16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability.

Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism.

Change in C-reactive protein after Roux-en-Y gastric bypass through 7 years of follow-up.

BACKGROUND: Long-term change in CRP is not well characterized in the context of RYGB. OBJECTIVE: To report C-reactive protein (CRP) after Roux-en-Y gastric bypass surgery (RYGB). SETTING: Between 2006 and 2009 1770 adults enrolled in a prospective cohort study underwent Roux-en-Y gastric bypass (RYGB) at 1 of 10 U.S. hospitals. METHODS: Research assessments were conducted before surgery and annually postoperatively for up to 7 years. This study included those with high-sensitivity CRP assessed before surgery and 1 or more follow-up assessments (n = 1180). RESULTS: Before surgery, participants' median age was 46 years, and the median body mass index (BMI) was 46 kg/m2; 80% were female. Before surgery, mean (95% confidence interval [CI]) CRP was the highest of all time points (1.01 [.95-1.08] mg/L); it then decreased to a nadir of .18 (.15-.22) mg/L at 2 years postoperatively (P < .001). CRP was higher at 7 years (.26 [.22, .29] mg/L) than at 2 years postoperatively (P < .001) but remained lower at 7 years than preoperatively (P < .001). Additionally, only 3.2% (95% CI: 1.6%-4.8%) of participants had elevated CRP (>1 mg/dL) 7 years postoperatively versus 32.9% (95% CI: 30.2%-35.3%) preoperatively (P < .001). Several preoperative factors were associated with following a less favorable CRP trajectory over time, including higher preoperative CRP level, higher BMI, current smoking, and diabetes. CONCLUSION: The vast majority of adults who underwent RYGB experienced a sustained improvement in CRP throughout 7 years of follow-up with nonelevated values. However, those with higher preoperative CRP and BMI levels and diabetes and who smoke may benefit from additional testing and monitoring to ensure nonelevated inflammation after surgery.

Mice lacking melatonin MT2 receptors exhibit attentional deficits, anxiety and enhanced social interaction.

BACKGROUND: Aside from regulating circadian rhythms, melatonin also affects cognitive processes, such as alertness, and modulates the brain circuitry underlying psychiatric diseases, such as depression, schizophrenia and bipolar disorder, via mechanisms that are not fully clear. In particular, while melatonin MT1 receptors are thought primarily to mediate the circadian effects of the hormone, the contribution of the MT2 receptor to melatonin actions remains enigmatic. AIMS: To characterise the contribution of MT2 receptors to melatonin's effects on cognition and anxiety/sociability. METHODS: Mice with a genetic deletion of the MT2 receptor, encoded by the Mtnr1b gene, were compared with wild-type littermates for performance in a translational touchscreen version of the continuous performance task (CPT) to assess attentional processes and then monitored over 3 days in an ethological home-cage surveillance system. RESULTS: Mtnr1b knockout (KO) mice were able to perform at relatively normal levels in the CPT. However, they showed consistent evidence of more liberal/risky responding strategies relative to control mice, with increases in hit rates and false alarm rates, which were maintained even when the cognitive demands of the task were increased. Assessment in the home-cage monitoring system revealed that female Mtnr1b KO mice have increased anxiety levels, whereas male Mtnr1b KO mice show increased sociability. CONCLUSIONS: The results confirm that the MT2 receptor plays a role in cognition and also modulates anxiety and social interactions. These data provide new insights into the functions of endogenous melatonin and will inform future drug development strategies focussed on the MT2 receptor.

Adipokines and Subclinical Cardiovascular Disease in Post-Menopausal Women: Study of Women's Health Across the Nation.

