Markers Of Subclinical Cardiovascular Disease Research Articles

Abstract 040: Sleep Regularity And Subclinical Markers Of Cardiovascular Disease: The Multi Ethnic Study Of Atherosclerosis (MESA)

Background: Sleep irregularity has been linked to incident cardiovascular disease (CVD). Less is known about sleep regularity and associations with atherosclerosis. Our objective was to examine associations of sleep regularity with measures of atherosclerosis in the diverse MESA cohort. Methods: Participants from the MESA Sleep Study (2010-2013; N=2,032, Mean age: 68.6 ± 9.2 years; 53% Female, 38% White, 28% Black or African American, 23% Hispanic, 11% Chinese) completed 7-days of actigraphy. At the same exam, coronary artery calcium (CAC) was derived from computed tomography, carotid plaque presence and carotid intima-media thickness (cIMT) were derived from ultrasonography, and the ankle brachial index (ABI) was calculated from extremity measured systolic blood pressure. Sleep regularity was quantified by standard deviations in sleep durations and sleep onset time across wear days and categorized in 30 minute (mins) increments. Adjusted relative risk regression models were used to calculate prevalence ratios (PRs) and 95% confidence intervals (CI) for associations of measures of sleep regularity with each subclinical marker of CVD. Models adjusted for demographics, CVD risk factors, and objectively-assessed obstructive sleep apnea. Results: After multivariable adjustment, and compared to those with regular sleep durations (SD≤60 mins), participants with greater sleep duration irregularity (SD>120 mins) were more likely to have high CAC burden [CAC >300; PR (95% CI): 1.36 (1.03-1.78)], carotid plaque [1.10 (1.00-1.22)] and an abnormal ABI [ABI <0.9; 1.74 (1.00-3.02)]. Compared to participants with regular sleep timing (SD≤30 mins), those with irregular sleep timing (SD>90 mins) were 1.38 (1.04-1.83) times more likely to have high CAC burden. Associations did not vary by age or sex. Conclusion: Sleep regularity, particularly sleep duration regularity, was associated with measures of subclinical CVD in this diverse cohort. Sleep regularity is a modifiable sleep dimension worthy of further investigation.

Abstract P149: The Relationship Between Daytime Sleepiness, Exhaustion, Fatigue, And Arterial Stiffness. The Atherosclerosis Risk In Communities (ARIC) Study

Background: Excessive Daytime Sleepiness (EDS) is positively associated with the risk of cardiovascular disease (CVD) events and CVD mortality. However, the association between EDS and subclinical markers of CVD, such as arterial stiffness, is not fully understood and could have implications for CVD screening. EDS is multifactorial in origin, thus we incorporated measures of exhaustion and fatigue in order to comprehensively assess the association of lethargy and central artery stiffness. We examined the separate relationships between EDS, exhaustion, fatigue, and aortic stiffness via carotid-femoral pulse wave velocity (cfPWV) in a large population-based study. Methods: A cross-sectional analysis of ARIC Study participants (n=2500, mean age: 79.7, 57.2% female) who underwent arterial stiffness measurements (cfPWV) and completed the Epworth Sleep Scale (ESS) questionnaire in 2016-2019. EDS was defined as ESS 11. Exhaustion was derived from the Center for Epidemiological Study’s Depression (CES-D) scale, with positive exhaustion corresponding to increased effort in daily activities and noticeable difficulty in getting “going’. Fatigue was assessed at annual follow up calls in 2012-2013 and calculated as a summary score with participants responses about feeling tired in various scenarios in the past 7 days noted as a numeric value (1-5: never, rarely, sometimes, often or always). We used multivariable linear regression to estimate the association between ESS, exhaustion, and fatigue with cfPWV, adjusting for age, race-study center, body mass index, diabetes, heart rate, mean arterial pressure, and blood-pressure medication use. We evaluated potential effect modification by race, sex, diabetes, and hypertension. Results are presented as unstandardized beta coefficients (β) and 95% confidence intervals (CI). Results: A total of 14.2% participants reported EDS, 17.2% reported exhaustion, and the average fatigue score was 8.0. ESS was not associated with cfPWV when adjusting for covariates (β; 95% CI: -1.4; -4.7, 1.9). Similarly, EDS was not associated with cfPWV (β; 95% CI: -4.9; -40.4, 30.6), nor was there an association between ESS quartiles and cfPWV. However, both exhaustion (β; 95% CI: 40.4; 7.8, 73.0) and fatigue (β; 95% CI: 5.4; 0.6, 10.3) were positively associated with cfPWV after adjusting for covariates. There was no evidence of effect modification by race, sex, diabetes, or hypertension. Conclusion: EDS was not associated with arterial stiffness. A (positive) association was observed for both exhaustion and fatigue with cfPWV, suggesting a need for further investigation of fatigue related conditions and arterial stiffness in older adults.

