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1.  Proximal Superficial Femoral Artery Occlusion, Collateral Vessels, and Walking Performance in Peripheral Artery Disease 
JACC. Cardiovascular imaging  2013;6(6):687-694.
We studied associations of MRI-measured SFA occlusions with functional performance, leg symptoms, and collateral vessel number in PAD. We studied associations of collateral vessel number with functional performance in PAD.
Associations of magnetic resonance imaging (MRI)-detected superficial femoral artery (SFA) occlusion and collateral vessel number with functional performance among individuals with peripheral artery disease (PAD) have not been reported.
457 participants with an ankle brachial index (ABI) < 1.00 had MRI measurement of the proximal SFA with twelve consecutive 2.5 millimeter cross-sectional images. An occluded SFA was defined as an SFA in which at least one segment was occluded. A non-occluded SFA was defined as absence of any occluded slices. Collateral vessels were visualized with magnetic resonance angiography (MRA). Lower extremity functional performance was measured with the six-minute walk, four-meter walking velocity at usual and fastest pace, and the short physical performance battery (SPPB) (0-12 scale, 12=best).
Adjusting for age, sex, race, comorbidities, and other confounders, the presence of an SFA occlusion was associated with poorer six-minute walk performance (1,031 vs. 1,169 feet, P=0.006), slower fast-paced walking velocity (1.15 vs. 1.22 meters/second, P =0.042), and lower SPPB score (9.07 vs. 9.75, P=0.038) compared to the absence of an SFA occlusion. More numerous collateral vessels were associated with better six-minute walk performance (0-3 collaterals-1,064 feet, 4-7 collaterals-1,165 feet, ≥ 8 collaterals-1,246 feet, P trend=0.007), faster usual-paced walking speed (0-3 collaterals-0.84 meters/second, 4-7 collaterals-0.88 meters/second, ≥ 8 collaterals-0.91 meters/second, P trend=0.029), and faster rapid-paced walking speed (0-3 collaterals-1.17 meters/second, 4-7 collaterals-1.22 meters/second, ≥ 8 collaterals-1.29 meters/second, P trend=0.002), adjusting for age, sex, race, comorbidities, ABI, and other confounders.
Among PAD participants, MRI-visualized occlusions in the proximal SFA are associated with poorer functional performance, while more numerous collaterals are associated with better functional performance.
Clinical Trial ID
PMCID: PMC3766720  PMID: 23647796
atherosclerotic plaque; intermittent claudication; peripheral arterial disease; physical functioning
2.  Associations of Calf Skeletal Muscle Characteristics and Peripheral Nerve Function with Self-Perceived Physical Functioning and Walking Ability in Persons with Peripheral Arterial Disease 
We determined whether more adverse calf muscle characteristics and poorer peripheral nerve function were associated with impairments in self-perceived physical functioning and walking ability in persons with lower extremity peripheral arterial disease (PAD). Participants included 462 persons with PAD; measures included the ankle-brachial index (ABI), medical history, electrophysiologic characteristics of nerves, and computed tomography of calf muscle. Self-perceived physical functioning and walking ability were assessed using the 36-Item Short Form Health Survey (SF-36) and the Walking Impairment Questionnaire (WIQ). Results were adjusted for age, sex, race, ABI, body-mass index, comorbidities, and other confounders. Lower calf muscle area was associated with a poorer SF-36 physical function (PF) score (overall p trend<0.001, 33.76 PF score for the lowest quartile vs. 59.74 for the highest, pair wise p<0.001) and a poorer WIQ walking distance score (p trend=0.001, 29.71 WIQ score for the lowest quartile vs. 48.43 for the highest, pair wise p<0.001). Higher calf muscle percent fat was associated with a poorer SF-36 PF score (p trend<0.001, 53.76 PF score for the lowest quartile vs. 40.28 for the highest, pair wise p=0.009). Slower peroneal nerve conduction velocity was associated with a poorer WIQ speed score (p trend=0.023, 30.49 WIQ score for the lowest quartile vs. 40.48 for the highest, pair wise p=0.031). In summary, adverse calf muscle characteristics and poorer peripheral nerve function are associated significantly and independently with impairments in self-perceived physical functioning and walking ability in PAD persons.
PMCID: PMC4034534  PMID: 21471147
peripheral arterial disease; calf muscle characteristics; peripheral nerve function; quality of life
4.  Bicc1 is a genetic determinant of osteoblastogenesis and bone mineral density 
The Journal of Clinical Investigation  2014;124(6):2736-2749.
Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network–based approach to determine how Bicc1 influences BMD. Based on this analysis, we inferred that Bicc1 was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency–dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Bicc1 as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels.