Background The menopausal transition is characterized by increased cardiovascular risk, weight gain, and increased adiposity for many women. The adipose-derived secretory proteins adiponectin and leptin are associated with insulin resistance, metabolic syndrome, and cardiovascular disease but their role in subclinical atherosclerotic disease is unclear. This cross-sectional study evaluated the associations of adiponectin and leptin with carotid artery intima-media thickness, adventitial diameter, presence of carotid plaques, and brachial-ankle pulse wave velocity (baPWV) in women aged 54 to 65 years. Methods and Results Participants were 1399 women from SWAN (Study of Women's Health Across the Nation), a community-based study of women transitioning through menopause. Carotid ultrasound and baPWV measures were obtained at SWAN follow-up visits 12 or 13, when 97% of participants were post-menopausal. Adipokines were assayed from serum specimens obtained concurrently at these visits. Linear and logistic regression models were used to evaluate adiponectin or leptin, both log-transformed attributable to skewness, in relationship to carotid artery intima-media thickness, adventitial diameter, baPWV, and presence of carotid plaque. Covariates included age, race, study site, smoking, alcohol use, obesity, cardiovascular disease risk factors, and menopausal status. Lower levels of adiponectin were related to greater carotid artery intima-media thickness, wider adventitial diameter, and faster baPWV; associations were attenuated after adjusting for cardiovascular disease risk factors. Higher levels of leptin were associated with greater carotid artery intima-media thickness and wider adventitial diameter in minimally and fully adjusted models, and contrary to expectation, with slower baPWV, particularly among women with diabetes mellitus or obesity. Conclusions Adiponectin and leptin are 2 important inflammatory pathways that may contribute to adverse subclinical cardiovascular disease risk profiles in women at midlife.

Predictors of change in cardiovascular disease risk and events following gastric bypass: a 7-year prospective multicenter study.

BACKGROUND: Change in short-term (i.e., 10-year) and lifetime risk of cardiovascular disease (CVD) following Roux-en-Y gastric bypass (RYGB) has significant heterogeneity. OBJECTIVE: To identify predictors of change in CVD risk and cardiovascular events following RYGB. METHODS: Between 2006-2009, 1625 adults without a history of CVD enrolled in a prospective cohort study and underwent RYGB at 1 of 10 U.S. hospitals. Participants were followed annually for a maximum of 7 years. Associations between presurgery characteristics (anthropometric, sociodemographic, physical and mental health, alcohol/drug use, eating behaviors) and 1) pre to postsurgery change in 10 year and lifetime atherosclerotic CVD (ASCVD) risk scores, respectively, and 2) having a CVD event (nonfatal myocardial infarction, stroke, ischemic heart disease, congestive heart failure, angina, percutaneous coronary intervention, coronary artery bypass grafting, or CVD-attributed death) as repeated measures (yr 1-7) were evaluated. SETTING: Observational cohort study at ten hospitals throughout the United States. RESULTS: Presurgery factors independently associated with decreases in both 10-year and lifetime risk scores 1-7 years post-RYGB were higher CVD risk score, female sex, higher household income, and normal kidney function. Additionally, Black race and having diabetes were independently associated with decreases in 10-year risk, while not having diabetes and a higher (better) composite mental health score were independently related to decreases in lifetime risk. A lower (worse) presurgery composite physical health score was associated with a higher CVD event risk (RR = 1.68, per 10 points). CONCLUSION: This study identified multiple presurgery factors that characterize patients who may have more cardiovascular benefit from RYGB, and patients who might require additional support to improve their cardiovascular health.

Impaired working memory, cognitive flexibility and reward processing in mice genetically lacking Gpr88: Evidence for a key role for Gpr88 in multiple cortico-striatal-thalamic circuits.

The GPR88 orphan G protein-coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze 'N-back' working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild-type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with enhanced motivation. Simultaneously, locomotor hyperactivity was apparent in this task, supporting previous findings of actions of GPR88 in a cortico-striatal-thalamic motor loop. Evidence for a role of GPR88 in reward processing was demonstrated in a touchscreen-based equivalent of the Iowa gambling task. Although both Gpr88 KO and wild-type mice showed a preference for an optimum contingency choice, Gpr88 KO mice selected more risky choices at the expense of more advantageous lower risk options. Together these novel data suggest that striatal GPR88 receptors influence activity in a range of procedures integrated by prefrontal, orbitofrontal and anterior cingulate cortico-striatal-thalamic loops leading to altered cognitive, motivational and reward evaluation processes.