Defining the effects of traffic-related air pollution on the human plasma proteome using an aptamer proteomic array: A dose-dependent increase in atherosclerosis-related proteins

BackgroundTraffic-related air pollution (TRAP) is a critical risk factor and major contributor to respiratory and cardiovascular disease (CVD). The effects of TRAP beyond the lungs can be related to changes in circulatory proteins. However, such TRAP-mediated changes have not been defined in an unbiased manner using a controlled human model. ObjectiveTo detail global protein changes (the proteome) in plasma following exposure to inhaled diesel exhaust (DE), a paradigm of TRAP, using controlled human exposures. MethodsIn one protocol, ex-smokers and never-smokers were exposed to filtered air (FA) and DE (300 μg PM2.5/m3), on order-randomized days, for 2 h. In a second protocol, independent never-smoking participants were exposed to lower concentrations of DE (20, 50 or 150 μg PM2.5/m3) and FA, for 4 h, on order-randomized days. Each exposure was separated by 4 weeks of washout. Plasma samples obtained 24 h post-exposure from ex-smokers (n = 6) were first probed using Slow off-rate modified aptamer proteomic array. Plasma from never-smokers (n = 11) was used for independent assessment of proteins selected from the proteomics study by immunoblotting. ResultsProteomics analyses revealed that DE significantly altered 342 proteins in plasma of ex-smokers (n = 6). The top 20 proteins therein were primarily associated with inflammation and CVD. Plasma from never-smokers (n = 11) was used for independent assessment of 6 proteins, amongst the top 10 proteins increased by DE in the proteomics study, for immunoblotting. The abundance of all six proteins (fractalkine, apolipoproteins (APOB and APOM), IL18R1, MIP-3 and MMP-12) was significantly increased by DE in plasma of these never-smokers. DE-mediated increase was shown to be concentration-dependent for fractalkine, APOB and MMP-12, all biomarkers of atherosclerosis, which correlated with plasma levels of IL-6, a subclinical marker of CVD, in independent participants. ConclusionThis investigation details changes in the human plasma proteome due to TRAP. We identify specific atherosclerosis-related proteins that increase concentration-dependently across a range of TRAP levels applicable worldwide.

Neutrophil Pathways of Inflammation Characterize the Blood Transcriptomic Signature of Patients with Psoriasis and Cardiovascular Disease.

Background: Patients with psoriasis have an increased risk of atherosclerotic cardiovascular disease (CVD). The molecular mechanisms behind this connection are not fully understood, but the involvement of neutrophils have drawn attention as a shared inflammatory factor. Methods: RNA sequencing using the Illumina platform was performed on blood from 38 patients with moderate to severe psoriasis; approximately half had prior CVD. The neutrophil to lymphocyte ratio (NLR) was obtained from blood samples. Subclinical atherosclerosis was assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and ultrasound imaging. Transcriptomic analysis for differential expression and functional enrichment were performed, followed by correlation analyses of differentially expressed genes (DEGs), NLR and subclinical measurers of CVD. Results: 291 genes were differentially expressed between patients with psoriasis with and without CVD. These included 208 upregulated and 83 downregulated DEGs. Neutrophil degranulation was identified as the most significant process related to the upregulated DEGs. Genes for the neutrophil-associated markers MPO, MMP9, LCN2, CEACAM1, CEACAM6 and CEACAM8 were identified as being of special interest and their mRNA levels correlated with NLR, high-sensitive C-reactive protein and markers of subclinical CVD. Conclusions: Patients with psoriasis and CVD had an increased expression of genes related to neutrophil degranulation in their blood transcriptome compared with patients with psoriasis without CVD. NLR may be a potential biomarker of subclinical CVD in psoriasis.

