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1.  Reproducibility of Arterial Elasticity Parameters Derived from Radial Artery Diastolic Pulse Contour Analysis: The Multi-Ethnic Study of Atherosclerosis 
Blood pressure monitoring  2010;15(6):312-315.
Objective
The aim of this report was to describe the reproducibility of arterial elasticity parameters derived from radial artery diastolic pulse contour analysis.
Methods
Two measurements were performed on the same day by the same technician with the HDI/Pulsewave CR-2000 (Eagan, MN) on each of a subset of participants selected at random from the Multi-Ethnic Study of Atherosclerosis (MESA). Large and small artery elasticity (C1 and C2), C1 and C2 each multiplied by systemic vascular resistance (C1xR and C2xR, which are functions of the radial artery pulse waveform only), and systolic and diastolic blood pressure (SBP and DBP) were evaluated.
Results
Two measurements were performed on each of 131 participants. The mean difference ± standard deviation of the difference was −0.13 ± 3.5 mmHgx10 for C1, −0.03 ± 1.5 mmHg ×100 for C2, 0.10 ± 4.6 seconds ×10 for C1xR, 0.05 ± 1.8 seconds ×100 for C2xR, 2.8 ± 8.2 mmHg for SBP, and 1.5 ± 5.0 mmHg for DBP. The between-measure correlation was 0.74 for C1, 0.84 for C2, 0.58 for C1xR, 0.74 for C2xR, 0.90 for SBP, and 0.86 for DBP.
Conclusion
The reproducibility of arterial elasticity measurements is less than that of systolic and diastolic blood pressure. Multiple measurements of arterial elasticity from a participant are recommended.
doi:10.1097/MBP.0b013e32833fe2a6
PMCID: PMC4028156  PMID: 20890179
arterial elasticity; arterial compliance; reproducibility; blood pressure measurement
2.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
doi:10.1161/HYPERTENSIONAHA.111.00272
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
3.  Circulating soluble ICAM-1 and subclinical atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Clinical chemistry  2011;58(2):10.1373/clinchem.2011.168559.
Background
Soluble intercellular adhesion molecule-1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
Methods
sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification through year 20 (CAC, n=2378), and both carotid artery stenosis (n=2432) and intima media thickness at year 20 (IMT, n = 2240).
Results
Median sICAM-1 was 145.9 ng/ml. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% confidence interval (CI) 0.003–0.017 mm) higher per standard deviation of sICAM-1 (44 ng/ml) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol lowering medication. With the same adjustment, the odds ratios (OR) for the presence of year 20 carotid artery stenosis per SD of sICAM-1 was 1.12 (CI 1.01–1.25, p<0.04), while for occurrence of CAC progression the OR was 1.16 (CI 1.04–1.31, p<0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
Conclusion
sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades prior to the development of clinical CVD.
doi:10.1373/clinchem.2011.168559
PMCID: PMC3867124  PMID: 22179741
4.  Arterial Stiffness and Left Ventricular Diastolic Function: Does Gender Matter? 
Hypertension  2012;60(2):283-284.
doi:10.1161/HYPERTENSIONAHA.112.197616
PMCID: PMC3449159  PMID: 22753204
5.  HIV Replication Alters the Composition of Extrinsic Pathway Coagulation Factors and Increases Thrombin Generation 
Background
HIV infection leads to activation of coagulation, which may increase the risk for atherosclerosis and venous thromboembolic disease. We hypothesized that HIV replication increases coagulation potentially through alterations in extrinsic pathway factors.
Methods and Results
Extrinsic pathway factors were measured among a subset of HIV participants from the Strategies for Management of Anti‐Retroviral Therapy (SMART) trial. Thrombin generation was estimated using validated computational modeling based on factor composition. We characterized the effect of antiretroviral therapy (ART) treatment versus the untreated state (HIV replication) via 3 separate analyses: (1) a cross‐sectional comparison of those on and off ART (n=717); (2) a randomized comparison of deferring versus starting ART (n=217); and (3) a randomized comparison of stopping versus continuing ART (n=500). Compared with viral suppression, HIV replication consistently showed short‐term increases in some procoagulants (eg, 15% to 23% higher FVIII; P<0.001) and decreases in key anticoagulants (eg, 5% to 9% lower antithrombin [AT] and 6% to 10% lower protein C; P<0.01). The net effect of HIV replication was to increase coagulation potential (eg, 24% to 48% greater thrombin generation from computational models; P<0.01 for all). The pattern of changes from HIV replication was reversed with ART treatment and consistent across all 3 independent comparisons.
