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1.  PHYSICAL ACTIVITY, INFLAMMATION, AND VOLUME OF THE AGING BRAIN 
Neuroscience  2014;273:199-209.
Physical activity influences inflammation, and both affect brain structure and Alzheimer’s disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3 ± 4.8 years) and 39 patients with AD (81.9 ± 5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact. Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.
doi:10.1016/j.neuroscience.2014.05.005
PMCID: PMC4076831  PMID: 24836855
tumor necrosis factor (TNFα); exercise; MRI; supramarginal gyrus; inferior parietal lobule; Alzheimer’s disease
2.  Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts 
Context
Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown.
Objective
Test associations of endothelial biomarkers with FEV1 using instrumental variables.
Methods
Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets.
Results
ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (−29 mL and −34 mL per standard deviation of log-transformed biomarker, p<0.001), as was endothelin-1 among African-Americans (−22 mL, p=0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative.
Conclusion
Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.
doi:10.3109/1354750X.2012.762805
PMCID: PMC3890095  PMID: 23557128
Genetic polymorphisms; growth factors/cytokines/inflammatory mediators; respiratory disease
3.  Improved coronary risk assessment among intermediate risk patients using a clinical and biomarker based algorithm developed and validated in two population cohorts 
Current medical research and opinion  2012;28(11):1819-1830.
Background
Many coronary heart disease (CHD) events occur in individuals classified as intermediate risk by commonly used assessment tools. Over half the individuals presenting with a severe cardiac event, such as Myocardial Infarction (MI), have at most one risk factor as included in the widely used Framingham risk assessment. Individuals classified as intermediate risk, who are actually at high risk, may not receive guideline recommended treatments. A clinically useful method for accurately predicting 5-year CHD risk among intermediate risk patients remains an unmet medical need.
Objective
This study sought to develop a CHD Risk Assessment (CHDRA) model that improves 5-year risk stratification among intermediate risk individuals.
Methods
Assay panels for biomarkers associated with atherosclerosis biology (inflammation, angiogenesis, apoptosis, chemotaxis, etc.) were optimized for measuring baseline serum samples from 1084 initially CHD-free Marshfield Clinic Personalized Medicine Research Project (PMRP) individuals. A multivariable Cox regression model was fit using the most powerful risk predictors within the clinical and protein variables identified by repeated cross-validation. The resulting CHDRA algorithm was validated in a Multiple-Ethnic Study of Atherosclerosis (MESA) case-cohort sample.
Results
A CHDRA algorithm of age, sex, diabetes, and family history of MI, combined with serum levels of seven biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, and sFas) yielded a clinical net reclassification index of 42.7% (p<0.001) for MESA patients with a recalibrated Framingham 5-year intermediate risk level. Across all patients, the model predicted acute coronary events (hazard ratio=2.17, p<0.001), and remained an independent predictor after Framingham risk factor adjustments.
Limitations
These include the slightly different event definition with the MESA samples and inability to include PMRP fatal CHD events.
Conclusions
A novel risk score of serum protein levels plus clinical risk factors, developed and validated in independent cohorts, demonstrated clinical utility for assessing the true risk of CHD events in intermediate risk patients. Improved accuracy in cardiovascular risk classification could lead to improved preventive care and fewer deaths.
doi:10.1185/03007995.2012.742878
PMCID: PMC3666558  PMID: 23092312
myocardial infarction; risk assessment; coronary heart disease; inflammation; clinical validation
4.  Lifestyle intervention and/or statins for the reduction of C-reactive protein in type 2 diabetes: From the Look AHEAD Study 
Obesity (Silver Spring, Md.)  2013;21(5):944-950.
Objective
Cardiovascular risk remains high despite statin use. Overweight/obese diabetic persons usually have normal/low LDL-cholesterol but high C-reactive protein (CRP) levels. We aimed to examine the effects of intensive lifestyle intervention for weight loss (ILI) on CRP levels in overweight/obese diabetic individuals by statin use.
Design and Methods
Look AHEAD was a randomized trial in overweight/obese type 2 diabetic individuals testing whether ILI would reduce cardiovascular mortality, when compared to usual care. We evaluated CRP changes in 1,431 participants with biomarker levels, who remained on or off statin treatment for 1-year.
Results
The reduction in CRP levels with ILI at 1 year in men and women on statins was −44.9 and −42.3 %, respectively, compared to −13.7 and −21.0 % for those on statins and usual care (p<0.0001). At 1 year, median CRP levels were: 1.8 mg/L in participants randomized to ILI on statin therapy; 2.6 mg/L for those on statins randomized to usual care and 2.9 mg/L for participants not on statins but randomized to ILI. Weight loss was associated with 1-year CRP reduction (p<0.0001) in statin and non-statin users.