POS0562 PULSE PRESSURE AS AN INDICATOR OF SUBCLINICAL ATHEROSCLEROSIS IN RHEUMATOID ARTHRITIS

Background:Pulse pressure (PP) is defined as the difference between systolic and diastolic blood pressure and represents arterial compliance and reflective properties of blood flow (1). It is well known that gender, age, and race / ethnicity are intrinsic factors of the patient that influence PP. Brachial PP has recently been associated with markers of subclinical cardiovascular disease after adjustment with traditional cardiovascular risk factors in the general population (2). However, this relationship has not been studied in patients with rheumatoid arthritis (RA) and its identification would allow earlier adjustments of cardiovascular therapies in this high-risk group.Objectives:The aim of the study is to analyze the difference in PP between patients with RA and healthy controls. Additionally, to analyze the difference between patients with carotid plaque (CP) and without CP.Methods:A cross-sectional, observational, and comparative study of ninety-two patients with RA aged 40-75 years and who fulfilled ACR/EULAR 2010 classification criteria. Also, we included ninety-two controls without RA, matched by gender, age and comorbidities. A carotid ultrasound was performed in patients with RA and it was divided into two subgroups, with the presence of CP and without CP. A blood pressure measurement was taken after 15 minutes of rest on the right arm of all patients. Distribution was evaluated with the Kolmogorov-Smirnov test. Descriptive analysis was done using measures of central tendency. Chi square, Student’s t test and Mann-Whitney U test were used for comparations between groups. A p value <0.05 was considered statistically significant.Results:We found no statistical difference between groups regarding age, gender and, comorbidities (type 2 diabetes mellitus, hypertension, dyslipidemia and, active smoking) (Table 1). There was a significant difference in PP between patients with RA and controls (50 mmHg vs 41 mmHg respectively, p = 0.032). Patients with RA had a significant difference in PP of patients with CP and without CP (50 mmHg vs 44 mmHg respectively, p = 0.008) (Figure 1). When performing a binary logistic regression, it was found that PP was the only independent factor for the presence of CP in patients with RA, OR 1.054 (95% CI 1.008-1.101, p = 0.020).Conclusion:Patients with RA had a higher PP than controls. Binary logistic regression showed PP as the only independent factor for the presence of subclinical atherosclerosis in patients with RA. PP is a parameter that all rheumatologists should consider when evaluating cardiovascular risk in patients with RA.

Pulse arrival time, a novel sleep cardiovascular marker: the multi-ethnic study of atherosclerosis

BackgroundPulse arrival time (PAT) is commonly used to estimate blood pressure response. We hypothesised that PAT response to obstructive respiratory events would be associated with increased cardiovascular risk in people...

Prevalence and risk factors for the development of abdominal aortic calcification among the US population: NHANES study.

IntroductionAbdominal aortic calcification (AAC) is an important marker of subclinical cardiovascular disease and its prognosis. Advanced age, hypertension, smoking, dyslipidemia, diabetes mellitus, and higher truncal fat are known markers of AAC in studies conducted around the world. However, literature for these risk factors and their co-occurrence is limited in the US.Material and methodsWe used data from dual energy X-ray absorptiometry (Hologic, v4.0) to detect the occurrence of AAC in a sample population (n = 3140) of the NHANES survey using a computer-assisted interviewing system to assess the risk factors for AAC.ResultsWe found the national prevalence of AAC in the US to be 28.8%. After adjusting for confounders, persons with hypertension: OR = 1.66 (95% CI: 1.30–2.13) and smokers: OR = 1.63 (95% CI: 1.24–2.14) were more likely to have AAC compared to their respective counterparts. Increasing age was positively associated with AAC: OR = 1.06 (95% CI: 1.04–1.08). There was a statistically significant negative association between body mass index (BMI) and AAC, more so in smokers than in non-smokers: OR = 0.97 (95% CI: 0.94–0.97). We did not observe any statistically significant association between diabetes and AAC.ConclusionsAdvanced age, smoking, and hypertension was associated with increased occurrence of AAC. Paradoxically, increasing BMI was inversely associated with AAC and there was no statistically significant association between total body and trunk fat percentages and AAC. To the best of our knowledge, this is the first study to establish the nationwide prevalence and associated factors in the US.

Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD. Observational, case-cohort study design. Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study. Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile. The primary outcomes were incident HF and AF. Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker. The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF. Observational study. In CKD, increases in NT-proBNPwere significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.