PMCID: PMC4038574  PMID: 24789909
5.  Comparative Effectiveness Study of Self-Directed Walking Exercise, Lower Extremity Revascularization, and Functional Decline in Peripheral Artery Disease 
Journal of vascular surgery  2013;57(4):990-996.e1.
Among individuals with peripheral artery disease (PAD), we compared annual change in six-minute walk performance between participants who neither underwent lower extremity revascularization nor walked for exercise (Group 1, reference), those who walked regularly for exercise (Group 2), and those who underwent lower extremity revascularization (Group 3).
Participants were recruited from Chicago-area vascular laboratories and followed annually. Change in six-minute walk was calculated beginning at the study visit preceding lower extremity revascularization or exercise behavior and continuing for one additional year after the therapy was reported. Results adjust for age, sex, race, comorbidities, and other confounders.
Of 348 PAD participants, 43 underwent revascularization during a median follow-up of 84 months. Adjusted annual declines in six-minute walk were Group 1: −96.6 feet/year, Group 2: −49.9 feet/year, and Group 3: −32.6 feet/year(p<.001). Forty-one percent of revascularizations were not associated with ankle brachial index (ABI) improvement. When Group 3 was limited to participants with ABI improvement of ≥ 0.15 after revascularization, annual adjusted changes in six-minute walk were Group 1:−97.7 feet/year; Group 2:−46.5 feet/year, and Group 3:+68.1 feet/year (P value<.001). When Group 3 was limited to participants without ABI improvement ≥ 0.15 after revascularization, annual adjusted changes in six-minute walk were Group 1:−99.2 feet/year, Group 2:−48.0 feet/year; and Group 3:−61.7 feet/year. (P value<.001).
A large proportion of PAD participants did not have an ABI improvement of at least 0.15 at their follow-up study visit after revascularization. The benefits of lower extremity revascularization in patients with PAD appear closely tied to improvements in the ABI after revascularization.
PMCID: PMC3612138  PMID: 23352363
Peripheral artery disease; intermittent claudication; physical functioning; exercise
6.  Ankle-Brachial Index (ABI), Abdominal Aortic Calcification (AAC), and Coronary Artery Calcification (CAC): the Jackson Heart Study 
To examine the associations of peripheral atherosclerosis, assessed by the ABI at baseline with the extent of AAC and with CAC measured by MDCT at follow-up examination in the Jackson Heart Study cohort.
Four categories of ABI: <0.90, 0.90–0.99, 1.00–1.39; >1.40. Presence of CAC/AAC was defined as scoring above the 75th percentile among participants with non-zero CT calcium scores. We conducted multivariable log-binomial models for this analysis examining the relationship between ABI and the presence of CAC or AAC using normal ABI (1.0 ≤ ABI ≤ 1.39) as the reference group. We estimated prevalence ratios adjusted for age, smoking, HTN, DM, BMI, LDL, HDL, CRP, systolic and diastolic blood pressure, and use of lipid-lowering medication.
There were 2,398 patients in this analysis (women: 65%, average age 55 years). AAC scores were not significantly different between sex. CAC scores were significantly higher in males than females regardless of ABI groups. The prevalence of significant AAC was 1.7 times higher for ABI < 0.90 (PR=1.70; 95% CI=1.26–2.28; p=0.0004) and 1.57 times higher for ABI 0.90–0.99 (PR=1.57; 95% CI=1.20–2.03; p=0.0008) than the normal ABI; AAC prevalence did not differ between subjects with ABI > 1.40 compared to those with normal ABI. The prevalence of the significant CAC was higher for ABI <0.90 (PR=1.55; 95% CI=1.12–2.14; p-value=0.0081) and ABI 0.90–0.99 (PR=1.60; 95% CI=1.05–2.46; p=0.0402) compared to normal ABI; CAC prevalence did not differ between subjects with ABI > 1.40 compared to those with normal ABI
Lower ABI was significantly associated with the extent of AAC and CAC in this cohort. ABI can provide clinicians with an inexpensive additional tool to assess vascular health and cardiovascular risk without exposing the patient to ionizing radiation.
PMCID: PMC3712513  PMID: 23111408
Coronary Artery Calcium; Abdominal Aortic Calcium; Ankle-Brachial Index; Peripheral Arterial Disease
Journal of human hypertension  2013;27(10):617-622.
Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1,897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor – α [TNFα], resistin and total adiponectin. The mean age and body mass index was 64.7 years and 28.1 respectively, and 50% were female. After adjustment for risk factors, a 1-standard deviation increment higher leptin level was significantly associated with higher systolic (5.0 mmHg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (p < 0.01 for all). These associations were not materially different when the other adipokines, as well as body mass index, waist circumference or waist to hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, body mass index or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.
