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1.  Longitudinal Effects of a Decade of Aging on Carotid Artery Stiffness: The Multi-Ethnic Study of Atherosclerosis 
Background and Purpose
Arterial stiffening is associated with hypertension, stroke, and cognitive decline; however, the effects of aging and cardiovascular disease risk factors on carotid artery stiffening have not been assessed prospectively in a large multi-ethnic, longitudinal study.
Methods
Distensibility coefficient and Young’s elastic modulus of the right common carotid artery were calculated at baseline and after a mean (standard deviation) of 9.4 (0.5) years in 2,650 participants. Effects of age and cardiovascular disease risk factors were evaluated by multivariable mixed regression and analysis of covariance models.
Results
At baseline, participants were 59.9 (9.4) years old (53% female; 25% Black, 22% Hispanic, 14% Chinese). Young’s elastic modulus increased from 1,581 (927) to 1,749 (1,306) mmHg (p<0.0001) and distensibility coefficient decreased from 3.1 (1.3) to 2.7 (1.1) x 10−3 mmHg−1 (p<0.001), indicating progressive arterial stiffening. Young’s elastic modulus increased more among participants who were >75 years old at baseline (p<0.0001). In multivariable analyses, older age and less education independently predicted worsening Young’s elastic modulus and distensibility coefficient. Stopping antihypertensive medication during the study period predicted more severe worsening of Young’s elastic modulus (β=360.2 mmHg, p=0.008). Starting antihypertensive medication after exam 1 was predictive of improvements in distensibility coefficient (β =1.1 x 10−4, mmHg−1; p=0.024).
Conclusions
Arterial stiffening accelerates with advanced age. Older individuals experience greater increases in Young’s elastic modulus than do younger adults, even after considering the effects of traditional risk factors. Treating hypertension may slow the progressive decline in carotid artery distensibility observed with aging and improve cerebrovascular health.
doi:10.1161/STROKEAHA.113.002649
PMCID: PMC3888489  PMID: 24253542
Aging; Carotid arteries; Elasticity; Hypertension; Cardiovascular disease risk factors
2.  25-hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the Multi-Ethnic Study of Atherosclerosis 
Objective
Observational evidence supports independent associations between 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH) and cardiovascular risk. A plausible hypothesis for these associations is accelerated development of atherosclerosis.
Approach and Results
We evaluated cross-sectional and longitudinal associations of 25-OHD and PTH with carotid intima-media thickness (IMT) and carotid plaques among 3251 participants free of cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. 25-OHD and PTH were measured at baseline by mass spectrometry and immunoassay, respectively. All subjects underwent a carotid ultrasound exam at baseline and 9.4 years later (median, range 8–11.1y). Multivariable linear and logistic regressions were used to test associations of 25-OHD and PTH with the extent and the progression of IMT and the prevalence and incidence of carotid plaque. Mean (SD) 25-OHD and PTH were 25.8ng/ml (10.6) and 44.2pg/ml (20.2). No independent associations were found between 25-OHD or PTH and IMT at baseline [increment of 1.9µm (95%CI −5.1 to 8.9) per 10ng/ml lower 25-OHD; increment of 0.8µm (95%CI −3.2 to 4.8) per 10pg/ml higher PTH] or progression of IMT [increment of 2.6µm (95%CI −2.5 to 7.8) per 10ng/ml lower 25-OHD, increment of 1.6µm (95%CI −1.9 to 5.2) per 10pg/ml higher PTH]. No associations were found with the baseline prevalence of carotid plaque or the incidence of new plaques over the study period. We did not observe any interaction by race or ethnicity (White, Chinese, Black and Hispanic).
Conclusions
The consistent lack of association of vitamin D and PTH with carotid IMT and plaque suggests that these hormones may influence cardiovascular risk through pathways not reflected by carotid atherosclerosis.
doi:10.1161/ATVBAHA.113.301781
PMCID: PMC3956469  PMID: 23814117
vitamin D; PTH; mineral metabolism; intima-media thickness; plaque; atherosclerosis; carotid
3.  Ultrasonographic measures of cardiovascular disease risk in antiretroviral treatment-naïve individuals with HIV infection 
AIDS (London, England)  2013;27(6):929-937.
Objective
To evaluate associations between traditional cardiovascular disease (CVD) risk factors, inflammatory markers, and markers of HIV disease activity with ultrasonographic measures of CVD risk in patients with HIV who are not receiving antiretroviral therapy (ART).
Design
Cross-sectional, baseline evaluation of ART-naïve HIV-infected individuals without known CVD or diabetes mellitus enrolled in a randomized ART treatment trial.
Methods
Prior to ART initiation, carotid artery intima-media thickness (CIMT) and brachial artery flow-mediated dilation (FMD) were measured. Additional parameters included CD4 cell count, HIV viral load, body composition, lipoproteins, and inflammatory markers. Associations with common CIMT, bifurcation CIMT, presence of carotid artery lesions, and brachial artery FMD were evaluated.