Cross‐sectional relations of subclinical cardiovascular disease to AD blood biomarkers in cognitively intact older adults

AbstractBackgroundSubclinical cardiovascular disease (CVD) is a key, early step in the development of frank CVD. Generally characterized by an age‐related increase in atherosclerosis and arterial stiffness, and/or reduced endothelial function, emerging evidence suggests subclinical CVD confers risk for Alzheimer’s disease and related dementias (ADRD) well before the onset of frank CVD. However, despite increasing recognition of the utility of blood biomarkers for understanding the pathophysiological events and progression of AD, little research has examined the association between markers of subclinical CVD and AD blood biomarkers. Thus, we sought to examine these associations in a sample of cognitively intact older adults enrolled in the Healthy Heart & Mind Study.MethodParticipants were 34% male and 41.7% African American with a mean age of 68.43y. Participants completed a health and medication screening, a battery of cognitive tests, a psychosocial assessment, a fasting blood draw, vascular testing (including assessment of carotid intimal‐media thickening (IMT), pulse wave velocity (PWV), and brachial artery flow‐mediated dilation (FMD), and structural brain MRI. Serum Ab1‐40 and Ab1‐42 (and ratio) were available for 99 participants at the time of this analysis.ResultBivariate correlation results showed a significant, positive association between % FMD change and Ab1‐40 only (p<.05). Ordinary least squares regression was run to further examine this association adjusting for the following potential confounding variables: age, gender, education, depression, and mean arterial BP. Results showed the significant, positive association between % FMD change and Ab1‐40 persisted after adjustment (p<.05).ConclusionFindings showed that worse endothelial function may be associated with lower Ab1‐40 in healthy older adults. While some research illustrates Ab1‐40 is reduced in AD, other research suggests increased levels are associated with vascular conditions such as hypertension, ischemic heart disease, and white matter lesions. Thus, our findings suggest a need to further examine the association between endothelial function and AD blood biomarkers to confirm the directionality of the relationship. Longitudinal research is also needed to examine the association over time.

Prolonged Circulation Time Is Associated With Mortality Among Older Men With Sleep-Disordered Breathing

Conventional metrics to evaluate sleep-disordered breathing (SDB) have many limitations, including their inability to identify subclinical markers of cardiovascular (CV) dysfunction. Does sleep study-derived circulation time (Ct) predict mortality, independent of CV risks and SDB severity? We derived average lung to finger Ct (LFCt) from sleep studies in older men enrolled in the multicenter Osteoporotic Fractures in Men (MrOS) Sleep study. LFCt was defined as the average time between end of scored respiratory events and nadir oxygen desaturations associated with those events. We calculated the hazard ratio (HRs) for the CV and all-cause mortality by LFCt quartiles, adjusting for the demographic characteristics, body habitus, baseline CV risk, and CV disease (CVD). Additional models included apnea-hypopnea index (AHI), time with oxygen saturation as measured by pulse oximetry (SpO2)< 90% (T90), and hypoxic burden. We also repeated analyses after excluding those with CVD at baseline. A total of 2,631 men (mean ± SD age, 76.4 ± 5.5 years) were included in this study. LFCt median (interquartile range) was 18 (15-22) s. During an average ± SD follow-up of 9.9 ± 3.5 years, 427 men (16%) and 1,205 men (46%) experienced CV death and all-cause death, respectively. In multivariate analysis, men in the fourth quartile of LFCt (22-52 s) had an HR of 1.36 (95%CI, 1.02-1.81) and 1.35 (95%CI, 1.14-1.60) for CV and all-cause mortality, respectively, when compared with men in the first quartile (4-15 s). The results were similar when additionally adjusting for AHI, T90, or hypoxic burden. Results were stronger among men with no history of CVD at baseline. LFCt is associated with both CV and all-cause mortality in older men, independent of baseline CV burden and SDB metrics. LFCt may be a novel physiologic marker for subclinical CVD and adverse outcomes in patients with SDB.