PMCID: PMC3735864  PMID: 23535989
adipokine; leptin; blood pressure; hypertension; ethnicity
8.  The Walking Impairment Questionnaire Stair-Climbing Score predicts mortality in men and women with peripheral arterial disease 
Journal of vascular surgery  2012;55(6):1662-73.e2.
The Walking Impairment Questionnaire (WIQ) measures self-reported walking distance, walking speed, and stair-climbing ability in men and women with lower extremity peripheral arterial disease (PAD). We determined whether poorer WIQ scores are associated with higher all-cause and cardiovascular disease (CVD) mortality in individuals with and without PAD.
1048 men and women with and without PAD were identified from Chicago-area medical centers. Participants completed the WIQ at baseline and were followed for a median of 4.5 years. Cox proportional hazards models were used to relate baseline WIQ scores with mortality, adjusting for age, sex, race, the ankle brachial index (ABI), comorbidities, and other covariates.
461 participants (44.0%) died during follow-up, including 158 deaths from cardiovascular disease. PAD participants in the lowest baseline quartile of the WIQ stair-climbing scores had higher all-cause mortality (HR = 1.70 [95% Confidence Interval (CI) 1.08-2.66, p=0.02] and higher CVD mortality (HR = 3.11 [95% CI 1.30 – 7.47, p=0.01]) compared to those with the highest baseline WIQ stair climbing score. Among PAD participants there were no significant associations of lower baseline WIQ distance or speed scores with rates of all-cause mortality (p for trend = 0.20 and 0.07, respectively) or CVD mortality (p for trend = 0.51 and p for trend = 0.33, respectively). Among non-PAD participants there were no significant associations of lower baseline WIQ stair climbing, distance, or speed score with rates of all-cause mortality (p for trend = 0.94, 0.69, and 0.26, respectively) or CVD mortality (p for trend = 0.28, 0.68, and 0.78, respectively).
Among participants with PAD, lower WIQ stair climbing scores are associated with higher all-cause and CVD mortality, independently of the ABI and other covariates.
PMCID: PMC3963605  PMID: 22608041
9.  Risk marker associations with venous thrombotic events: a cross-sectional analysis 
BMJ Open  2014;4(3):e003208.
To examine the interrelations among, and risk marker associations for, superficial and deep venous events—superficial venous thrombosis (SVT), deep venous thrombosis (DVT) and pulmonary embolism (PE).
Cross-sectional analysis.
San Diego, California, USA.
2404 men and women aged 40–79 years from four ethnic groups: non-Hispanic White, Hispanic, African-American and Asian. The study sample was drawn from current and former staff and employees of the University of California, San Diego and their spouses/significant others.
Outcome measures
Superficial and deep venous events, specifically SVT, DVT, PE and combined deep venous events (DVE) comprising DVT and PE.
Significant correlates on multivariable analysis were, for SVT: female sex, ethnicity (African-American=protective), lower educational attainment, immobility and family history of varicose veins. For DVT and DVE, significant correlates included: heavy smoking, immobility and family history of DVEs (borderline for DVE). For PE, significant predictors included immobility and, in contrast to DVT, blood pressure (BP, systolic or diastolic). In women, oestrogen use duration for hormone replacement therapy, in all and among oestrogen users, predicted PE and DVE, respectively.
These findings fortify evidence for known risk correlates/predictors for venous disease, such as family history, hormone use and immobility. New risk associations are shown. Striking among these is an association of PE, but not DVT, to elevated BP: we conjecture PE may serve as cause rather than consequence. Future studies should evaluate the temporal direction of this association. Oxidative stress and cell energy compromise are proposed to explain and predict many risk factors, operating through cell-death mediated triggering of coagulation activation.
PMCID: PMC3963072  PMID: 24657882
10.  Superficial Femoral Artery Plaque and Functional Performance in Peripheral Arterial Disease 
JACC. Cardiovascular imaging  2011;4(7):730-739.
We studied associations of magnetic resonance imaging measurements of plaque area and relative percent lumen reduction in the proximal superficial femoral artery with functional performance among participants with peripheral arterial disease.
The clinical significance of directly imaged plaque characteristics in lower extremity arteries is not well established.
A total of 454 participants with an ankle brachial index <1.00 underwent magnetic resonance cross-sectional imaging of the proximal superficial femoral artery and completed a 6-min walk test, measurement of 4-m walking velocity at usual and fastest pace, and measurement of physical activity with a vertical accelerometer.