Results
The 331 enrolled subjects were a median (1st–3rd quartile) of 36 (28–45) years old. Common and bifurcation CIMT values were higher and lesions more prevalent with older age (p <0.001). FMD was lower with older age (p =0.009). Those with a Framingham Risk Score >6%/10 years (N =44) had higher common and bifurcation CIMT (p <0.001), carotid lesion prevalence (p <0.001), and lower FMD (p =0.035). Independent associations with common CIMT were identified for increasing age, height, weight, small LDL particles, and black race; these were similar for bifurcation CIMT. Presence of carotid artery lesions was associated with increasing age, presence of metabolic syndrome, interleukin-6, and lower HIV-1 RNA.
Conclusions
In a contemporary cohort of ART-naive HIV-infected individuals, ultrasonographic measures of CVD risk were more strongly associated with traditional risk factors than CD4 cell counts, HIV replication, or inflammatory markers.
doi:10.1097/QAD.0b013e32835ce27e
PMCID: PMC3664137  PMID: 23196938
atherosclerosis; carotid arteries; endothelial function; human immunodeficiency virus; inflammation
4.  Mitochondrial DNA Variation and Changes in Adiponectin and Endothelial Function in HIV-Infected Adults After Antiretroviral Therapy Initiation 
AIDS Research and Human Retroviruses  2013;29(10):1293-1299.
Abstract
Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow-mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A>G mtDNA polymorphism (N=8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 μg/ml; p=0.003), greater absolute (−1.9 vs. −0.2 μg/ml) and relative (−33% vs. −3%) adiponectin decreases (p<0.001 for both), and lower week 24 brachial artery FMD (3.6% vs. 5.4%; p=0.04). Individual mtDNA haplogroups, including haplogroups H (N=13) and U (N=6), were not associated with adiponectin or FMD changes. In this small pilot study, adiponectin and brachial artery FMD on ART differed in non-Hispanic whites with a nonsynonymous mtDNA variant associated with several human diseases. These preliminary findings support the hypothesis that mtDNA variation influences metabolic ART effects. Validation studies in larger populations and in different racial/ethnic groups that include m.10398G carriers are needed.
doi:10.1089/aid.2013.0079
PMCID: PMC3785797  PMID: 23944767
5.  Long-term effects of smoking and smoking cessation on exercise stress testing: Three-year outcomes from a randomized clinical trial 
American Heart Journal  2011;163(1):81-87.e1.
Background
The long-term effects of smoking and smoking cessation on markers of cardiovascular disease (CVD) prognosis obtained during treadmill stress testing (TST) are unknown. The purpose of this study was to evaluate the long-term effects of smoking cessation and continued smoking on TST parameters that predict CVD risk.
Methods
In a prospective, double-blind, randomized, placebo-controlled trial of 5 smoking cessation pharmacotherapies, symptom-limited TST was performed to determine peak METs, rate-pressure product (RPP), heart rate (HR) increase, HR reserve, and 60-second HR recovery, before and 3 years after the target smoking cessation date. Relationships between TST parameters and treatments among successful abstainers and continuing smokers were evaluated using multivariable analyses.
Results
At baseline, the 600 current smokers (61% women) had a mean age of 43.4 (SD 11.5) years and smoked 20.7 (8.4) cigarettes per day. Their exercise capacity was 8.7 (2.3) METs, HR reserve was 86.6 (9.6)%, HR increase was 81.1 (20.9) beats/min, and HR recovery was 22.3 (11.3) beats. Cigarettes per day and pack-years were independently and inversely associated with baseline peak METs (P < .001), RPP (P < .01, pack-years only), HR increase (P < .05), and HR reserve (P < .01). After 3 years, 168 (28%) had quit smoking. Abstainers had greater improvements than continuing smokers (all P < .001) in RPP (2,055 mm Hg beats/min), HR increase (5.9 beats/min), and HR reserve (3.7%), even after statistical adjustment (all P < .001).
Conclusions
Smokers with a higher smoking burden have lower exercise capacity, lower HR reserve, and a blunted exercise HR response. After 3 years, TST improvements suggestive of improved CVD prognosis were observed among successful abstainers.
doi:10.1016/j.ahj.2011.06.023
PMCID: PMC3348587  PMID: 22172440
6.  β-AR Polymorphisms and Glycemic and Lipid Parameters in Hypertensive Individuals Receiving Carvedilol or Metoprolol 
American journal of hypertension  2012;25(8):920-926.
Background
β-blocker therapy and β-adrenergic receptor (β-AR) polymorphisms are associated with increases in glucose and lipid levels. We investigated associations of common β1 and β2- AR single nucleotide polymorphisms (SNPs) with metabolic and lipid variables, and examined interactions with β-blocker treatment assignment to affect these parameters.