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.

Change in predicted 10-year and lifetime cardiovascular disease risk after Roux-en-Y gastric bypass.

BACKGROUND: Long-term changes in cardiovascular disease (CVD) risk after bariatric surgery are not well characterized. OBJECTIVE: To report sex-specific changes in CVD risk after Roux-en-Y gastric bypass surgery (RYGB). SETTING: Observational cohort study at ten hospitals throughout the United States. METHODS: Between 2006 and 2009, 1770 adults enrolled in a prospective cohort study underwent RYGB at 1 of 10 U.S. hospitals. Research assessments were conducted presurgery and annually postsurgery over 7 years. Sex specific-predicted 10-year and lifetime CVD risk were calculated using the Framingham10-year and lifetime risk scores, Framingham-body mass index, and atherosclerotic CVD scoring algorithms among participants with no history of CVD. Of 1566 eligible participants, 1234 (75.9%) with CVD risk determination pre- and postsurgery were included (1013 females, 221 males). RESULTS: Based on the Framingham10-year and lifetime risk scores, the percentage of females with predicted high (>20%) 10-year CVD risk declined from presurgery (6.5% [95% confidence interval: 6.7-7.5]) to 1 year postsurgery (1.0% [95% confidence interval: .8-1.2]; P < .001), then increased 1 to 7 years postsurgery (to 2.8% [95% confidence interval: 1.6-3.3]; P = .003), but was lower 7 years postsurgery versus presurgery (P < .001). Time trends for percentage of high-risk participants and mean CVD risk scores were similar for both sexes and other evaluated CVD risk scores. For example, among males mean lifetime atherosclerotic CVD score declined from presurgery to 1 year postsurgery, then increased 1 to 7 years postsurgery. However, there was a net decline from presurgery (P < .001). CONCLUSION: Among both females and males, predicted 10-year and lifetime CVD risk was substantially lower 7 years post RYGB than presurgery, suggesting RYGB surgery can lead to sustained improvements in short- and long-term CVD risk.

Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system - implications for the 3Rs and preclinical drug discovery.

BACKGROUND: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias. AIM: To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an N-methyl-D-aspartate (NMDA) receptor antagonist commonly utilised to model aspects of schizophrenia. METHODS: Rats housed in groups of three were implanted with radio frequency identification (RFID) tags. Each homecage was placed over a RFID reader baseplate for the automated monitoring of the social and locomotor activity of each individual rat. For all rats, we acquired homecage data for 24 h following administration of both saline and PCP (2.5 mg/kg). RESULTS: PCP resulted in significantly increased distance travelled from 15 to 60 min post injection. Furthermore, PCP significantly enhanced time spent isolated from cage mates and this asociality occured from 60 to 105 min post treatment. CONCLUSIONS: Unlike conventional assays, in-cage monitoring captures the temporal duration of drug effects on multiple behaviours in the same group of animals. This approach could benefit psychiatric preclinical drug discovery through improved welfare and increased between-laboratory replicability.

16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia.

Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze "N-back" working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.

Women with Preterm Birth Have Evidence of Subclinical Atherosclerosis a Decade After Delivery.