Adjusting for age, sex, race, body mass index, smoking, statin use, comorbidities, and other covariates, higher mean plaque area (1st quintile [least plaque]: 394 m, 2nd quintile: 360 m, 3rd quintile: 359 m, 4th quintile: 329 m, 5th quintile [greatest plaque]: 311 m; p trend <0.001) and smaller mean percent lumen area (1st quintile [greatest plaque]: 319 m, 2nd quintile: 330 m, 3rd quintile: 364 m, 4th quintile: 350 m, 5th quintile: 390 m; p trend <0.001) were associated with shorter distance achieved in the 6-min walk test. Greater mean plaque area was also associated with slower usual-paced walking velocity (p trend = 0.006) and slower fastest-paced 4-m walking velocity (p trend = 0.003). Associations of mean plaque area and mean lumen area with 6-min walk distance remained statistically significant even after additional adjustment for the ankle brachial index and leg symptoms.
Among participants with peripheral arterial disease, greater plaque burden and smaller lumen area in the proximal superficial femoral artery are associated independently with poorer functional performance, even after adjusting for the ankle brachial index and leg symptoms.
PMCID: PMC3906625  PMID: 21757163
atherosclerotic plaque intermittent claudication; peripheral arterial disease; physical functioning
11.  Higher soluble P-selectin is associated with chronic venous insufficiency: the San Diego Population Study 
Thrombosis research  2012;130(5):716-719.
P-selectin is a cell adhesion molecule shown to play a role in venous thromboembolism. We evaluated whether higher P-selectin is associated with chronic venous insufficiency (CVI).
Materials and Methods
In a cohort of 2408 participants, the San Diego Population Study, peripheral venous disease was established by symptoms, clinical examination, and ultrasound. We measured P-selectin in a subsample of 352 CVI cases frequency matched to controls. Cases included four hierarchical groups of increasing severity of CVI.
The association of P-selectin with CVI considering all cases was weak, with an age, race and sex-adjusted odds ratio (OR) of 1.3 (95% CI 1.0-2.2) for values in the 3rd versus 1st tertile. The OR for cases in the two most severe groups was 2.3 (95% CI 1.2-4.2). Addition of body mass index to the model reduced this OR to 1.9 (95% CI 1.0-3.6).
Higher circulating P-selectin was associated with more severe CVI, but not CVI overall. Results support that platelet and endothelial cell activation may be involved in the pathogenesis of CVI.
PMCID: PMC3474873  PMID: 22892384
P-selectin; chronic venous insufficiency; risk factor; blood coagulation
12.  The Group Oriented Arterial Leg Study (GOALS) to improve walking performance in patients with peripheral arterial disease 
Contemporary clinical trials  2012;33(6):1311-1320.
People with lower extremity peripheral artery disease (PAD) have greater functional impairment and faster functional decline than those without PAD. We describe methods for the Group Oriented Arterial Leg Study (GOALS), an ongoing randomized controlled clinical trial designed to determine whether a Group-Mediated Cognitive Behavioral (GMCB) intervention improves functional performance in PAD participants, compared to a health education control condition. In GOALS, PAD participants are randomized to either an intervention or a health education control condition in a parallel design. Both conditions consist of weekly group sessions with other PAD participants. In the intervention, cognitive behavioral techniques are used to assist participants in setting and adhering to home-based walking exercise goals. Participants are encouraged to walk for exercise at home at least five days per week. In the control condition, participants receive lectures on health-related topics. After six months of on-site weekly sessions, participants are transitioned to telephone follow-up for another six months. Participants in the intervention are asked to continue home walking exercise. The primary outcome is change in six-minute walk performance between baseline and six-month follow-up. Secondary outcomes include change in six-minute walk performance at 12-month follow-up, and change in treadmill walking performance, the Walking Impairment Questionnaire, quality of life, and physical activity at six and 12-month follow-up. In conclusion, if our group-mediated cognitive behavioral intervention is associated with improved walking performance in individuals with PAD, results will have major public health implications for the large and growing number of people with PAD.
PMCID: PMC3502883  PMID: 23158112
Peripheral artery disease; intermittent claudication; clinical trial; exercise
13.  Prevalence of Major Cardiovascular Risk Factors and Cardiovascular Diseases Among Hispanic/Latino Individuals of Diverse Backgrounds in the United States 
Major cardiovascular diseases (CVDs) are leading causes of mortality among US Hispanic and Latino individuals. Comprehensive data are limited regarding the prevalence of CVD risk factors in this population and relations of these traits to socioeconomic status (SES) and acculturation.