Methods
This was a Post hoc analysis of a double-blinded clinical trial of non-diabetic, hypertensive individuals that were randomized to receive carvedilol or metoprolol succinate. Fasting glucose, insulin, and lipid levels were measured at baseline, 3, and after 6 months. Genotypes for β1-AR SNPs Ser49Gly & Gly389Arg and β2-AR Arg16Gly & Gln27Glu were determined. Multivariable mixed models were used to examine associations between β-AR polymorphisms, metabolic parameters, and SNP interactions with β-blocker therapy (pinteraction).
Results
The 322 subjects were mean (standard deviation) 51.5 (11.2) years old. After 6 months, insulin levels increased by 35.6% on metoprolol but decreased by 9.9% on carvedilol (p=0.015). In univariate models, the Gln27Gln genotype had higher overall insulin levels with β-blockade compared to the Glu27Glu genotype (p=0.006). Both Arg16Gly (p=0.012) and Gln27Glu (p=0.037) SNPs were associated with triglycerides levels. An interaction between the Arg16Gly SNP and treatment was identified (pint=0.048).
Conclusions
These data suggest that insulin and triglycerides may be influenced by β2-AR polymorphisms in patients taking β–blockers.
doi:10.1038/ajh.2012.54
PMCID: PMC4126246  PMID: 22647787
beta blocker; beta adrenergic receptor gene polymorphism; triglycerides
7.  Body Composition, Soluble Markers of Inflammation, and Bone Mineral Density in Antiretroviral Therapy-Naïve HIV-1 Infected Individuals 
Objective
To determine the association between bone mineral density (BMD), inflammatory markers, and alterations in fat and lean mass in untreated HIV-infected individuals.
Design
Cross-sectional analysis of antiretroviral therapy (ART)-naïve persons enrolled into a randomized clinical trial
Methods
Dual energy x-ray absorptiometry (DXA) for BMD, lean and fat mass, and a laboratory assessment were performed. Soluble biomarkers included adipocytokines (leptin, adiponectin), inflammatory markers (hsCRP, IL-6), and markers related to bone metabolism (osteoprotegerin (OPG)), receptor activator of NFκB Ligand (RANKL)). BMD at the lumbar spine, total hip, and femoral neck was expressed as a Z-score (number of standard deviations away from an age-, race-, sex-matched reference population).
Results
331 subjects had a median (Q1, Q3) age of 36 (28,45) years, were 89% male, and 44% white. The prevalence of low BMD (Z-score ≤ −2 at any of the 3 sites) was 10%. No associations were detected between Z-scores and hsCRP, IL-6, or RANKL (P≥0.1). In a linear model adjusting for age, gender, race, and total fat mass, lower lumbar spine Z-scores were associated with lower total lean mass, higher serum adiponectin, and lower OPG. Results at the total hip or femoral neck were similar.
Conclusions
Among ART-naïve HIV-infected individuals, lower BMD was associated with lower lean mass, higher adiponectin, and lower OPG, but not HIV disease variables or any of the inflammatory markers. These findings may have implications for bone metabolism in untreated HIV, in which hypoadiponectinemia and higher OPG may mitigate bone loss.
doi:10.1097/QAI.0b013e318295eb1d
PMCID: PMC3693854  PMID: 23591634
Bone mineral density; Body composition; Human Immunodeficiency Virus; Inflammation
8.  Smoking Cessation and the Risk of Diabetes Mellitus and Impaired Fasting Glucose: Three-Year Outcomes after a Quit Attempt 
PLoS ONE  2014;9(6):e98278.
Weight gain after smoking cessation may increase diabetes mellitus and impaired fasting glucose (IFG) risk. This study evaluated associations between smoking cessation and continued smoking with incident diabetes and IFG three years after a quit attempt. The 1504 smokers (58% female) were mean (standard deviation) 44.7 (11.1) years old and smoked 21.4 (8.9) cigarettes/day. Of 914 participants with year 3 data, the 238 abstainers had greater weight gain, increase in waist circumference, and increase in fasting glucose levels than the 676 continuing smokers (p≤0.008). In univariate analyses, Year 3 abstinence was associated with incident diabetes (OR = 2.60, 95% CI 1.44–4.67, p = .002; 4.3% absolute excess) and IFG (OR = 2.43, 95% CI 1.74–3.41, p<0.0001; 15.6% absolute excess). In multivariate analyses, incident diabetes was associated independently with older age (p = 0.0002), higher baseline body weight (p = 0.021), weight gain (p = 0.023), baseline smoking rate (p = 0.008), baseline IFG (p<0.0001), and baseline hemoglobin A1C (all p<0.0001). Smoking more at baseline predicted incident diabetes among eventual abstainers (p<0.0001); weighing more at baseline predicted incident diabetes among continuing smokers (p = 0.0004). Quitting smoking is associated with increased diabetes and IFG risk. Independent risk factors include older age, baseline body weight, baseline glycemic status, and heavier pre-quit smoking. These findings may help target smokers for interventions to prevent dysglycemia.