Background: Women with preterm birth (PTB) have excess risk of cardiovascular disease (CVD) and metabolic dysregulation after delivery, but vascular mechanisms are poorly understood. We considered that women with PTB may have evidence of subclinical atherosclerosis after delivery, perhaps related to cardiometabolic risk factors. Materials and Methods: The Pregnancy Outcomes and Community Health Moms (POUCHmoms) study followed women from pregnancy through 7 to 15 years after delivery (n = 678). Women underwent B-mode ultrasound to measure the average intima-media thickness (IMT) across the common carotid, bulb, and internal carotid artery segments at follow-up (n = 605). Linear regression estimated the overall and segment-specific difference in IMT between women with preterm and term births. Results: Women were, on average, 38 years old (SD 5.7) at the follow-up visit. Those with a prior preterm versus term birth had thicker mean IMT (average of eight segments, 0.592 mm vs. 0.575, p = 0.04). Differences persisted after accounting for age, race, smoking, and body mass index (difference = +0.018 mm, p = 0.019) and were attenuated after adjustment for blood pressure, medication use, and total cholesterol (difference = +0.014, p = 0.052). Thicker mean bulb IMT in women with PTB was robust to cardiovascular risk factor adjustments (fully adjusted difference = +0.033, p = 0.029). Excluding cases of prepregnancy hypertension or preeclampsia did not change results. Conclusions: Mechanisms leading to subclinical atherosclerosis may link PTB with future CVD. PTB differences in maternal vessel remodeling in the carotid bulb, an arterial segment more prone to early development of atherosclerosis, were independent of traditional risk factors suggesting that novel processes may be involved.

Comparison of carotid plaque burden among healthy middle-aged men living in the US, Japan, and South Korea.

BACKGROUND: Carotid plaque has emerged as a marker of coronary heart disease (CHD) risk. Comparison of carotid plaque burden between different race/ethnic groups may provide a relative estimate of their future CHD risk. METHODS: We conducted a population-based study among apparently healthy middle-aged men aged 40-49 years (ERA JUMP study (n = 924)) and recruited 310 Whites in Pittsburgh, US, 313 Japanese in Otsu, Japan, and 301 Koreans in Ansan, South Korea. The number of carotid plaque and CHD risk factors was assessed using a standardized protocol across all centers. The burden of carotid plaque was compared between race/ethnic groups after adjustment for age and BMI, and after multivariable adjustment for other CHD risk factors using marginalized zero-inflated Poisson regression models. Cross-sectional associations of risk factors with plaque were examined. RESULTS: Whites (22.8%) had more than four-fold higher prevalence (p < 0.01) of carotid plaque than Japanese men (4.8%) while the prevalence among Koreans was 10.6%. These differences remained significant after adjustment for age, BMI as well as other risk factors - incidence density ratio (95% confidence interval) for plaque was 0.13 (0.07, 0.24) for Japanese and 0.32 (0.18, 0.58) for Koreans as compared to Whites. Age, hypertension and diabetes were the only risk factors significantly associated with presence of carotid plaque in the overall population. CONCLUSION: Whites have significantly higher carotid plaque burden than men in Japan and Korea. Lower carotid plaque burden among Japanese and Koreans is independent of traditional CVD risk factors.

Common carotid artery intima-media thickness increases throughout the pregnancy cycle: a prospective cohort study.

BACKGROUND: High parity is associated with greater cardiovascular disease (CVD) among mid-life and older women. Prospective studies of arterial change throughout pregnancy are needed to provide insight into potential mechanisms. This study assessed vascular adaptation across pregnancy in healthy first-time pregnant women. METHODS: The Maternal Vascular Adaptation to Healthy Pregnancy Study (Pittsburgh, PA, 2010-2015) assessed 37 primigravid women each trimester, 6-8 weeks after delivery and 1-5 years postpartum, with B-mode ultrasound imaging of common carotid artery (CCA) intima-media thickness (IMT) and inter-adventitial diameter (IAD) to assess associations with physical and cardiometabolic measures. RESULTS: Thirty-seven women (age 28.2 ± 4.5 years, pre-pregnant BMI 24.4 ± 3.2 kg/m2) experienced uncomplicated pregnancies. After adjustment for age and pre-pregnancy BMI, mean (SE) IAD (mm) increased each trimester, from 6.38 (0.08) in the 1st trimester to 6.92 (0.09) in the 3rd trimester, and then returned to 1st trimester levels postpartum (6.35 [0.07], P <  0.001). In contrast, mean (SE) CCA IMT (mm) increased from the 2nd trimester (i.e., 0.546 [0.01]) onward, and remained higher at an average of 2.7 years postpartum (0.581 [0.02], P = 0.03). Weight partially explained changes in IAD. CONCLUSIONS: In uncomplicated first pregnancies, IAD increased and returned to 1st trimester levels postpartum. In contrast, CCA IMT remained increased 2 years postpartum. Maternal weight explained vascular changes better than did metabolic changes. Increased postpartum CCA IMT may persist and contribute to long-term CVD risk.