To describe prevalence of major CVD risk factors and CVD (coronary heart disease [CHD] and stroke) among US Hispanic/Latino individuals of different backgrounds, examine relationships of SES and acculturation with CVD risk profiles and CVD, and assess cross-sectional associations of CVD risk factors with CVD.
Design, Setting, and Participants
Multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos including individuals of Cuban (n =2201), Dominican (n = 1400), Mexican (n=6232), Puerto Rican (n=2590), Central American (n=1634), and South American backgrounds (n = 1022) aged 18 to 74 years. Analyses involved 15 079 participants with complete data enrolled between March 2008 and June 2011.
Main Outcome Measures
Adverse CVD risk factors defined using national guidelines for hypercholesterolemia, hypertension, obesity, diabetes, and smoking. Prevalence of CHD and stroke were ascertained from self-reported data.
Age-standardized prevalence of CVD risk factors varied by Hispanic/Latino background; obesity and current smoking rates were highest among Puerto Rican participants (for men, 40.9% and 34.7%; for women, 51.4% and 31.7%, respectively); hypercholesterolemia prevalence was highest among Central American men (54.9%) and Puerto Rican women (41.0%). Large proportions of participants (80% of men, 71% of women) had at least 1 risk factor. Age- and sex-adjusted prevalence of 3 or more risk factors was highest in Puerto Rican participants (25.0%) and significantly higher (P<.001) among participants with less education (16.1%), those who were US-born (18.5%), those who had lived in the United States 10 years or longer (15.7%), and those who preferred English (17.9%). Overall, self-reported CHD and stroke prevalence were low (4.2% and 2.0% in men; 2.4% and 1.2% in women, respectively). In multivariate-adjusted models, hypertension and smoking were directly associated with CHD in both sexes as were hypercholesterolemia and obesity in women and diabetes in men (odds ratios [ORs], 1.5–2.2). For stroke, associations were positive with hypertension in both sexes, diabetes in men, and smoking in women (ORs, 1.7–2.6).
Among US Hispanic/Latino adults of diverse backgrounds, a sizeable proportion of men and women had adverse major risk factors; prevalence of adverse CVD risk profiles was higher among participants with Puerto Rican background, lower SES, and higher levels of acculturation.
PMCID: PMC3777250  PMID: 23117778
14.  Renal artery calcification and mortality among clinically asymptomatic adults 
To assess the associations between renal artery calcification (RAC) and mortality in a healthy outpatient cohort without known cardiovascular disease (CVD).
Studies in individuals with known diabetes and kidney disease have suggested that RAC confers additional mortality risk independent of coronary artery calcification, but this has not been explored in healthier populations.
We assessed RAC by CT scan in 4450 healthy outpatients without known CVD. We used Cox proportional-hazards models to examine the association of RAC with mortality.
The mean age of participants was 57; 42.6% were women. RAC was present in 622 of 4,450 (14%) participants. Over a median follow-up of 8.2 years, 178 deaths occurred. After adjustment for age, gender, diabetes, smoking, cholesterol and family history of CVD, the presence of RAC conferred a more than 60% increased hazard for all-cause mortality (HR 1.63, 95% CI 1.17–2.29). Adjustment for calcification in other vascular beds attenuated this association (HR 1.40, 95% CI 0.99–1.97). Adjustment for hypertension, a potential mediator of the association, did not substantially change the results (HR 1.44, 95% CI, 1.02–2.03). Adding RAC to a model including Framingham risk and CAC improved the predictive ability of the model, from 0.73 to 0.77 (p 0.0002); the net reclassification index was 14.4% for addition of RAC. Results for cardiovascular mortality were not significant, limited by a small number of cardiovascular deaths.
We found that RAC is associated with an increased risk of subsequent all-cause mortality in healthy outpatient individuals, independent of traditional cardiac risk factors. The risk was modestly attenuated by adjustment for vascular calcification in other vascular beds, suggesting partial confounding by systemic calcified atherosclerosis. The effect did not appear to be mediated by hypertension.
PMCID: PMC3684424  PMID: 22939556
15.  Genetic Associations with Valvular Calcification and Aortic Stenosis 
The New England journal of medicine  2013;368(6):503-512.
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
PMCID: PMC3766627  PMID: 23388002
16.  Test Characteristics of the Ankle Brachial Index and Ankle Brachial Difference for Medial Arterial Calcification on X-ray in Type 1 Diabetes 
Medial arterial calcification (MAC) is common in diabetes, has characteristic x-ray appearance and has been linked with peripheral arterial stiffness and CVD. However few studies have measured x-ray MAC. It has been suggested that an ankle brachial index (ABI) > 1.30 or ankle brachial difference (ABD) > 75mmHg may identify x-ray MAC, but test characteristics are unknown. We hypothesized that an ABI > 1.30 and ABD > 75mmHg would have high specificity but low sensitivity for MAC on x-ray.