Trial Registration
Clinicaltrials.gov NCT00332644
doi:10.1371/journal.pone.0098278
PMCID: PMC4043674  PMID: 24893290
9.  Carotid Artery Imaging: Insights Into Inflammation and Cardiovascular Disease Risk in Patients With HIV Infection 
doi:10.1161/JAHA.112.001396
PMCID: PMC3487375  PMID: 23130129
atherosclerosis; carotid arteries; carotid intima-media thickness; human immunodeficiency virus
10.  Long-Term Effects of Carotid Screening on Patient Outcomes and Behaviors 
Archives of internal medicine  2011;171(6):589-591.
doi:10.1001/archinternmed.2011.90
PMCID: PMC3075090  PMID: 21444853
Atherosclerosis; Carotid arteries; Risk factors; Ultrasound
11.  Effects of an Office-Based Carotid Ultrasound Screening Intervention 
Background
Carotid ultrasound screening (CUS) has been recommended for cardiovascular disease (CVD) risk prediction; however, its effectiveness in clinical practice is unknown. The purpose of this study was to prospectively determine the effects of office-based CUS on physician decision-making and patient health-related behaviors (HRBs).
Methods
Physicians from 5 non-academic, community practices recruited patients ≥40 years old with ≥1 CVD risk factor. Abnormal carotid ultrasound screening (AbnlCUS) was defined as carotid intima-media thickness >75th percentile or carotid plaque presence. Subjects completed questionnaires before and immediately after CUS, then 30 days later to determine self-reported behavioral changes. Odds ratios (OR) for changes in physician management and patient HRBs were determined from multivariate hierarchical logistic regression models.
Results
There were 355 subjects (mean [standard deviation] 53.6 [7.9] years old, 2.3 [0.9] risk factors, 58% women); 266 (74.9%) had AbnlCUS. Presence of AbnlCUS altered physicians’ prescription of aspirin (p<0.001) and cholesterol medications (p<0.001). Immediately after CUS, subjects reported increased ability to change HRBs (p=0.002), regardless of their test results. Subjects with AbnlCUS reported increased CVD risk perception (OR 4.14, p<0.001), intentions to exercise (OR 2.28, p=0.008), make dietary changes (OR 2.95, p<0.001), and quit smoking (OR 4.98, p=0.022). After 30 days, 34% increased exercise frequency and 37% reported weight loss; but these changes were not predicted by the CUS results. AbnlCUS modestly predicted reduced dietary sodium (OR 1.45, p=0.002) and increased fiber (OR 1.55, p=0.022) intake.
Conclusions
Finding abnormal results on CUS had major effects on physician but not patient behaviors.
doi:10.1016/j.echo.2011.02.013
PMCID: PMC3279118  PMID: 21477989
Atherosclerosis; Carotid arteries; Risk factors; Ultrasound
12.  Risk Factors for Subclinical Carotid Atherosclerosis among Current Smokers 
Preventive Cardiology  2010;13(4):166-171.
This study characterized the determinants of carotid atherosclerosis in a large, contemporary sample of current smokers. Associations between risk factors, carotid intima-media thickness (CIMT) and carotid plaque presence were determined by multivariable regression. Subjects included 1,504 current smokers (58% female) who were a median (interquartile range) of 44.7 (38–53) years old and smoked 25 (15–40) pack-years; 55% had plaque. Pack-years, age, male sex, non-white race, body-mass index, systolic blood pressure, small low-density lipoproteins (LDL), and total high-density lipoproteins were independently associated with CIMT (model R2=0.434, p<0.001). Pack-years (OR 1.14 per 10 pack-years, p=0.001), age (OR 1.75 per 10 years, p<0.001), body-mass index (OR 0.91 per 5 kg/m2, p =0.035), and small LDL (OR 1.11 per 100 nmol/L, p<0.001), were independently associated with carotid plaque presence (model X2=210.7, p<0.001). The association between pack-years and carotid plaque was stronger in women (OR 1.09 per 10 pack-years, pinteraction=0.018).
doi:10.1111/j.1751-7141.2010.00068.x
PMCID: PMC3276243  PMID: 20860639
atherosclerosis; carotid; arteries; lipoproteins; smoking
13.  Effects of Smoking and Smoking Cessation on Lipids and Lipoproteins: Outcomes from a Randomized Clinical Trial 
American heart journal  2011;161(1):145-151.
Background
The effects of smoking and smoking cessation on lipoproteins have not been studied in a large contemporary group of smokers. This study was designed to determine the effects of smoking cessation on lipoproteins.
Methods
One-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. Fasting nuclear magnetic resonance spectroscopy lipoprotein profiles were obtained before and 1-year after the target smoking cessation date. The effects of smoking cessation and predictors of changes in lipoproteins after one year were identified by multivariable regression.