International Comparison of Abdominal Fat Distribution Among Four Populations: The ERA-JUMP Study.

BACKGROUND: Abdominal fat distribution varies across groups with different races or environments. Whether environmental factors, apart from racial differences, affect abdominal fat distribution is unknown. METHODS: We compared the abdominal fat distribution of four groups; different races with similar environments (Caucasians vs. Japanese Americans), different environments with an identical race (Japanese Americans vs. Japanese), and similar races with similar environments (Japanese vs. Koreans). A population-based sample of 1212 men aged 40-49 were analyzed: 307 Caucasians and 300 Japanese Americans in the United States, 310 Japanese in Japan, and 295 Koreans in Korea. We compared the proportion of visceral adipose tissue area to total abdominal adipose tissue area (VAT%) and other factors that can affect abdominal fat distribution (smoking, alcohol use, physical activity levels, and metabolic factors). RESULTS: VAT% was significantly higher in Japanese and Koreans than in Japanese Americans and Caucasians (50.0, 48.5, 43.2, 41.0%, respectively, P < 0.001). Even after adjustment for possible confounders, the significant VAT% difference remained in comparing groups with identical race but different environments (i.e., Japanese vs. Japanese Americans). In contrast, comparing groups with different races but similar environments (i.e., Caucasians vs. Japanese Americans), VAT% was not significantly different. Comparing groups with similar races and similar environments (i.e., Japanese vs. Koreans), VAT% did not significantly differ. CONCLUSIONS: Environmental differences, apart from racial differences, affect the difference in abdominal fat distribution across different groups in middle-aged men.

Relationship of femoral artery ultrasound measures of atherosclerosis with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is strongly associated with peripheral artery disease (PAD). Detection of subclinical PAD may allow early interventions for or prevention of PAD in persons with CKD. Whether the presence of atherosclerotic plaque and femoral intima-media thickness (IMT) are associated with kidney function is unknown. METHODS: We performed a cross-sectional observational study of 1029 community-living adults. We measured superficial and common femoral artery IMT and atherosclerotic plaque presence by ultrasound. Estimated glomerular filtration rate (eGFR; continuous) and eGFR <60 mL/min/1.73 m2 (binary) were evaluated as outcomes. RESULTS: Mean age was 70 ± 10 years, mean eGFR was 78 ± 17 mL/min/1.73 m2, and 156 (15%) individuals had eGFR <60 mL/min/1.73 m2; 260 (25%) had femoral artery plaque. In models adjusted for demographics and cardiovascular risk factors, individuals with femoral artery plaque had mean eGFR approximately 3.0 (95% confidence interval, -5.3 to -0.8) mL/min/1.73 m2 lower than those without plaque (P < .01). The presence of plaque was also associated with a 1.7-fold higher odds of eGFR <60 mL/min/1.73 m2 (95% confidence interval, 1.1-2.8; P < .02). Associations were similar in persons with normal ankle-brachial index. The directions of associations were similar for femoral IMT measures with eGFR and CKD but were rendered no longer statistically significant with adjustment for demographic variables and cardiovascular disease risk factors. CONCLUSIONS: Femoral artery plaque is significantly associated with CKD prevalence in community-living individuals, even among those with normal ankle-brachial index. Femoral artery ultrasound may allow evaluation of relationships and risk factors linking PAD and kidney disease earlier in its course.

Lipid Changes Around the Final Menstrual Period Predict Carotid Subclinical Disease in Postmenopausal Women.