Conclusions
HIV replication leads to complex changes in extrinsic pathway factors, with the net effect of increasing coagulation potential to a degree that may be clinically relevant. The key influence of changes in FVIII and AT suggests that HIV‐related coagulation abnormalities may involve changes in hepatocyte function in the context of systemic inflammation.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00027352.
doi:10.1161/JAHA.113.000264
PMCID: PMC3828789  PMID: 23896681
antiretroviral therapy; coagulation; HIV infection; HIV replication; inflammation; thrombin generation
6.  A Review of Genetics, Arterial Stiffness, and Blood Pressure in African Americans 
The prevalence of hypertension in African Americans in the United States is amongst the highest in the world and increasing. The identification of genes and pathways regulating blood pressure in African Americans has been challenging. An early predictor of hypertension is arterial stiffness. The prevalence of arterial stiffness is significantly higher in African Americans compared to Caucasians. Approximately 20% of the variance in arterial stiffness is estimated to be heritable. Identifying genes and biological pathways regulating arterial stiffness may provide insight into the genetics underlying the increased risk of hypertension in African Americans. This paper reviews the genetic findings to date in the area of arterial stiffness and blood pressure in African Americans with an emphasis on the current limitations and new efforts to move the field forward.
doi:10.1007/s12265-012-9362-y
PMCID: PMC3381797  PMID: 22492025
African Americans; arterial stiffness; arterial elasticity; compliance; genetics; DNA; variants; SNP; elastin; collagen; health and medicine
7.  Pulmonary Function is Associated with Distal Aortic Calcium, not Proximal Aortic Distensibility. MESA Lung Study 
COPD  2011;8(2):71-78.
Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV1 has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV1 and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.
The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45–84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors.
Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV1 was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60–0.97, p=0.02) but not proximal aortic calcification or proximal aortic distensibility (−0.04 mmHg−1; 95%CI −0.16–0.09 mmHg−1, p=0.60). Percent emphysema was associated with neither measure.
FEV1 was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta.
doi:10.3109/15412555.2011.558543
PMCID: PMC3629728  PMID: 21495835
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
8.  Protease inhibitors and cardiac autonomic function in HIV-infected patients: a cross-sectional analysis from the Strategies for Management of Antiretroviral Therapy (SMART) Trial 
BMJ Open  2013;3(3):e002523.
Objective
To compare cardiac autonomic function as measured by heart rate variability for HIV-infected participants taking protease inhibitors (PIs) with those taking a non-nucleoside reverse transcriptase inhibitor without a PI (NNRTI-no PI) regimen.
Design
Cross-sectional analysis.
Setting
Multicentre study.
Participants
2998 participants (average age 44 years, 28% females) enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial.
Primary outcome measures
Heart rate and two heart rate variability measures (the SD of all filtered RR intervals over the length of the recording (SDNN) and the root mean square of successive differences in normal RR intervals (rMSSD)).
Results
At study entry, 869 participants were taking a boosted PI (PI/r), 579 a non-boosted PI and 1550 an NNRTI-no PI. Median values (IQR) of heart rate, SDNN and rMSSD were: 68 (60–75) beats/min (bpm), 21 (13–33) ms, 22 (13–35) ms in the PI/r group, 68 (60–75) bpm, 21 (13–33) ms and 21 (14–33) ms in the non-boosted PI group and 69 (62–77) bpm, 20 (13–31) ms and 21(13–33) ms in the NNRTI-no PI group. After adjustment for baseline factors, for those given PI/r and non-boosted PI, heart rate was 2.2 and 2.8 bpm, respectively, lower than the NNRTI-no PI group (p<0.001 for both). On the other hand, compared with the NNRTI-no PI group, log SDNN and log rMSSD were significantly greater for those in the non-boosted PI (p values for baseline adjusted differences in log-transformed SDNN and rMSSD were 0.004 and 0.001) but not for those in the PI/r group at the 0.01 α-level.