Lung to finger circulation time in sleep study and coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis

BackgroundLung to finger circulation time (LFCT) measured from sleep studies may represent a novel physiologic marker for cardiovascular risk in patients with sleep disordered breathing (SDB). We hypothesized that sleep study-derived LFCT would improve risk classification of markers of subclinical cardiovascular disease. MethodsWe included participants in the Multi-Ethnic Study of Atherosclerosis (MESA) Sleep cohort with moderate-severe SDB (apnea hypopnea index [AHI] ≥ 15/hr) (N = 598). ResultsThose with average LFCT above the median (19.4 s) (vs. shorter LFCT) tended to be older, more obese and male. In multivariable analysis, no significant associations were found between average LFCT and subclinical cardiovascular markers including coronary artery calcium, carotid intima-media thickness or left ventricular hypertrophy. However, there was modest improvement in risk classification of coronary artery calcification as compared with AHI alone when average LFCT was added to AHI (C statistics 0.53 vs. 0.62, p = 0.0066). ConclusionsIn conclusion, LFCT may be a useful addition to conventional SDB metrics to improve cardiovascular risk assessment.

0550 Insomnia is Associated with Greater Arterial Stiffness and Cardiac Dysfunction

Abstract Introduction Insomnia is a novel and modifiable risk factor for incident cardiovascular disease (CVD). However, identification of early markers of subclinical CVD in diagnosed insomnia is understudied. Our aim for this ongoing study is to contrast markers of cardiovascular structure and function between people with insomnia and good-sleeping controls. Methods Persons with insomnia (met ICSD-III criteria) and good sleeping controls (&amp;lt;8 Insomnia Severity Index, mean 8-night SOL and WASO&amp;lt;31min) were recruited from the community. Twenty-two adults (21-39y; 55% women) with no history of CVD, diabetes, inflammatory conditions, significant hypertension, or current sleep-disordered breathing (WatchPat200, Itamar Medical) were enrolled and underwent fasting cardiovascular testing. Testing included: Central augmented aortic pressure (AP) and carotid-femoral pulse wave velocity (cfPWV) for vascular stiffness; brachial artery flow mediated dilation (FMD) to assess endothelial function; and 2D echocardiography to assess ejection fraction (EF%), left ventricular global longitudinal strain (LVGLS), left atrial volume index (LAVI), mitral valve E/e’ ratio (E/e’), and lateral e’. ANCOVA models, adjusting for age, comparing persons with insomnia (n=6) to good sleeping controls (n=16) on each cardiovascular measure were conducted. Results AP (range:-5,10mmHg), cfPWV (range: 4.8-7.6m/s), EF% (range:55.0-72.0%), LVGLS (range:-26,-19%) LAVI (range:14.1-26.7mL/m2), E/e’ (range:3.2-7.8), and lateral e’ (range:0.09-0.22cm/sec) were all within normal ranges according to age and sex normative standards. Mean FMD was 8.8% (SD=4.3, range:4.3-19.8%). Age adjusted ANCOVA models indicated that the insomnia group had significantly worse cardiovascular function than good sleeping controls on cfPWV (M=6.8±0.3 vs. M=5.7±0.2; p=0.004), EF% (M=60.0±1.7 vs. M=65.2±1.0; p=0.017), LVGLS (M=-21.6±0.6 vs. M=-24.3±0.4; p=0.001), and lateral e’ (M=0.12±0.01 vs. M=0.18±0.01; p=0.003). No group differences were found for AP, FMD, LAVI, and E/e’. Conclusion Among relatively healthy young adults, people with insomnia had greater arterial stiffness and worse left ventricular systolic and diastolic functioning. Support American Academy of Sleep Medicine Foundation Focused Projects Award for Junior Investigators 179-FP-18

Abstract P548: Poorer Objective Sleep is Associated With Greater Arterial Stiffness and Worsening Cardiac Diastolic Function