Study Design
Cross-sectional study
185 community-living individuals with type 1 diabetes.
The ABI and the ABD.
Linear “tram-track” calcifications in the lower limbs characteristic of MAC
Mean age was 32±6 and mean diabetes duration was 23±7 years. Ninety seven individuals (57%) had x-ray MAC, 15 (8%) had ABI > 1.30, and 14 (8%) had ABD > 75 mmHg. Using the ABI, the area under the ROC for MAC was modest (0.65) and was slightly higher for the ABD (0.75). An ABI > 1.30 had high specificity (99%) and PPV (93%), but poor sensitivity (14%), and an overall accuracy of 55% for MAC. In turn, an ABD > 50mmHg remained highly specific (98%), but had higher sensitivity (30%) and overall accuracy (62%).
Individuals with type 1 diabetes and an ABI > 1.30 or ABD > 50mmHg are very likely to have MAC on x-ray, yet many with MAC will not have ABI or ABD above these thresholds. Given high specificity, evaluating high ABI or ABD may be useful to understand correlates of MAC, but may underestimate MAC prevalence.
PMCID: PMC3415559  PMID: 22560306
diabetes; cardiovascular disease; risk factor; calcium; test characteristics
17.  Associations of Non-Invasive Measures of Arterial Compliance and Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis (MESA) 
American journal of hypertension  2012;25(5):535-541.
The association between measures of arterial compliance and peripheral arterial disease (PAD) is unclear. Early changes in arterial wall compliance could be a useful marker of patients at high risk for developing lower extremity atherosclerosis.
We used linear and logistic regression models on baseline data from 2803 female and 2558 male participants in the Multi-Ethnic Study of Atherosclerosis (MESA) to study associations between tonometry-derived baseline measures of arterial compliance (large artery compliance [C1] and small artery compliance [C2]) and the baseline ankle-brachial index (ABI), as well as change in the ABI over approximately 3 years of follow up.
In cross-sectional analyses, lower C1 and C2 values, indicating poorer arterial compliance, were associated with lower ABI. There were significant linear trends across strata of ABI, especially in C2 which ranged from 3.7ml/mmHg × 100 (95% confidence interval (CI) 3.3 to 4.2) in women with an ABI < 0.90 to 4.2ml/mmHg × 100 (95% CI 4.1 to 4.3 p<0.001) in women with ABI 1.10 - <1.40. Similar significant trends (p<0.001) were seen in men. In prospective analyses, those with the lowest tertile of C2 values at baseline had a greater multivariable-adjusted odds for decline in ABI of ≥ 0.15 over 3 years compared to those with the highest C2 values at baseline (OR 1.80 95% CI 1.23–2.64).
We observed that less compliant arteries were significantly associated with low ABI in cross-sectional analysis and with greater decline in ABI over time.
PMCID: PMC3748962  PMID: 22357412
Ankle-Brachial Index; Arterial Compliance; Peripheral Arterial Disease
18.  Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium 
Atherosclerosis  2012;222(1):138-147.
Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ~50,000 SNPs across ~2100 candidate genes to identify genetic variants for ABI.
Methods and results
We studied subjects of European ancestry from 8 studies (n = 21,547, 55% women, mean age 44–73 years) and African American ancestry from 5 studies (n = 7267, 60% women, mean age 41–73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI > 1.40) and PAD (defined as ABI < 0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p < 2 × 10−6 to denote statistical significance.
In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β = −0.007, p = 6.02 × 10−7) and rs290481 in TCF7L2 (β = −0.008, p = 7.01 × 10−7) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p = 4.99 × 10−5) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n = 15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p = 0.75; rs290481, p = 0.19) and in the combined discovery and replication analysis the SNP–ABI associations were no longer significant (rs2171209, p = 1.14 × 10−3; rs290481, p = 8.88 × 10−5). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
PMCID: PMC3596171  PMID: 22361517
Ankle brachial index; Peripheral artery disease; Genetics; Candidate gene array; Meta-analysis; Ethnicity
19.  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.
PMCID: PMC3629728  PMID: 21495835
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
20.  Higher Body Mass Index is Associated with more Adverse Changes in Calf Muscle Characteristics in Peripheral Arterial Disease 
Journal of Vascular Surgery  2012;55(4):1015-1024.
To determine whether higher body mass index (BMI) is associated with more adverse lower extremity muscle characteristics at baseline and more adverse changes in muscle over time among participants with lower extremity peripheral arterial disease (PAD).
Longitudinal, observational study.