Conclusions
Compared to an NNRTI-no PI regimen, heart rate was lower for those taking a PI/r or non-boosted PI and heart rate variability was greater, reflecting better cardiac autonomic function, for those taking a non-boosted PI regimen but not PI/r.
doi:10.1136/bmjopen-2012-002523
PMCID: PMC3612790  PMID: 23471611
Virology; Cardiology; Clinical Pharmacology
9.  Rate of decline of forced vital capacity predicts future arterial hypertension: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Hypertension  2011;59(2):219-225.
Lung function studies in middle-aged subjects predict cardiovascular disease (CVD) mortality. We studied if greater loss of forced vital capacity (FVC) early in life predicted incident hypertension (HTN). The sample was 3205 black and white men and women in the Coronary Artery Risk Development in Young Adults (CARDIA) study examined between 1985-86 (CARDIA year 0, ages 18-30 years) and 2005-06 and who were not hypertensive by year 10. FVC was assessed at years 0, 2, 5, 10, and 20. Proportional hazard ratios (HR) and linear regression models predicted incident HTN at years 15 or 20 (n=508) from the change in FVC (FVC at year 10 – peak FVC, where peak FVC was estimated as the maximum across years 0, 2, 5 and 10). Covariates included demographics, center, systolic blood pressure, FVC max, smoking, physical activity, asthma and BMI. Unadjusted cumulative incident HTN was 25% in the lowest FVC loss quartile (Q1, median loss=370ml) compared to 12% cumulative incident HTN in those who achieved peak FVC at year 10 (Q4). Minimally adjusted HR for Q1 vs. Q4 was 2.21 (95% CI: 1.73-2.83) and this association remained significant in the fully adjusted model (1.37, 95% CI: 1.05-1.80). Decline in FVC from average age at peak (29.4 years) to 35 years old predicted incident hypertension between average ages 35 and 45. The findings may represent a common pathway that may link low normal FVC to cardiovascular disease morbidity and mortality.
doi:10.1161/HYPERTENSIONAHA.111.184101
PMCID: PMC3269403  PMID: 22203738
forced vital capacity; hypertension; CARDIA; adults; cohort
10.  Association of Pulse Pressure, Arterial Elasticity, and Endothelial Function With Kidney Function Decline Among Adults With Estimated GFR > 60 mL/min/1.73 m2: The Multi-Ethnic Study of Atherosclerosis 
Background
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
Study Design
Prospective cohort study
Setting & Participants
MESA participants with eGFR ≥60 ml/min/1.73m2 with follow-up of 5 years
Predictors
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
Outcomes
kidney function decline
Measurements
SAE and LAE were measured by pulse contour analysis of the radial artery. Kidney function was measured by serum creatinine- and cystatin C-based eGFR.
Results
Among 4,853 adults, higher pulse pressure and lower SAE and LAE had independent and linear associations with faster rates of kidney function decline. Compared to persons with pulse pressure 40–50mmHg, eGFRSCysC decline was 0.29 (p=0.006), 0.56 (p<0.001), and 0.91 (p<0.001) ml/min/1.73m2/year faster among persons with pulse pressure 50–60, 60–70, and >70mmHg, respectively. Compared to the highest quartile of SAE (most elastic), eGFRSCysC decline was 0.26 (p=0.009), 0.35 (p=0.001), and 0.70 (p<0.001) ml/min/1.73m2/year faster for the second, third and fourth quartiles respectively. For LAE, compared to the highest quartile, eGFRSCysC decline was 0.28 (p=0.004), 0.58 (p<0.001), and 0.83 (p<0.001) ml/min/1.73m2/year faster for each decreasing quartile of LAE. Findings were similar with creatinine-based eGFR. In contrast, among 2,997 adults with flow-mediated dilation and kidney function measures, flow-mediated dilation was not significantly associated with kidney function decline. For every 1-SD greater flow-mediated dilation, eGFRSCysC and eGFRSCr changed by 0.05 ml/min/1.73m2/year (p=0.3) and 0.06 ml/min/1.73m2/year (p=0.04), respectively.
Limitations
We had no direct measure of GFR, in common with nearly all large population based studies.