BACKGROUND AND PURPOSE: Atherogenic changes in lipids occur among women around the time of the natural menopause, that is, within 1 year of the final menstrual period (FMP). We investigated whether lipid changes around the FMP are related to carotid intima-media thickness, interadventitial diameter, and plaque in postmenopausal women. METHODS: A total of 863 natural postmenopausal women with no history of heart attack or stroke underwent carotid ultrasound scans at follow-up year 12 or 13 of the Study of Women's Health Across the Nation. Estimates of their annual change in lipids were segmented into the year before and after the FMP, before the year before FMP, and 1 year after FMP. Multivariate analyses were adjusted for sociodemographic characteristics, time from FMP to scan, baseline body mass index and systolic blood pressure, and use of medications for hypertension and diabetes mellitus at the scan. RESULTS: Smaller increases in high-density lipoprotein cholesterol and apolipoprotein A1 within 1 year of the FMP were related to greater interadventitial diameter, ß (SE)=-0.036 (0.015), P=0.02, and ß (SE)=-0.035 (0.013), P=0.006, respectively. Greater increases in low-density lipoprotein cholesterol within 1 year of FMP were related to greater likelihood of plaque scores ≥2, odds ratio, 1.071; 95% confidence interval, 1.018-1.127; P=0.009. Magnitude of associations was reduced but remained significant with further adjustment for premenopausal lipid levels. The difference in probability of elevated plaque scores was 50% between those in the highest and lowest low-density lipoprotein cholesterol change tertiles. CONCLUSIONS: Changes in lipids as women approach the FMP provide useful clinical information for understanding postmenopausal carotid indices.

Progression of coronary artery calcium in Japanese American men and white men in the ERA JUMP study.

BACKGROUND: Progression of coronary artery calcium (CAC) is associated with increased risk of coronary heart disease (CHD) and is reported to be greater in whites than blacks, Hispanics, and Chinese in the US. Our objective was to compare progression of CAC between Japanese Americans and whites. METHODS: Population-based sample of 303 Japanese American men and 310 white men aged 40-49years, free of clinical cardiovascular disease at baseline, were examined for CAC at baseline (2004-2007) and follow-up (2008-2013). Progression of CAC was defined as change in coronary calcium scores (CCS) in participants with baseline CCS>0 and incident CAC in participants with baseline CCS=0. Multiple linear regression and relative risk regression were used to compare change in CCS scores and incident CAC between the two races, respectively. RESULTS: Japanese American men had significantly greater annual change in CCS than white men (median [interquartile range]: 11.3 Agatston units [1.4, 24.9] vs 2.5 [-0.22, 14.5]) in the unadjusted analyses. After adjusting for cardiovascular risk factors and follow-up time, change in CCS (beta±CI) and incidence rate ratio of CAC was similar in Japanese American men and white men: -0.12 (-0.34, 0.15) and (0.87 [95% CI: 0.20, 3.9]), respectively. CONCLUSIONS: In contrast to previously reported greater progression of CAC in whites than other races, we found a similar progression of CAC in Japanese American men as white men. Our study identifies Japanese American men as a target group for prevention of CHD. Large prospective studies are warranted to confirm these findings.

The role of initial and longitudinal change in blood pressure on progression of arterial stiffness among multiethnic middle-aged men.

OBJECTIVE: A few studies have examined the longitudinal association of blood pressure (BP) with arterial stiffness progression, and the results were inconsistent. The objective of this study was to investigate the roles of initial BP and its longitudinal change on the progression of arterial stiffness measured using brachial-ankle pulse wave velocity (baPWV). METHOD: Study participants (n = 656) were from population-based samples of healthy men aged 40-49 years at baseline (213 White Americans, 47 African-Americans, 152 Japanese Americans and 244 Japanese in Japan). BP measures, baPWV and other factors were examined at baseline and 4-7 years later. General linear regression was applied for statistical analyses. RESULT: Annual change in SBP (standardized coefficient: 0.33, P < 0.001), but not its baseline level (standardized coefficient: 0.03, P = 0.495), had a positive significant association with the progression of baPWV after adjusting for a wide range of standard cardiovascular risk factors. Similarly, annual changes in DBP (standardized coefficient: 0.35, P < 0.001), pulse pressure (standardized coefficient: 0.15, P = 0.001) and mean arterial pressure (standardized coefficient: 0.37, P < 0.001) were positively associated with the progression of baPWV. None of the baseline measures were related to the progression of baPWV. CONCLUSION: Our findings imply that, regardless of initial BP, effective monitoring and controlling of BP is important to slow down arterial wall stiffening and hence reduce cardiovascular risk.