Conclusions
Our findings suggest that in overweight/obese diabetic persons, ILI and statin therapy may have substantial additive anti-inflammatory benefits.
doi:10.1002/oby.20431
PMCID: PMC3689862  PMID: 23512860
5.  Physical activity and physiological cardiac remodelling in a community setting: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Objective
To evaluate the association of physical activity with left ventricular structure and function in the general population in a community setting.
Design
Cross-sectional study.
Setting
The Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of subclinical atherosclerosis.
Participants
A multiethnic sample of 4992 participants (aged 45–84 years; 52% female) free of clinically apparent cardiovascular disease.
Interventions
Physical activity induces beneficial physiological cardiac remodelling in a cross-sectional study of non-athlete individuals.
Main Outcome Measures
Left ventricular mass, volumes and function were assessed by cardiac magnetic resonance imaging. Physical activity, defined as intentional exercise and total moderate and vigorous physical activity, was assessed by a standard semiquantitative questionnaire.
Results
Left ventricular mass and end-diastolic volume were positively associated with physical activity (eg, 1.4 g/m2 (women) and 3.1 g/m2 (men) greater left ventricular mass in the highest category of intentional exercise compared with individuals reporting no intentional exercise; p = 0.05 and p<0.001, respectively). Relationships were non-linear, with stronger positive associations at lower levels of physical activity (test for non-linearity; p = 0.02 and p = 0.03, respectively). Cardiac output and ejection fraction were unchanged with increased physical activity levels. Resting heart rate was lower in women and men with higher physical activity levels (eg, −2.6 beats/minute lower resting heart rate in the highest category of intentional exercise compared with individuals reporting no intentional exercise; p<0.001).
Conclusions
In a community-based population free of clinically apparent cardiovascular disease, higher physical activity levels were associated with proportionally greater left ventricular mass and end-diastolic volume and lower resting heart rate.
doi:10.1136/hrt.2009.178426
PMCID: PMC3037117  PMID: 19858139
6.  A Quantitative Trait Locus on Chromosome 5p Influences D-Dimer Levels in the San Antonio Family Heart Study 
Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.
doi:10.1155/2010/490241
PMCID: PMC2989697  PMID: 21151504
7.  Longitudinal assessment of fibrinogen in relation to subclinical cardiovascular disease: the CARDIA study 
Summary
Objective
To examine the strength of the associations of fibrinogen with subclinical atherosclerosis in healthy persons.
Methods
A population-based, prospective, observational study of black and white men and women (Coronary Artery Risk Development in Young Adults [CARDIA]). Fibrinogen levels were measured at year 7 (ages 25–37, n = 2969), and again at year 20 (ages 38–50, n = 2832). Measures of subclinical atherosclerosis (coronary artery calcification [CAC] and carotid intimal-medial thickness [CIMT]) were recorded at year 20.
Results
Over the 13-year study interval (1992–1993 to 2005–2006), fibrinogen rose from a mean of 3.32 to 4.05 g L−1. After adjusting for age, gender and race, fibrinogen was positively associated with greater incidence of CAC and increased CIMT cross-sectionally as well as after 13 years of follow-up (all P-trend < 0.001). After further adjustment for field center, BMI, smoking, education, systolic blood pressure, diabetes, antihypertensive medication use, total and HDL cholesterol, and CRP, significant positive relationships between fibrinogen and incidence of CAC remained for the total cohort longitudinally (P-trend = 0.037), but not cross-sectionally (P-trend = 0.147).
Conclusion
This 13-year study demonstrates that higher levels of fibrinogen during young adulthood are positively associated with incidence of CAC and increased CIMT in middle-age, but the strength of the association declines with increasing age.
doi:10.1111/j.1538-7836.2009.03727.x
PMCID: PMC2856753  PMID: 20025644
atherosclerosis; carotid thickening; coronary calcification; fibrinogen
8.  Impact of stearic acid and oleic acid on hemostatic factors in the context of controlled diets consumed by healthy men 
The effects of stearic acid (STA) on cardiovascular disease risk beyond lipid and lipoprotein risk factors, including hemostasis, are unclear, particularly when compared with unsaturated fatty acids. The aim of the present study is to compare the effects of STA with those of oleic acid (OL) on markers of hemostasis. In a randomized crossover study, 50 men consumed six controlled diets for 5 weeks each (39% energy from fat, 15% energy from protein, 46% energy from carbohydrate (CHO)). Fat (8% energy) was replaced across diets by: STA, OL, CHO (control), trans fatty acids (TFAs), TFA/STA and 12:0–16:0 saturated fatty acids. Factor VIIc, plasminogen activator inhibitor-1 (PAI-1) and plasmin alpha-2-antiplasmin complex concentrations were not different between OL and STA (P>0.05). Compared with control, OL increased factor VIIc and PAI-1 (P⩽0.05), whereas there were no differences with STA (P>0.05). STA and OL similarly affect markers of hemostasis in healthy men, within the context of a highly controlled diet.
doi:10.1038/ejcn.2014.62
PMCID: PMC4155798  PMID: 24736679

Results 1-8 (8)