Conclusions
Higher pulse pressure and lower arterial elasticity, but not flow-mediated dilation, were linearly and independently associated with faster kidney function decline among persons with eGFR ≥60 ml/min/1.73m2. Future studies investigate whether treatments to lower stiffness of large and small arteries may slow the rate of kidney function loss.
doi:10.1053/j.ajkd.2011.08.015
PMCID: PMC3242889  PMID: 22000727
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
11.  Prevalence and Prognostic Significance of ECG Abnormalities in HIV-infected Patients: Results from the Strategies for Management of Antiretroviral Therapy (SMART) Study 
Journal of electrocardiology  2010;44(6):779-785.
Background
It remains debated whether to include resting electrocardiogram (ECG) in the routine care of patients infected with Human immunodeficiency virus (HIV). This is largely because data are limited regarding the prevalence and prognostic significance of ECG abnormalities in HIV-infected patients.
Methods
This analysis included 4518 HIV-infected patients (28% females and 29% blacks) from The Strategies for Management of Antiretroviral Therapy (SMART) study, a clinical trial aimed to compare two HIV treatment strategies. ECG abnormalities were classified using the Minnesota Code. Multivariable adjusted Cox proportional hazards analysis was used to examine the association between baseline ECG abnormalities and incident cardiovascular disease.
Results
More than half of the participants (N=2325, 51.5%) had either minor or major ECG abnormalities. Minor ECG abnormalities (48.6%) were more common than major ECG abnormalities (7.7%). During a median follow-up of 28.7 months, 155 (3.4%) participants developed incident cardiovascular disease. After adjusting for the study treatment arms, the presence of major, minor, and either minor or major ECG abnormalities were significantly predictive of incident cardiovascular disease [Hazard ratio (95% Confidence Interval): 2.76 (1.74, 4.39), p<0.001; 1.58 (1.14, 2.20), p=0.006; 1.57 (1.14, 2.18), p=0.006, respectively]. However, after adjusting for demographics, common cardiovascular risk factors and HIV characteristics (full model), presence of major ECG abnormalities was still significantly predictive of cardiovascular disease [1.83 (1.12, 2.97), p=0.015)], but not minor or minor or major abnormalities taken together [1.26 (0.89, 1.79), p=0.18; 1.25 (0.89, 1.76), p=0.20, respectively]. Individual ECG abnormalities that significantly predicted cardiovascular disease in the fully adjusted model included major isolated ST/T abnormalities, major prolongation of QT interval, minor isolated ST/T and minor isolated Q/QS abnormalities.
Conclusion
Nearly one in two of the HIV-infected patients in SMART study had ECG abnormalities; one in thirteen had major ECG abnormalities. Presence of ECG abnormalities, especially major ECG abnormalities was independently predictive of incident cardiovascular disease. These results suggest that the ECG could provide a convenient risk screening tool in HIV-infected patients.
doi:10.1016/j.jelectrocard.2010.10.027
PMCID: PMC3060290  PMID: 21145066
HIV/AIDS; ECG; Cardiovascular Disease; SMART Study
12.  Association of Self-Reported Race/Ethnicity and Genetic Ancestry with Arterial Elasticity: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
African-Americans have a disproportionate burden of hypertension compared to Caucasians, while data on Hispanics is less well-defined. Mechanisms underlying these differences are unclear, but could be due in part to ancestral background and vascular function.
Methods and Results
660 African-Americans and 635 Hispanics from the Multi-Ethnic Study of Atherosclerosis (MESA) with complete data on genetic ancestry, pulse pressure (PP), and large and small arterial elasticity (LAE, SAE) were studied. LAE and SAE were obtained using the HDI PulseWave CR-2000 Research CardioVascular Profiling Instrument. Among African-Americans higher European ancestry was marginally associated with higher LAE (p=0.05) and lower PP (p=0.05) among African-Americans; results for LAE were attenuated after adjustment for potential mediators (p=0.30). Ancestry was not associated with SAE in African-Americans. Among Hispanics, higher Native American ancestry was associated with higher SAE (p=0.0006); higher African ancestry was marginally associated with lower SAE (p=0.07). Ancestry was not significantly associated with LAE or PP in Hispanics.
Conclusions
Among African-Americans, higher European ancestry may be associated with less large artery damage as measured by LAE and PP, although these associations warrant further study. Among Hispanics, ancestry is strongly associated with SAE. Future studies should consider information on genetic ancestry when studying hypertension burden in race/ethnic minorities, particularly among Hispanics.
doi:10.1016/j.jash.2011.07.005
PMCID: PMC3218223  PMID: 21890448
large artery elasticity; small artery elasticity; admixture; pulse pressure
13.  Angiotensin Converting Enzyme Inhibitor and HMG-CoA Reductase Inhibitor as Adjunct Treatment for Persons with HIV Infection: A Feasibility Randomized Trial 
PLoS ONE  2012;7(10):e46894.