Results
The 1,504 current smokers were mean (standard deviation) 45.4 (11.3) years old and smoked 21.4 (8.9) cigarettes/day at baseline. Of the 923 adult smokers who returned at 1 year, 334 (36.2%) had quit smoking. Despite gaining more weight (4.6 kg [5.7] vs. 0.7 kg [5.1], p<0.001], abstainers had increases in high-density lipoprotein cholesterol (HDL-C) (2.4 [8.3] vs. 0.1 [8.8] mg/dL, p<0.001], total HDL (1.0 [4.6] vs. −0.3 mcmol/L [5.0], p<0.001) and large HDL (0.6 [2.2] vs. 0.1 [2.1] mcmol/L, p=0.003) particles, compared with continuing smokers. Significant changes in low-density lipoprotein (LDL) cholesterol and particles were not observed. After adjustment, abstinence from smoking (p<0.001) was independently associated with increases in HDL-C and total HDL particles. These effects were stronger in women.
Conclusions
Despite weight gain, smoking cessation improved HDL-C, total HDL and large HDL particles, especially in women. Smoking cessation did not affect LDL or LDL size. Increases in HDL may mediate part of the reduced cardiovascular disease risk observed after smoking cessation.
doi:10.1016/j.ahj.2010.09.023
PMCID: PMC3110741  PMID: 21167347
Clinical Trial; High-density lipoprotein cholesterol; Lipoproteins; Low-density lipoprotein cholesterol; Risk Factors; Smoking
14.  Effects of Smoking Intensity and Cessation on Inflammatory Markers in a Large Cohort of Active Smokers 
American heart journal  2010;160(3):458-463.
Background
Cigarette smoking has been associated with increases in C-reactive protein (CRP) and leukocyte counts (WBC); however, the effects of smoking intensity and smoking cessation on inflammatory markers have not been evaluated prospectively in a large, modern cohort of current smokers.
Methods
WBC count and high-sensitivity CRP were measured in current smokers enrolled in a randomized, prospective clinical trial of five smoking cessation pharmacotherapies. Smoking intensity parameters included: cigarettes/day, pack-years, Fagerstrom Test of Nicotine Dependence (FTND) score, and carbon monoxide (CO) levels. CRP also was measured after 1 year with assessment of abstinence status.
Results
The 1,504 current smokers (58% female) were mean (standard deviation): 44.7 (11.1) years old, smoked 21.4 (8.9) cigarettes/day and had a smoking burden of 29.4 (20.4) pack-years. Log (CRP) was not associated with any marker of smoking intensity, except for a weak correlation with pack-years (r=0.05, p=0.047). In contrast, statistically significant correlations were observed between all 4 markers of smoking intensity and WBC count (all p≤0.011). In multivariable models, waist circumference (p<0.001) and triglycerides (p<0.05), but no markers of smoking intensity, were associated with log(CRP). However, pack-years (p=0.002), cigarettes/day (p=0.013), CO (p<0.001), and FTND (p<0.001) were independently associated with WBC count. After 1 year, log(CRP) (p=0.296) and changes in log(CRP) (p=0.455) did not differ between abstainers and continuing smokers.
Conclusions
Smoking intensity is associated with increased WBC count, but not CRP levels. Smoking cessation does not reduce CRP. The relationship between CRP and smoking intensity may be masked by CRP’s stronger relationship with adiposity.
doi:10.1016/j.ahj.2010.06.006
PMCID: PMC2937015  PMID: 20826253
C-reactive protein; Inflammation; Leukocytes; Risk factors; Smoking
15.  Effects of Smoking and Smoking Cessation on Endothelial Function: One-Year Outcomes from a Randomized Clinical Trial 
Objectives
To determine if smoking cessation improves flow-mediated dilation (FMD) of the brachial artery (BA).
Background
The long-term effects of continued smoking and smoking cessation on endothelial function have not been described previously.
Methods
This was a one-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. FMD was measured by B-mode ultrasound before and 1-year after the target smoking cessation date. Cessation was verified by exhaled carbon monoxide levels. ΔFMD was compared among study arms and between subjects that successfully quit and those who continued to smoke. Predictors of baseline FMD and ΔFMD were identified by multivariable regression.
Results
The 1,504 current smokers (58% female, 84% white) were mean (standard deviation): 44.7 (11.1) years old and smoked 21.4 (8.9) cigarettes/day. Baseline FMD was similar in each treatment arm (p=0.499) and was predicted by BA diameter (p<0.001), reactive hyperemia blood flow (p<0.001), high-density lipoprotein cholesterol (p=0.001), and carbon monoxide (p=0.012) levels. After one year, 36.2% quit smoking. FMD increased by 1% [6.2% (4.4%) to 7.2% (4.2%)] after 1 year (p=0.005) in those who quit, but did not change (p=0.643) in those who continued to smoke. Improved FMD among quitters remained significant (p=0.010) after controlling for changes in BA diameter, reactive hyperemia, low-density lipoprotein cholesterol, and presence of a home smoking ban.