A Significant Positive Association of Vitamin D Deficiency with Coronary Artery Calcification among Middle-aged Men: For the ERA JUMP Study.

OBJECTIVE: Although a significant positive association of vitamin D deficiency with coronary heart disease has been demonstrated in cross-sectional as well as prospective studies, only a few studies have examined the association of vitamin D deficiency with subclinical atherosclerosis. We examined whether vitamin D deficiency is associated with subclinical atherosclerosis, as measured by coronary artery calcification (CAC) in asymptomatic adults. METHODS: In a population-based cross-sectional study, 195 men aged 40 to 49 years without cardiovascular disease were randomly selected (98 Caucasian and 97 Japanese American men). Liquid chromatography-tandem mass spectrometry was utilized to measure serum vitamin D. CAC was examined by electron beam computed tomography using standardized protocols and read centrally at the University of Pittsburgh using Agatston's methods. To investigate an association between vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL) and CAC (defined as Agatston score ≥ 10), we utilized multivariable logistic regression models. RESULTS: Prevalence of CAC and vitamin D deficiency was 27.2% and 10.3%, respectively. Participants with CAC were significantly older, had significantly higher body mass index (BMI), and had higher rates of smoking. Those with CAC were 3.31 times likely to be vitamin D deficient, after adjusting for traditional cardiovascular risk factors (odds ratio [OR] = 3.31, 95% confidence interval [CI], 1.12-9.77). CONCLUSIONS: In this population-based study of healthy middle-aged men, vitamin D deficiency had a significant positive association with the presence of CAC.

Inflammatory/Hemostatic Biomarkers and Coronary Artery Calcium Progression in Women at Midlife (from the Study of Women's Health Across the Nation, Heart Study).

It is unknown whether inflammatory/hemostatic biomarkers are associated with coronary artery calcium (CAC) progression. Our purpose was to evaluate the associations of baseline levels of C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen, and circulating factor VII with CAC progression in healthy midlife women. Inflammatory/hemostatic biomarkers were measured at baseline. CAC was quantified by computed tomography scans at baseline and after 2.3 ± 0.5 years of follow-up. Significant CAC progression was defined as present if (1) follow-up CAC Agatston score was >0 if baseline CAC score = 0; (2) annualized change in CAC score was ≥10 if baseline CAC score >0 to <100; and (3) annualized percent change in CAC score was ≥10% if baseline CAC score ≥100. Extent of CAC progression was defined as [log(CAC(follow-up)+25) - log(CAC(baseline)+25)]/year. Logistic and linear regression models were used as appropriate, and the final models were adjusted for baseline CAC score, age, study site, race/ethnicity, menopausal status, sociodemographics, traditional cardiovascular disease (CVD) risk factors, family history of CVD, and CVD medication use. The study included 252 women (baseline age 51.2 ± 2.6 years; 67.5% white; 56.4% premenopausal or early perimenopausal). In final models, only log(PAI-1) was associated with presence of CAC progression (odds ratio 1.91, 95% CI 1.24 to 2.93; per 1 log unit increase in PAI-1; p = 0.003). In addition, higher log(PAI-1) was marginally associated with greater extent of CAC progression (p = 0.06). In conclusion, PAI-1 is associated with the presence of CAC progression in middle-aged women. Targeting PAI-1 may decrease atherogenesis beyond conventional CVD risk factors.