Background
Treatments that reduce inflammation and cardiovascular disease (CVD) risk among individuals with HIV infection receiving effective antiretroviral therapy (ART) are needed.
Design and Methods
We conducted a 2×2 factorial feasibility study of lisinopril (L) (10 mg daily) vs L-placebo in combination with pravastatin (P) (20 mg daily) vs P-placebo among participants receiving ART with undetectable HIV RNA levels, a Framingham 10 year risk score (FRS) ≥3%, and no indication for ACE-I or statin therapy. Tolerability and adherence were evaluated. Longitudinal mixed models assessed changes in blood pressure (BP), blood lipids, and inflammatory biomarkers from baseline through months 1 and 4.
Results
Thirty-seven participants were randomized and 34 [lisinopril/pravastatin (n = 9), lisinopril/P-placebo (n = 8), L-placebo/pravastatin (n = 9), L-placebo/P-placebo (n = 8)] attended at least one follow-up visit. Participants were 97% male, 41% white, 67% were current smokers, and 65% were taking a protease inhibitor. Median age was 48 years, CD4 count 483 cells/mm3, FRS 7.79%, total cholesterol 184 mg/dL, and LDL-C 95 mg/dL. There was no treatment difference for pravastatin vs P-placebo in total cholesterol, LDL-C, or any of the inflammatory biomarkers. Participants randomized to lisinopril vs. L-placebo had significant declines in diastolic BP (−3.3 mmHg, p = 0.05), hsCRP (−0.61 µg/mL, p = 0.02) and TNF-α (−0.17 pg/mL, p = 0.04). Participants taking lisinopril vs L-placebo were more likely to report missed doses (88 vs 35%; p = 0.001) and have adherence <90% by pill count (42 vs. 0%; p = 0.02). Few participants from either group reported side effects (n = 3 vs. n = 1).
Conclusions
The modest BP changes and decreased adherence with lisinopril and absence of lipid differences with pravastatin suggest future studies of these drug classes should consider a run-in period to assess adherence and use a different statin. Our results also indicate that ACE-I therapy may have anti-inflammatory benefits for ART-treated persons with HIV infection and this should be further evaluated.
Trial Registration
ClinicalTrials.gov NCT00982189
doi:10.1371/journal.pone.0046894
PMCID: PMC3474775  PMID: 23082133
14.  Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals 
PLoS ONE  2012;7(9):e44454.
Background
The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.
Methods
A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.
Results
There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).
Conclusions
In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.
doi:10.1371/journal.pone.0044454
PMCID: PMC3438173  PMID: 22970224
15.  Association of Small Artery Elasticity With Incident Cardiovascular Disease in Older Adults 
American Journal of Epidemiology  2011;174(5):528-536.
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
doi:10.1093/aje/kwr120
PMCID: PMC3202150  PMID: 21709134
arteries; cardiovascular diseases; elasticity; risk factors
16.  HIV Replication, Inflammation, and the Effect of Starting Antiretroviral Therapy on Plasma Asymmetric Dimethylarginine, a Novel Marker of Endothelial Dysfunction 
Background
HIV infection is associated with premature development of cardiovascular disease (CVD). Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce CVD risk.
Methods
A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy (SMART) study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40L and P-selectin levels.
Results
At study entry, median (IQR) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n=114), participants randomized to immediate ART (n=134) had 10.3% lower ADMA levels (p=0.003) at 12 months; treatment differences in sCD40L (95% CI:-17 to 44%; p=0.53) and P-selectin (95% CI:-10 to 10%; p=0.95) were not significant. The difference in ADMA for those assigned immediate ART compared to those assigned ART deferral was greater among younger patients and those with higher levels of hsCRP and D-dimer (p≤0.05 for interaction for both), but not HIV RNA level at baseline (p=0.51).