Conclusions
Despite weight gain, smoking cessation leads to prolonged improvements in endothelial function, which may mediate part of the reduced cardiovascular disease risk observed after smoking cessation.
doi:10.1016/j.jacc.2010.03.002
PMCID: PMC2947952  PMID: 20236788
Endothelial dysfunction; Clinical Trial; Risk Factors; Smoking
16.  Smoking Intensity and Lipoprotein Abnormalities in Active Smokers 
Journal of clinical lipidology  2009;3(6):372-378.
Background
Smoking is associated with decreased high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides.
Objective
To evaluate the effects of five markers of smoking intensity on lipoprotein concentrations and particle sizes in a large, modern cohort of current smokers.
Methods
Fasting nuclear magnetic resonance spectroscopy lipoprotein profiles were obtained in a large cohort of current smokers enrolled in a smoking cessation trial. Multivariate linear regression models were constructed to determine predictors of lipoprotein fractions. Models included age, sex, race, waist circumference, level of physical activity and alcohol consumption. Smoking intensity parameters included: current cigarettes smoked/day, pack-years, the Fagerström Test of Nicotine Dependence (FTND) score, and carbon monoxide (CO) levels.
Results
The 1,504 subjects (58% women, 84% white) had a mean (standard deviation) age of 45 (11.0) years. They smoked 21.4 (8.9) cigarettes/day (29.4 [20.4] pack-years). HDL-C (42.0 [13.5] mg/dL) and total HDL particles (30.3 [5.9] μmol/L) were low. Cigarettes smoked/day independently predicted higher total cholesterol (p=0.009), low-density lipoprotein cholesterol (p=0.023), and triglycerides (p=0.002). CO levels predicted lower HDL-C (p=0.027) and total HDL particles (p=0.009). However, the incremental R2 for each marker of smoking intensity on each lipoprotein was small. Relationships between the FTND score and lipoproteins were weak and inconsistent. Participants in the lowest quintiles of current smoking, pack-years, and CO had more favorable lipoproteins (all p<0.04).
Conclusions
Among current smokers, increased smoking burden is associated with small increases in total cholesterol, LDL-C, and triglycerides. Increased recent smoke exposure is associated with small decreases in HDL-C and HDL particles.
doi:10.1016/j.jacl.2009.10.008
PMCID: PMC2802067  PMID: 20161531
High-density lipoprotein cholesterol; Low-density lipoprotein cholesterol; Lipoproteins; Risk factors; Smoking; Triglycerides
17.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
doi:10.1093/aje/kws169
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
18.  Effects of Atorvastatin on Cerebral Blood Flow in Middle-Aged Adults at Risk for Alzheimer’s Disease: A Pilot Study 
Current Alzheimer research  2012;9(8):990-997.
Background/Aims
Hypercholesterolemia in midlife increases risk for Alzheimer’s disease (AD) and contributes to cerebrovascular dysregulation - an early finding in preclinical AD pathology. Statins improve vascular reactivity, but it is unknown if they increase regional cerebral blood flow (CBF) in individuals at risk for AD.
Methods
In a randomized, controlled, double-blind pilot study, 16 asymptomatic middle-aged adults with parental history of AD were randomized to atorvastatin or placebo daily for 4 months. At baseline and month 4, regional CBF was measured using arterial spin-labeling magnetic resonance imaging and endothelial function was measured using brachial artery ultrasound.
Results
At baseline, participants with low HDL-cholesterol, higher global vascular risk, and greater endothelial dysfunction had reduced regional CBF in areas of the brain related to memory and learning (all p<0.03). Using voxel-based analysis, 4 months of atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices compared to placebo.
Conclusion
In this pilot study, atorvastatin increased regional CBF in persons at risk for AD. Further research is warranted to confirm whether statins increase CBF in areas of the brain related to memory and learning and whether such perfusion changes are associated with a delay in the onset of AD.
PMCID: PMC3576818  PMID: 22175654
Alzheimer’s disease; cerebral blood flow; dementia; MRI perfusion; prevention; statins
19.  Lipoprotein Changes in HIV-Infected Antiretroviral-Naïve Individuals after Starting Antiretroviral Therapy: ACTG Study A5152s Stein: Lipoprotein Changes on Antiretroviral Therapy 
Journal of clinical lipidology  2008;2(6):464-471.
Background
Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are less well-understood, and have not been investigated in a prospective study where assignment to ART is randomized.
Objective
To evaluate the effects of three class-sparing ART regimens on lipids and lipoproteins.
Methods
This was a substudy of a prospective, multicenter study treatment-naïve HIV-infected individuals randomly assigned to receive a regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + the non-nucleoside reverse transcriptase inhibitor efavirenz, NRTIs + the protease inhibitor lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. Lipoproteins were measured by nuclear magnetic resonance spectroscopy.