Aim: Few studies have examined the association between objective sleep metrics and arterial and echocardiographic (left ventricular systolic/diastolic function) markers of sub-clinical cardiovascular disease (CVD). The present study examined the association of wrist actigraphy-assessed sleep metrics with arterial stiffness, endothelial dysfunction, and left ventricular systolic/diastolic function. Methods: Fifteen young, healthy adults (21-39y; 60% women) with no history of CVD, and no current sleep-disordered breathing (WatchPat200, Itamar Medical) or sleep complaints wore Actiwatch Spectrum Plus actigraphs for eight nights (Philips Respironics, Bend OR) with accompanying sleep logs. Participants underwent fasting vascular testing including central augmented aortic pressure (AP), carotid-femoral pulse wave velocity (cfPWV) to assess arterial stiffness (SphymocorXCEL TM ), brachial artery flow mediated dilation (FMD) to assess endothelial function, and 2D echocardiography to assess left ventricular function (Terason uSmart 3300 TM ). Left ventricular function was assessed by ejection fraction (EF%), left atrial volume index (LAVI), deceleration time (DT), and mitral valve E/e’ ratio (MVE/e’) using standardized methods. Bivariate correlations investigating the association between mean total sleep time (TST), sleep efficiency % (SE), sleep-onset latency (SOL), and wake after sleep time (WASO) with cardiovascular indices were conducted. Curvilinear regression models examining quadratic relationships between TST and the cardiovascular indices were conducted. Results: On average, participants obtained 6 hrs 44 min of TST (SD=29.1), with 86.0% SE (SD=3.1), 10.6 min SOL (SD=8.5), and 37.0 min WASO (SD=11.6). cfPWV (range: 4.8-7.5), EF% (range: 60.0-72.0), LAVI (range: 15.0-26.7 mL/m 2 ), and MVE/e’ (range: 3.2-7.8) were all within normal ranges according to age and sex normative standards. Mean FMD was 9.2% (SD=4.62, range: 4.3-19.8). Correlations indicated that greater SOL was associated with greater cfPWV (r=.63, p=0.01), and AP (r=.57, p=0.03). Lower SE (r= -.70, p=0.003) and higher WASO (r=.71, p=0.003) were associated with higher MVE/e’. WASO was associated with higher DT (r=.57, p=0.04). Curvilinear regression models revealed a quadratic relationship between TST and cfPWV (F[2,11]=9.78, p=0.004) such that shorter and longer TST were associated with greater cfPWV. No sleep metrics were associated with FMD, EF%, or LAVI. Conclusions: Among normal sleeping, apparently healthy young adults, with no history of CVD, lower levels of objective sleep quality and both shorter and longer sleep duration were associated with greater arterial stiffness, whereas only lower levels of objective sleep quality were related to worsening left ventricular diastolic dysfunction. These data may have implications for CVD risk reduction in young, healthy adults.

Markers of Subclinical Cardiovascular Disease in Patients with Adrenal Incidentaloma.

Due to the growing availability of imaging examinations the percentage of patients with incidentally diagnosed adrenal tumors has increased. The vast majority of these lesions are benign, non-functioning adenomas, although according to various estimates even up to 30%–50% of patients with adrenal incidentaloma may present biochemical hypercortisolemia, without typical clinical features of Cushing’s syndrome. Adrenal adenomas secreting small amounts of glucocorticoids may cause morphological and functional changes in the myocardium and blood vessels. Early stages of cardiovascular remodeling may be observed among asymptomatic patients with adrenal adenoma. Vascular changes precede the development of cardiovascular diseases and can increase morbidity and mortality in patients with adrenal incidentaloma. This risk may result not only from the traditional risk factors. Seemingly hormonally inactive adrenal tumors can indeed produce small amounts of glucocorticoids that have metabolic implications. Therefore, evaluation of patients with incidental adrenal findings presenting with subclinical cardiovascular disease seems of particular importance.

Rice Intake, Arsenic Exposure, and Subclinical Cardiovascular Disease Among US Adults in MESA.

BackgroundArsenic‐related cardiovascular effects at exposure levels below the US Environmental Protection Agency's standard of 10 μg/L are unclear. For these populations, food, especially rice, is a major source of exposure. We investigated associations of rice intake, a marker of arsenic exposure, with subclinical cardiovascular disease (CVD) markers in a multiethnic population.Methods and ResultsBetween 2000 and 2002, MESA (Multi‐Ethnic Study of Atherosclerosis) enrolled 6814 adults without clinical CVD. We included 5050 participants with baseline data on rice intake and markers of 3 CVD domains: inflammation (hsCRP [high‐sensitivity C‐reactive protein], interleukin‐6, and fibrinogen), vascular function (aortic distensibility, carotid distensibility, and brachial flow‐mediated dilation), and subclinical atherosclerosis at 3 vascular sites (carotid intima‐media thickness, coronary artery calcification, and ankle‐brachial index). We also evaluated endothelial‐related biomarkers previously associated with arsenic. Rice intake was assessed by food frequency questionnaire. Urinary arsenic was measured in 310 participants. A total of 13% of participants consumed ≥1 serving of rice/day. Compared with individuals consuming <1 serving of rice/week, ≥1 serving of rice/day was not associated with subclinical markers after demographic, lifestyle, and CVD risk factor adjustment (eg, geometric mean ratio [95% CI] for hsCRP, 0.98 [0.86–1.11]; aortic distensibility, 0.99 [0.91–1.07]; and carotid intima‐media thickness, 0.98 [0.91–1.06]). Associations with urinary arsenic were similar to those for rice intake.ConclusionsRice intake was not associated with subclinical CVD markers in a multiethnic US population. Research using urinary arsenic is needed to assess potential CVD effects of low‐level arsenic exposure. Understanding the role of low‐level arsenic as it relates to subclinical CVD may contribute to CVD prevention and control.