Discussion
ART initiation leads to declines in ADMA levels, a marker of nitric-oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that up-regulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.
doi:10.1097/QAI.0b013e318252f99f
PMCID: PMC3360839  PMID: 22421746
HIV infection; antiretroviral therapy; inflammation; endothelial dysfunction; asymmetric dimethylarginine (ADMA); CD40 ligand; P-selectin
17.  Correlation of natriuretic peptides and inferior vena cava size in patients with congestive heart failure 
Background
The inferior vena cava (IVC) diameter and degree of inspiratory collapse are used as echocardiographic indices in the estimation of right atrial pressure. Brain-natriuretic peptides (BNPs) are established biomarkers of myocardial wall stress. There is no information available regarding the association between the IVC diameter and BNPs in patients with heart failure and various degrees of systolic performance. The purpose of this investigation is to quantify the degree to which natriuretic peptides (BNP and N-terminal pro-B natriuretic peptide [NT-ProBNP]) and echocardiographic-derived indices of right atrial pressure correlate in this patient population.
Methods
We examined 77 patients (mean age 61 ± 17 years, 44% male) with decompensated heart failure who underwent transthoracic echocardiography and, within a timeframe of 24 hours, determination of BNP and NT-ProBNP levels in venous blood. BNP and NT-ProBNP were analyzed after log transformation. The degree of association was measured by the correlation coefficient using the Pearson’s method.
Results
The mean ejection fraction was 50% ± 20%, and 33% of the study cohort had a remote history of heart failure. The mean IVC diameter was 1.85 cm ± 0.5, the mean BNP was 274 pg/mL, the confidence interval (CI) was 95% (95% CI: 197–382), and the mean NT-ProBNP was 1994 pg/mL (95% CI: 1331–2989). There was a positive, albeit small, association between IVC diameter and BNP (r = 0.24, 95% CI: 0.01–0.44; P = 0.03) and NT-ProBNP (r = 0.27, 95% CI: 0.05–0.47; P = 0.01). Among patients with different degrees of IVC collapse in response to inspiration, values for BNP and NT-ProBNP did not differ substantially (P = 0.36 and 0.46 for BNP and NT-ProBNP, respectively).
Conclusion
Natriuretic peptides correlate weakly with IVC size and do not predict changes in response to intrathoracic pressure.
doi:10.2147/VHRM.S30001
PMCID: PMC3333469  PMID: 22536076
heart failure; inferior vena cava; natriuretic peptides
18.  Inflammation Predicts Changes in High-Density Lipoprotein Particles and Apolipoprotein A1 Following Initiation of Antiretroviral Therapy 
AIDS (London, England)  2011;25(17):2133-2142.
Background
The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high- and low-density lipoprotein particle concentrations (HDL-P and LDL-P) and apolipoprotein (Apo) levels are not well described.
Methods
In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) to immediately initiate ART (‘VS group’) or to defer it (‘DC group’), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization.
Results
Compared to DC group (n=126), HDL-P and ApoA1 levels increased among VS participants (n=128) after starting ART. At 6 months, VS participants had 13% higher total HDL-P (p < 0.001) and 9% higher ApoA1 (p < 0.001). LDL-P, VLDL-P, and ApoB did not differ significantly between the VS and DC groups. Among VS participants, predictors of HDL-P and ApoA1 increases included baseline levels of hsCRP and IL-6, but not HIV RNA level, CD4 count or traditional CVD risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (p=0.001 and 0.08, respectively, for interaction) or hsCRP (p=0.01 and 0.04, respectively, for interaction).
Conclusion
HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.
doi:10.1097/QAD.0b013e32834be088
PMCID: PMC3320724  PMID: 21857489
HIV infection; antiretroviral therapy; high-density lipoprotein; apolipoprotein A1; inflammation
19.  Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations 
AIDS (London, England)  2011;25(3):367-377.
Background
There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown.
Methods
This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazett’s (QTcB) and Fredericia’s (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group.
Results
Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P <0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P <0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P <0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P <0.01).
Conclusion
Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.
doi:10.1097/QAD.0b013e328341dcc0
PMCID: PMC3111078  PMID: 21150558
electrocardiogram; HIV/AIDS; PR; protease inhibitors; QTc
20.  Untreated HIV Infection and Large and Small Artery Elasticity 
Background
Untreated HIV infection may increase risk for cardiovascular disease, and arterial elasticity is a marker of cardiovascular risk and early disease.