Academic medical center in Chicago.
Participants were 425 men and women with PAD and 261 without PAD.
Computed Tomography was used to measure calf muscle characteristics at baseline and every two years. Knee extension isometric strength, power, and six-minute walk were measured at baseline and annually. Baseline BMI categories were ideal (20-25 kg/m2), overweight (>25-30 kg/m2), and obese (>30 kg/m2). Analyses adjust for age, race, gender, ankle brachial index (ABI), comorbidities, and other covariates.
At baseline, among participants with PAD, higher BMI was associated with greater calf muscle area (ideal BMI: 5181 mm2, overweight: 5513 mm2, obese: 5695 mm2, p trend=0.0009), higher calf muscle percent fat (6.38%, 10.28%, 17.44% respectively, p trend<0.0001), lower calf muscle density (p trend<0.0001), and higher isometric knee extension strength (p trend=0.015). Among participants with PAD, higher BMI was associated with greater declines in calf muscle area p trend=0.030) and greater increases in calf muscle percent fat (p trend=0.023). Among participants without PAD, there were no significant associations of baseline BMI with changes in lower extremity muscle outcomes over time.
Among PAD participants, higher BMI is associated with greater calf muscle area at baseline. However, higher BMI is associated with more adverse calf muscle density and percent fat at baseline and greater declines in calf muscle area over time.
PMCID: PMC3319256  PMID: 22365177
We studied whether lower calf muscle density and poorer upper and lower extremity strength are associated with higher mortality rates in men and women with PAD.
Men and women with lower extremity peripheral arterial disease (PAD) have lower calf muscle density and reduced lower extremity strength compared to individuals without PAD.
At baseline, participants underwent measurement of calf muscle density with computed tomography in addition to knee extension power, and isometric knee extension, plantar flexion, and hand grip strength measures. Participants were followed annually for up to four years. Results are adjusted for age, sex, race, body mass index, the ankle brachial index (ABI), smoking, physical activity, and comorbidities.
Among 434 PAD participants, 103 (24%) died during a mean follow-up of 47.6 months. Lower calf muscle density was associated with higher all-cause mortality (lowest density tertile-hazard ratio (HR)=1.80 (95% Confidence Interval (CI)-1.07-3.03), 2nd tertile-HR=0.91 (95% CI-0.51-1.62); highest density tertile (HR=1.00), P trend=0.020) and higher cardiovascular disease mortality (lowest density tertile-HR=2.39 (95% CI-0.90-6.30), 2nd tertile-HR=0.85 (95% CI-0.27-2.71); highest density tertile (HR=1.00), P trend=0.047). Poorer plantar flexion strength (P trend=0.004), lower baseline leg power (P trend=0.046), and poorer handgrip (P trend=0.005) were associated with higher all-cause mortality.
These data demonstrate that lower calf muscle density and weaker plantar flexion strength, knee extension power, and hand grip are associated with increased mortality in participants with PAD, independently of the ABI and other confounders.
PMCID: PMC3465664  PMID: 22440216
Mortality; intermittent claudication; prognosis; Physical functioning
22.  Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies 
Murabito, Joanne M. | White, Charles C. | Kavousi, Maryam | Sun, Yan V. | Feitosa, Mary F. | Nambi, Vijay | Lamina, Claudia | Schillert, Arne | Coassin, Stefan | Bis, Joshua C. | Broer, Linda | Crawford, Dana C. | Franceschini, Nora | Frikke-Schmidt, Ruth | Haun, Margot | Holewijn, Suzanne | Huffman, Jennifer E. | Hwang, Shih-Jen | Kiechl, Stefan | Kollerits, Barbara | Montasser, May E. | Nolte, Ilja M. | Rudock, Megan E. | Senft, Andrea | Teumer, Alexander | van der Harst, Pim | Vitart, Veronique | Waite, Lindsay L. | Wood, Andrew R. | Wassel, Christina L. | Absher, Devin M. | Allison, Matthew A. | Amin, Najaf | Arnold, Alice | Asselbergs, Folkert W. | Aulchenko, Yurii | Bandinelli, Stefania | Barbalic, Maja | Boban, Mladen | Brown-Gentry, Kristin | Couper, David J. | Criqui, Michael H. | Dehghan, Abbas | Heijer, Martin den | Dieplinger, Benjamin | Ding, Jingzhong | Dörr, Marcus | Espinola-Klein, Christine | Felix, Stephan B. | Ferrucci, Luigi | Folsom, Aaron R. | Fraedrich, Gustav | Gibson, Quince | Goodloe, Robert | Gunjaca, Grgo | Haltmayer, Meinhard | Heiss, Gerardo | Hofman, Albert | Kieback, Arne | Kiemeney, Lambertus A. | Kolcic, Ivana | Kullo, Iftikhar J. | Kritchevsky, Stephen B. | Lackner, Karl J. | Li, Xiaohui | Lieb, Wolfgang | Lohman, Kurt | Meisinger, Christa | Melzer, David | Mohler, Emile R | Mudnic, Ivana | Mueller, Thomas | Navis, Gerjan | Oberhollenzer, Friedrich | Olin, Jeffrey W. | O’Connell, Jeff | O’Donnell, Christopher J. | Palmas, Walter | Penninx, Brenda W. | Petersmann, Astrid | Polasek, Ozren | Psaty, Bruce M. | Rantner, Barbara | Rice, Ken | Rivadeneira, Fernando | Rotter, Jerome I. | Seldenrijk, Adrie | Stadler, Marietta | Summerer, Monika | Tanaka, Toshiko | Tybjaerg-Hansen, Anne | Uitterlinden, Andre G. | van Gilst, Wiek H. | Vermeulen, Sita H. | Wild, Sarah H. | Wild, Philipp S. | Willeit, Johann | Zeller, Tanja | Zemunik, Tatijana | Zgaga, Lina | Assimes, Themistocles L. | Blankenberg, Stefan | Boerwinkle, Eric | Campbell, Harry | Cooke, John P. | de Graaf, Jacqueline | Herrington, David | Kardia, Sharon L. R. | Mitchell, Braxton D. | Murray, Anna | Münzel, Thomas | Newman, Anne | Oostra, Ben A. | Rudan, Igor | Shuldiner, Alan R. | Snieder, Harold | van Duijn, Cornelia M. | Völker, Uwe | Wright, Alan F. | Wichmann, H.-Erich | Wilson, James F. | Witteman, Jacqueline C.M. | Liu, Yongmei | Hayward, Caroline | Borecki, Ingrid B. | Ziegler, Andreas | North, Kari E. | Cupples, L. Adrienne | Kronenberg, Florian
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
PMCID: PMC3303225  PMID: 22199011
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
23.  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 
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
Pulse pressure (pulse pressure), small and large arterial elasticity (SAE, LAE), and flow mediated dilation.
kidney function decline
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.
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.
We had no direct measure of GFR, in common with nearly all large population based studies.
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.
PMCID: PMC3242889  PMID: 22000727
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
24.  The older the better: are elderly study participants more non-representative? A cross-sectional analysis of clinical trial and observational study samples 
BMJ Open  2012;2(6):e000833.
Study participants can differ from the target population they are taken to represent. We sought to investigate whether older age magnifies such differences, examining age-trends, among study participants, in self-rated level of activity compared to others of the same age.
Cross-sectional examination of the relation of participant age to reported ‘relative activity’ (ie, compared to others of the same age), a bidirectionally correlated proxy for relative vitality, in exemplars of randomised and observational studies.
University of California, San Diego (UCSD)
2404 adults aged 40–79 including employees of UCSD, and their partners (San Diego Population Study, observational study). 1016 adults (aged 20-85) not on lipid medications and without known heart disease, diabetes, cancer or HIV (UCSD Statin Study, randomised trial).
Self-rated activity relative to others’ age, 5-point Likert Scale, was evaluated by age decade, and related via correlation and regression to a suite of health-relevant subjective and objective outcomes.
Successively older participants reported successively greater activity relative to others of their age (greater departure from the norm for their age), p<0.001 in both studies. Relative activity significantly predicted (in regression adjusted for age) actual activity (times/week exercised), and numerous self-rated and objective health-predictors. These included general self-rated health, CES-D (depression score), sleep, tiredness, energy; body mass index, waist circumference, serum glucose, high-density lipoprotein-cholesterol, triglycerides and white cell count. Indeed, some health-predictor associations with age in participants were ‘paradoxical,’ consistent with greater apparent health in older age—for study participants.
Study participants may not be representative of the population they are intended to reflect. Our results suggest that departures from representativeness may be amplified with increasing age. Consequently, the older the age, the greater the disparity may be between what is recommended based on ‘evidence, ’ and what is best for the patient.
Trial Registration
UCSD Statin Study— # NCT00330980 (
PMCID: PMC3533104  PMID: 23242479
25.  Association of Self-Reported Race/Ethnicity and Genetic Ancestry with Arterial Elasticity: The Multi-Ethnic Study of Atherosclerosis (MESA) 
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.
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.
PMCID: PMC3218223  PMID: 21890448
large artery elasticity; small artery elasticity; admixture; pulse pressure

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