Results
Among the 82 participants, total and small low-density lipoprotein concentrations increased (median, interquartile range) by 152 (-49 - +407, p<0.01) and 130 (-98 - +417, p<0.01) nmol/L, respectively, especially in the arms containing lopinavir/ritonavir (pKW<0.04). Very low-density lipoproteins also increased (p<0.01), with a larger increase in the arms that contained lopinavir/ritonavir (p=0.022). High-density lipoproteins increased by 6.0 nmol/L (2.8 - 10.4, p<0.01), but differences between arms were not significant (pKW=0.069). Changes were not related to changes in markers of insulin/glucose metabolism.
Conclusions
Total and small low-density lipoprotein concentrations increased, especially in the arms containing lopinavir/ritonavir, as did increases in total very low-density lipoproteins. Adverse changes were especially prominent in the arm with efavirenz + lopinavir/ritonavir.
doi:10.1016/j.jacl.2008.08.442
PMCID: PMC2636959  PMID: 19956354
Antiretroviral therapy; Cardiovascular risk; Clinical trial; Human immunodeficiency virus; Lipids; Lipoproteins
20.  Vitamin D Levels and Markers of Arterial Dysfunction in HIV 
Abstract
HIV-infected patients have low vitamin D levels as well as an increase in cardiovascular (CVD) risk. We examined the relationship between vitamin D and three markers of arterial dysfunction among HIV-infected individuals on stable antiretroviral (ARV) therapy. Levels of 25-hydroxyvitamin D [25(OH)D] were assessed by chemiluminescent immunoassay (DiaSorin) in 100 enrollees into the Hawaii Aging with HIV-Cardiovascular Cohort Study, a cohort of HIV-infected subjects age ≥40 years on stable (≥6 months) ARV therapy. The relationships between 25(OH)D levels and brachial artery flow-mediated dilation (FMD), right common carotid artery intima-media thickness (cIMT), and coronary artery calcium (CAC) were examined. Analytical methods included Pearson's correlations, Kruskal–Wallis tests, relative risks, and linear regression models. The cohort was 86% male and 60% white with a median age of 52 years and CD4 of 510 cells/mm3. The median (Q1, Q3) level of 25(OH)D was 27.9 ng/ml (21.8, 38.3). There were 72 FMD, 50 cIMT, and 90 CAC measurements available for analyses. A significant correlation was observed between 25(OH)D levels and FMD (r=0.30, p=0.01) but not with cIMT (r=−0.05, p=0.76). In a linear regression model, Framingham risk score attenuated the relationship between FMD and 25(OH)D. Those with lower 25(OH)D levels were at slightly higher risk of having CAC (RR=1.02, p=0.04). Among those with CAC, lower 25(OH)D levels were not associated with higher CAC scores (p=0.36). Lower vitamin D levels are associated with evidence of subclinical arterial dysfunction in HIV-infected individuals. The significance of these findings warrants further investigation.
doi:10.1089/aid.2011.0086
PMCID: PMC3399561  PMID: 21978287
21.  Electrocardiographic Changes Associated with Smoking and Smoking Cessation: Outcomes from a Randomized Controlled Trial 
PLoS ONE  2013;8(4):e62311.
Introduction
Cardiovascular disease (CVD) can be detected and quantified by analysis of the electrocardiogram (ECG); however the effects of smoking and smoking cessation on the ECG have not been characterized.
Methods
Standard 12-lead ECGs were performed at baseline and 3 years after subjects enrolled in a prospective, randomized, placebo-controlled clinical trial of smoking cessation pharmacotherapies. ECGs were interpreted using the Minnesota Code ECG Classification. The effects of (i) smoking burden on the prevalence of ECG findings at baseline, and (ii) smoking and smoking cessation on ECG changes after 3 years were investigated by multivariable and multinomial regression analyses.
Results
At baseline, 532 smokers were (mean [SD]) 43.3 (11.5) years old, smoked 20.6 (7.9) cigarettes/day, with a smoking burden of 26.7 (18.6) pack-years. Major and minor ECG criteria were identified in 87 (16.4%) and 131 (24.6%) of subjects, respectively. After adjusting for demographic data and known CVD risk factors, higher pack-years was associated with major ECG abnormalities (p = 0.02), but current cigarettes/day (p = 0.23) was not. After 3 years, 42.9% of subjects were abstinent from smoking. New major and minor ECG criteria were observed in 7.2% and 15.6% of subjects respectively, but in similar numbers of abstinent subjects and continuing smokers (p>0.2 for both). Continuing smokers showed significant reduction in current smoking (–8.4 [8.8] cigarettes/day, p<0.001) compared to baseline.
Conclusions
In conclusion, major ECG abnormalities are independently associated with lifetime smoking burden. After 3 years, smoking cessation was not associated with a decrease in ECG abnormalities, although cigarettes smoked/day decreased among continuing smokers.
doi:10.1371/journal.pone.0062311
PMCID: PMC3633867  PMID: 23626800
22.  Pentoxifylline, Inflammation, and Endothelial Function in HIV-Infected Persons: A Randomized, Placebo-Controlled Trial 
PLoS ONE  2013;8(4):e60852.
Background
Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.
Methods
We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.
Results
The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [−1.06 (1.45)%] and PTX [−1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [−83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.