Methods
HIV-infected participants not taking antiretroviral therapy (n = 32) were compared with HIV-negative controls (n = 30). Large and small artery elasticity (LAE and SAE) were estimated via analysis of radial pulse waveforms. Differences in LAE and SAE by HIV status were compared using analysis of covariance, with and without adjustment for Framingham risk (model 1); covariates that differed between groups [smoking, injection drug use, hepatitis C, and high-density lipoprotein cholesterol (HDLc); model 2]; or age, sex, race/ethnicity, smoking, injection drug use, hepatitis C, HDLc, and non-HDLc (model 3).
Results
HIV infection was associated with impaired LAE (−2.55 mL/mm Hg × 10; P = 0.02) and SAE (−1.50 mL/mm Hg × 100; P = 0.02). Associations with traditional risk factors were often stronger for SAE than LAE, including with Framingham score (per 1% higher; SAE −0.18, P = 0.01; LAE −0.19, P = 0.13). Fasting lipid levels were not significantly associated with LAE and SAE. After adjustment, differences between HIV-infected and HIV-uninfected participants were similar in model 1 (−2.36 for LAE, P = 0.04; −1.31 for SAE, P = 0.04), model 2 (−2.67 for LAE, P = 0.02; −1.13 for SAE, P = 0.07) and model 3 (−2.91 for LAE, P = 0.02; −1.34 for SAE, P = 0.03). CD4 count and HIV RNA level were not associated with LAE and SAE among HIV-infected participants.
Conclusions
Untreated HIV infection is associated with impaired arterial elasticity, of both the large and small vasculature, after controlling for additional risk factors. Pulse waveform analysis is a noninvasive technique to assess cardiovascular disease risk that should be evaluated in larger studies of HIV-infected persons.
PMCID: PMC2764552  PMID: 19731451
arterial elasticity; arterial stiffness; cardiovascular disease; endothelial dysfunction; HIV; untreated HIV infection
21.  Race/Ethnic And Sex Differences In Large And Small Artery Elasticity – Results Of The Multi-Ethnic Study Of Atherosclerosis (MESA) 
Ethnicity & disease  2009;19(3):243-250.
Objective
Reduction in arterial elasticity marks progression toward cardiovascular morbidity and mortality. Variability in arterial elasticity may help account for race/ethnic and gender differences in cardiovascular risk.
Design
Cross-sectional study.
Setting
Whites, African Americans, Hispanics and Chinese aged 45–84 years free of clinically recognized cardiovascular disease were recruited in six US communities.
Participants
We examined 3,316 women and 3,020 men according to race/ethnicity and sex.
Main Outcome Measures
Large (LAE) and small artery (SAE) elasticity, derived from radial artery diastolic pulse wave contour registration in all subjects in a supine position using tonometry. LAE and SAE were adjusted for ethnicity, age, clinical site, height, heart rate, blood pressure, antihypertensive medication and body mass index, diabetes, smoking, and circulating lipids.
Results
Much of the sex difference in arterial elasticity was explained by height. After adjustment, LAE did not differ by race/ethnicity, but mean SAE in African Americans was 4.2 mL/mm Hg × 100 and 4.4 mL/mm Hg × 100 in Hispanics compared to means of 4.6 mL/mm Hg × 100 in Whites, and 4.8 mL/mm Hg × 100 in Chinese.
Conclusions
Reduced SAE may indicate earlier vascular disease in African Americans and Hispanics than other groups.
PMCID: PMC2924814  PMID: 19769004
Blood Pressure; Arterial Elasticity; MESA Study
22.  Association between Endothelial Biomarkers and Arterial Elasticity in Young Adults – The CARDIA Study 
Background
Reduced arterial elasticity and endothelial dysfunction both may indicate early cardiovascular (CV) disease in young adults. Pulse waveform analysis estimates large (LAE) and small (SAE) artery elasticity noninvasively. We assessed the associations between LAE and SAE and markers of endothelial dysfunction and CV risk factors.
Methods
The Coronary Artery Risk Development in Young Adults (CARDIA) assessed arterial elasticity and other characteristics cross-sectionally in 389 men and 381 women aged 27–42 years in 1995 (CARDIA year 10) and circulating levels of P-selectin and soluble intercellular adhesion molecule 1 (sICAM-1) in 2000. We adjusted for variables included in the estimation of arterial elasticity (year 10 height, body mass index, age, heart rate, and blood pressure) and other year 10 characteristics.
