year) was significantly inversely associated with the IM-GSM progression (beta (95% CI) = -4.63 (-5.6,-3.7), p < 0.001). Conclusions: HT, primarily with oral estradiol, reduced atherogenic progression of arterial wall composition in healthy postmenopausal women who were within 6 years from menopause. Trial registration number: NCT01553084

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Maximum carotid plaque thickness (MCPT) measures the largest plaque thickness in the carotid artery and reflects atherosclerosis plaque burden. MCPT may be a better predictor of cardiovascular disease than carotid artery intima-media thickness (cIMT) because it identifies potential unstable arterial atherosclerosis plaques. We assessed the relationships of monocyte and T cell populations and plasma soluble mediators with MCPT measures. We performed a cross-sectional and small follow-up analysis in people living with HIV (PLWH) aged >40 years on stable antiretroviral therapy (ART) >6 months. MCPT was acquired by high-resolution B-mode ultrasound. Existing monocyte subsets and T cell activation frequencies were determined by flow cytometry and plasma mediators of inflammation and apolipoproteins were measured by Luminex assay. One hundred twenty-five ART-treated PLWH, 88% male, 55% Caucasian, with a median age of 51 years, median CD4 count of 477 cells/mu L (Q1: 325, Q3: 612), 84% undetectable plasma HIV RNA (<50 copies/mL). Twenty-five PLWH had detectable carotid plaque. MCPT correlated with monocyte chemoattractant protein-1 (MCP-1;r = 0.487,p = .016), tumor necrosis factor-alpha (TNF-alpha;r = 0.474p = .019), soluble vascular cell adhesion molecule-1 (sVCAM-1;r = 0.472,p = .020), apolipoprotein B6 (ApoB6;r = -0.473,p = .019), and interleukin-6 (IL-6;r = 0.455,p = .025). In a multivariable regression model, MCP-1, TNF-alpha, and sVCAM-1 remained significant after adjustment for age. Carotid plaque burden was associated with increased inflammatory, monocyte, and endothelial measures, including MCP-1, TNF-alpha, and sVCAM-1 levels. Further investigation on the evolution or severity of plaque burden in this population is warranted.

BACKGROUNDData suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.METHODSA total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.RESULTSAfter a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.CONCLUSIONSOral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

Background: Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT). Methods: Longitudinal study of HIV-infected subjects ≥40 years and on stable antiretroviral therapy (ART) ≥3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14++CD16–), intermediate (CD14++CD16+), non-classical (CD14low/+CD16++) and transitional (CD14+CD16–) monocyte subsets and activated (CD38+HLA-DR+) CD8+ T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High-resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables. Results: We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm3, and with HIV RNA ≤ 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-α (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA. Conclusions: Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors.

BACKGROUND:Age and human immunodeficiency virus (HIV) treatment may affect the association of HIV infection with atherosclerosis.METHODS:We used identical carotid artery B-mode ultrasonographic methods in 5 cohorts participating in the National Heart, Lung, and Blood Institute HIV-CVD Collaborative to measure intima-media thickness of the right far wall of the common carotid artery (CCA-IMT) and carotid artery bifurcation (BIF-IMT) between 2010 and 2013. Participants aged 6-75 years were either HIV infected or uninfected. Linear regression assessed associations of CCA-IMT and BIF-IMT with HIV infection and cardiovascular disease risk factors, within age and HIV treatment groups. Adjustment variables included sex, race/ethnicity, smoking, height, weight, and use of antihypertensive and lipid-lowering drugs.RESULTS:We studied 867 HIV-infected and 338 HIV-uninfected male and 696 HIV-infected and 246 HIV-uninfected female participants. Among both middle-aged (30-49 years) and older adults (50-75 years), HIV-infected participants had CCA-IMT and BIF-IMT values that were similar to or lower than those in HIV-uninfected participants. In contrast, among those aged 6-29 years, HIV infection was associated with higher CCA-IMT and BIF-IMT values. Among HIV-infected participants, associations of higher systolic blood pressure and lower high-density lipoprotein cholesterol with Carotid artery intima-media thickness strengthened with age.CONCLUSIONS:The effects of HIV on carotid artery structure may differ across the lifespan, with traditional determinants of cardiovascular disease burden playing a larger role and HIV playing a lesser role in older adults than in young adults and children.