A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke

Background and PurposeTo search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach. MethodsWe identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites. ResultsIn TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR .69 per SD change, 95% CI .57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively). ConclusionsAn inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.

Associations of recreational and non-recreational physical activity with coronary artery calcium density vs. volume and cardiovascular disease events: the Multi-Ethnic Study of Atherosclerosis.

The benefits of physical activity (PA) on cardiovascular disease (CVD) are well known. However, studies suggest PA is associated with coronary artery calcium (CAC), a subclinical marker of CVD. In this study, we evaluated the associations of self-reported recreational and non-recreational PA with CAC composition and incident CVD events. Prior studies suggest high CAC density may be protective for CVD events. We evaluated 3393 participants of the Multi-Ethnic Study of Atherosclerosis with prevalent CAC. After adjusting for demographics, the highest quintile of recreational PA was associated with 0.07 (95% confidence interval 0.01-0.13) units greater CAC density but was not associated with CAC volume. In contrast, the highest quintile of non-recreational PA was associated with 0.08 (0.02-0.14) units lower CAC density and a trend toward 0.13 (-0.01 to 0.27) log-units higher CAC volume. There were 520 CVD events over a 13.7-year median follow-up. Recreational PA was associated with lower CVD risk (hazard ratio 0.88, 0.79-0.98, per standard deviation), with an effect size that was not changed with adjustment for CAC composition or across levels of prevalent CAC. Recreational PA may be associated with a higher density but not a higher volume of CAC. Non-recreational PA may be associated with lower CAC density, suggesting these forms of PA may not have equivalent associations with this subclinical marker of CVD. While PA may affect the composition of CAC, the associations of PA with CVD risk appear to be independent of CAC.

P4492Peripheral blood mononuclear cell expression of the stabilizing RNA-binding protein HuR is associated with incidence and extent of human atherosclerotic cardiovascular disease

Abstract Background Human Antigen R (HuR) is a stabilizing RNA-binding protein that regulates the expression of several pro-inflammatory molecules. However, its regulation in human atherosclerotic cardiovascular disease remains unknown. Purpose To determine the association of peripheral blood mononuclear cell HuR expression with established markers of increased cardiovascular risk and atherosclerosis burden in patients with subclinical or clinically overt coronary artery disease (CAD). Methods HuR mRNA expression was measured in peripheral blood mononuclear cells derived from 289 patients with stable CAD or acute myocardial infarction (AMI) and 373 individuals without clinically overt cardiovascular disease (CVD). Structural and functional vascular measurements including intima-media thickness (IMT) and number of atheromatous plaques by carotid and femoral artery ultrasonophaphy, markers of arterial wave reflections by pulse wave analysis and pulse wave velocity were used as surrogate markers of subclinical CVD. The number of angiographically confirmed diseased coronary arteries (&gt;50% stenosis) was used to assess the extent of CAD. Results HuR mRNA expression was significantly increased in patients with CAD (both stable and AMI) compared to controls (p=0.039). Subgroup analysis revealed that STEMI patients (n=107) had increased levels of HuR expression compared to NSTEMI (n=49, p=0.03). Among patients with stable CAD (n=133), high HuR expression was independently associated with the number of diseased coronary arteries (OR=1.35 for 1-SD increase in HuR, 95% CI 1.07–1.72, p=0.012), as well as with reduced ejection fraction (EF&lt;45%, OR=1.32 per 1-SD increase, 95% CI 1.05–1.85, p=0.024). Among individuals without CVD, high HuR was associated with lower HDL levels (adjusted beta=-5.2 mg/dl for highest versus lowest quartile, p=0.03) and higher diastolic blood pressure (adjusted beta=3.6 mmHg, p=0.007), while, after adjustment for traditional cardiovascular risk factors, HuR levels in individuals without CVD were independently associated with increased IMT in the common carotid artery (mean increase 6.2% for highest versus lowest quartile, p=0.019). Conclusion HuR expression is associated with early subclinical arterial disease in individuals without clinically overt CVD and with the presence and severity of cardiac and vascular dysfunction in patients with clinically overt CAD. These findings imply a clinical role of the HuR pathway in cardiovascular disease and warrant further investigation.