Results
Mean adjusted SAE was 8.5 vs. 7.6 ml/mmHg ×100 in those with urine albumin/creatinine ratio ≤4 vs. microalbuminuria (ratio > 25; ptrend =0.008). Mean LAE was 25.6 vs. 24.2 ml/mmHg ×10 in the lowest vs. highest quintile of P-selectin (ptrend =0.004). sICAM-1 was unrelated to either LAE or SAE. Plasma triglycerides were inversely related to LAE (ptrend =0.029). Cigarette smokers had lower SAE than nonsmokers (ptrend = 0.009).
Conclusion
In addition to smoking and triglycerides, biomarkers for endothelial dysfunction were associated with impaired LAE and SAE in young adults.
doi:10.1016/j.jash.2007.10.002
PMCID: PMC2390876  PMID: 19343081
Blood lipids; smoking; albuminuria; endothelial dysfunction
23.  Determination of the Underlying Cause of Death in Three Multicenter International HIV Clinical Trials 
HIV clinical trials  2008;9(3):177-185.
Purpose
Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials.
Method
Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999–2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated.
Results
Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached.
Conclusion
ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths.
doi:10.1310/hct0903-177
PMCID: PMC2441601  PMID: 18547904
cause of death; endpoint review committees; clinical trials; HIV; mortality
24.  Noninvasive measurements of arterial stiffness: Repeatability and interrelationships with endothelial function and arterial morphology measures 
Background
Many noninvasive arterial assessment techniques have been developed, measuring different parameters of arterial stiffness and endothelial function. However, there is little data available comparing different devices within the same subject. Therefore, the purpose of this study was to examine the repeatability and interrelationships between 3 different techniques to measure arterial stiffness and to compare this with forearm-mediated dilation.
Methods
Carotid-radial pulse wave velocity was measured by the Sphygmocor (SPWV) and Complior (CPWV) devices, cardio-ankle vascular index (CAVI) was measured by the VaSera device, vascular structure and function was assessed using ultrasonography and evaluated for reliability and compared in 20 apparently healthy, college-aged men and women.
Results
The intraclass correlation coefficient and standard error of the mean for the Sphygmocor (R = 0.56, SEM = 0.69), Complior (R = 0.62, SEM = 0.69), and VaSera (R = 0.60, SEM = 0.56), indicated moderate repeatability. Bland-Altman plots indicated a mean difference of 0.11 ± 0.84 for SPWV, 0.13 ± 1.15 for CPWV, and −0.43 ± 0.90 for CAVI. No significant interrelationships were found among the ultrasound measures and SPWV, CPWV, and CAVI.
Conclusions
The three noninvasive modalities to study arterial stiffness reliably measures arterial stiffness however, they do not correlate with ultrasound measures of vascular function and structure in young and apparently healthy subjects.
PMCID: PMC2293959  PMID: 17703642
Pulse wave velocity; intima-media thickness; flow-mediated dilation
25.  A Study of 15N/14N Isotopic Exchange over Cobalt Molybdenum Nitrides 
ACS Catalysis  2013;3(8):1719-1725.
The 14N/15N isotopic exchange pathways over Co3Mo3N, a material of interest as an ammonia synthesis catalyst and for the development of nitrogen transfer reactions, have been investigated. Both the homomolecular and heterolytic exchange processes have been studied, and it has been shown that lattice nitrogen species are exchangeable. The exchange behavior was found to be a strong function of pretreatment with ca. 25% of lattice N atoms being exchanged after 40 min at 600 °C after N2 pretreatment at 700 °C compared to only 6% following similar Ar pretreatment. This observation, for which the potential contribution of adsorbed N species can be discounted, is significant in terms of the application of this material. In the case of the Co6Mo6N phase, regeneration to Co3Mo3N under 15N2 at 600 °C occurs concurrently with 14N15N formation. These observations demonstrate the reactivity of nitrogen in the Co–Mo–N system to be a strong function of pretreatment and worthy of further consideration.
doi:10.1021/cs400336z
PMCID: PMC3831547  PMID: 24265977
nitrogen; isotopic exchange; cobalt molybdenum nitride; ammonia synthesis; heterogeneous catalysis

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