Conclusions
PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.
Trial Registration
ClinicalTrials.gov NCT00796822
doi:10.1371/journal.pone.0060852
PMCID: PMC3621886  PMID: 23593327
23.  Trends in Low-Density Lipoprotein Cholesterol Goal Achievement in High Risk United States Adults: Longitudinal Findings from the 1999–2008 National Health and Nutrition Examination Surveys 
PLoS ONE  2013;8(4):e59309.
Background
Previous studies have demonstrated gaps in achievement of low-density lipoprotein-cholesterol (LDL-C) goals among U.S. individuals at high cardiovascular disease risk; however, recent studies in selected populations indicate improvements.
Objective
We sought to define the longitudinal trends in achieving LDL-C goals among high-risk United States adults from 1999–2008.
Methods We analyzed five sequential population-based cross-sectional National Health and Nutrition Examination Surveys 1999–2008, which included 18,656 participants aged 20–79 years. We calculated rates of LDL-C goal achievement and treatment in the high-risk population.
Results
The prevalence of high-risk individuals increased from 13% to 15.5% (p = 0.046). Achievement of LDL-C <100 mg/dL increased from 24% to 50.4% (p<0.0001) in the high-risk population with similar findings in subgroups with (27% to 64.8% p<0.0001) and without (21.8% to 43.7%, p<0.0001) coronary heart disease (CHD). Achievement of LDL-C <70 mg/dL improved from 2.4% to 17% (p<0.0001) in high-risk individuals and subgroups with (3.4% to 21.4%, p<0.0001) and without (1.7% to 14.9%, p<0.0001) CHD. The proportion with LDL-C ≥130 mg/dL and not on lipid medications decreased from 29.4% to 18% (p = 0.0002), with similar findings among CHD (25% to 11.9% p = 0.0013) and non-CHD (35.8% to 20.8% p<0.0001) subgroups.
Conclusion
The proportions of the U.S. high-risk population achieving LDL-C <100 mg/dL and <70 mg/dL increased over the last decade. With 65% of the CHD subpopulation achieving an LDL-C <100 mg/dL in the most recent survey, U.S. LDL-C goal achievement exceeds previous reports and approximates rates achieved in highly selected patient cohorts.
doi:10.1371/journal.pone.0059309
PMCID: PMC3615020  PMID: 23565146
24.  Coronary Flow Velocity Changes in Response to Hypercapnia: Assessment by Transthoracic Doppler Echocardiography 
Background
The effects of hypercapnia on coronary arteries in humans are not known. We used transthoracic Doppler echocardiography (TTDE) to evaluate coronary blood flow velocity (CFV) changes in response to hypercapnia in healthy adults.
Methods and Results
Twenty adults underwent TTDE of the left anterior descending coronary artery while breathing room air, 40% FiO2, and 40% FiO2 with CO2 supplemented to end-tidal tensions of +5, +7.5, and +10 mmHg above baseline. Mean (standard deviation) diastolic peak CFV values for these conditions were 23.1(9.1), 23.0(9.0), 25.5(9.3), 27.9(11.5), and 31.5(13.0) cm/s. Significant overall differences between conditions (p<0.001) and progressive levels of hypercapnia (p≤0.01) were observed. CFV increases remained significant after adjusting for increases in cardiac output (p=0.038).
Conclusions
CFV increases with hypercapnia. This is the first report of human coronary artery flow responses to hypercapnia. TTDE methodology is feasible for measuring CFV and the effects of hypercapnia on the coronary circulation.
doi:10.1016/j.echo.2006.10.002
PMCID: PMC1892636  PMID: 17400123
Blood flow; Coronary arteries; Carbon dioxide; Echocardiography
25.  The Effects of Ramipril in Individuals at Risk for Alzheimer’s Disease: Results of a Pilot Clinical Trial 
Research shows that certain antihypertensives taken during midlife confer Alzheimer’s disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including CSF amyloid β levels (Aβ) and ACE activity, arterial function and cognition in participants with a parental history of AD.
This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier (BBB) crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ1–42 and ACE activity, arterial function and cognition.
Participants were middle-aged (mean 54yrs) highly educated (mean 15.4yrs), and included 50% men and 50% APOEε4 carriers. While results did not show a treatment effect on CSF Aβ1–42 (p=0.836), data revealed that ramipril can inhibit CSF ACE activity (p=0.009) and improve blood pressure (BP), however there were no differences between groups in arterial function or cognition.
In this study, ramipril therapy inhibited CSF ACE activity and improved BP, but did not influence CSF Aβ1–42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of Angiotensin II-mediated inhibition of acetylcholine.
doi:10.3233/JAD-2012-120763
PMCID: PMC3593582  PMID: 22776970
Alzheimer’s disease; Hypertension; Blood Pressure; Clinical Trial; Vascular Risk; Cognition; Angiotensin Converting Enzyme; Antihypertensive; Arterial Function; Prevention

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