Relation of Dietary Sodium Intake With Subclinical Markers of Cardiovascular Disease (from MESA)

The associations between dietary sodium intake and markers of subclinical cardiovascular disease (CVD), such as high-sensitivity cardiac troponin T (hs-cTnT) and amino terminal pro b-type natriuretic peptide (NT-proBNP), may provide mechanistic insight into the relation between dietary sodium and cardiovascular events. We studied 6,131 participants of the Multi-Ethnic Study of Atherosclerosis, who were free of clinical CVD at baseline. Food frequency questionnaires were used to assess estimated sodium intake (ESI) at baseline. We tested the associations between 5 quintiles of ESI (quintile 1: 0.2 to 1.3 grams/day, quintile 2: 1.3 to 1.8 grams/day, quintile 3: 1.8 to 2.4 grams/day, quintile 4: 2.4 to 3.2 grams/day, and quintile 5: 3.2 to 9.9 grams/day) with cross-sectional and 5-year longitudinal change in hs-cTnT and NT-proBNP concentrations. Restricted cubic spline plots were utilized to explore the shape of the associations between ESI and biomarker outcomes. A cross-sectional association between baseline sodium intake and hs-cTnT (but not NT-proBNP) was observed, driven predominantly by a strong positive relation at an intake range of 0.2 to 2.4 g/day. Conversely, a longitudinal association between baseline sodium intake and NT-proBNP (but not hs-cTnT) was observed, driven predominantly by a strong positive relation at intake levels ≥2.4 g/day. In conclusion, temporal shifts in the association between increased ESI and markers of subclinical CVD, hs-cTnT in the short term and NT-proBNP in the longer term, point to the complex pathobiology of the association between sodium intake and CVD. There was also no consistent evidence supporting a J-curve (i.e., excess biomarker values at very low ESI).

Nonalcoholic Fatty Liver Disease Is Associated With Arterial Distensibility and Carotid Intima-Media Thickness: (from the Multi-Ethnic Study of Atherosclerosis)

Nonalcoholic fatty liver disease (NAFLD) is considered a potential independent risk factor for cardiovascular disease (CVD). The Multi-Ethnic Study of Atherosclerosis cohort enrolled 6,814 adults without previous CVD. We excluded 2,692 participants who had missing variables, were heavy drinkers, or history of steroid use and/or chronic liver disease. NAFLD was defined using noncontrast cardiac CT and a liver/spleen Hounsfield Unit attenuation ratio <1. Ultrasound-measured carotid arterial compliance and stiffness, was expressed as distensibility coefficient and Young's modulus. Common and internal carotid intima-media thickness (CIMT) and coronary artery calcium (CAC) >0 were used as markers of subclinical CVD. A multivariate robust linear regression and logistic regression analysis were done to evaluate the association of NAFLD and this subclinical CVD markers. Our analysis of 4,123 participants showed 55% were female with a mean age of 63 (±10) years, 39% white, 10% Chinese, 28% black, and 23% were Hispanic. The prevalence of NAFLD was 17% (n = 729). Patients with NAFLD had higher distensibility coefficient and higher CIMT. Multivariate linear regression analysis showed the presence of NAFLD was associated with both the common carotid and internal carotid IMT and logCAC. Logistic analysis showed an independent association with CAC > 0 (odds ratio [OR] 1.44 95% confidence interval [CI] 1.18, 1.75) and CIMT > 1 mm (OR 1.30 95% 1.08, 1.56). When stratified by race the association with CIMT > 1 mm was significant in whites (OR 1.37 95% 1.00, 1.90) and Hispanic (OR 1.53 95% 1.08, 2. 17) and CAC > 0 was significant in Hispanics (OR 1.52 95% 1.06, 2.19). In conclusion, NAFLD is modestly associated with carotid IMT and coronary artery calcification in a multiethnic population.