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.
P-selectin; chronic venous insufficiency; risk factor; blood coagulation
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.
Peripheral artery disease; intermittent claudication; clinical trial; exercise
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.
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.
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.
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.
diabetes; cardiovascular disease; risk factor; calcium; test characteristics
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.
Ankle-Brachial Index; Arterial Compliance; Peripheral Arterial Disease
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.
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
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.
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.
Mortality; intermittent claudication; prognosis; Physical functioning
The association of subclinical vascular disease and early declines in kidney function has not been well studied.
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.
kidney function; arterial elasticity; chronic kidney disease; atherosclerosis
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.
UCSD Statin Study—Clinicaltrials.gov # NCT00330980 (http://ClinicalTrials.gov)
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.
large artery elasticity; small artery elasticity; admixture; pulse pressure
The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)2) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged ≥65 years at baseline (1989–1990 or 1992–1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age.
ankle brachial index; body mass index; cardiovascular diseases; peripheral arterial disease
To determine whether poor lower extremity nerve function is associated with more adverse calf muscle characteristics and greater functional impairment in people with and without peripheral arterial disease (PAD).
Three Chicago-area medical centers
413 participants with PAD (ankle-brachial index (ABI) <0.90) and 271 participants without PAD.
Electrodiagnostic testing of the peroneal nerve was performed. Calf muscle cross-sectional area and percent fat were measured using computed tomography at 66.7% of the distance between the distal and proximal tibia. 6-minute walk performance was measured.
Adjusting for age, sex, race, ABI, leg symptoms, smoking, physical activity, comorbidities, and other covariates, lower peroneal nerve conduction velocity (NCV) was associated with lower calf muscle area (1st quartile: 5571.1 mm2, 4th quartile: 4770.3 mm2, p-value<0.001) and poorer 6-minute walk distance (1st quartile: 989.2 ft, 4th quartile: 1210.8 ft, p-value<0.001) in non-diabetic PAD participants. Lower peroneal NCV was associated with lower calf muscle area (1st quartile: 5166.0 mm2, 4th quartile: 6003.8 mm2, p-value=0.014) and poorer 6-minute walk distance (1st quartile: 866.4 ft, 4th quartile: 1082.5 ft, p-value=0.012) in diabetic PAD participants as well. Among non-PAD participants, lower peroneal NCV was not associated with lower calf muscle area but was associated with poorer 6-minute walk distance in non-diabetic participants only (1st quartile 1317.0 ft, 4th quartile 1570.4 ft; p-trend<0.001).
Lower peroneal nerve function is associated with smaller calf muscle area in individuals with PAD and greater functional impairment in individuals with PAD. Future study is needed to determine whether improving peroneal NCV prevents loss of calf muscle and functional decline in PAD.
Claudication; Muscles; Peripheral Nervous System; Peripheral Vascular Disease; Physical functioning
To determine the association of family history of peripheral artery disease (PAD) with PAD prevalence and severity.
PAD is a significant public health problem. Shared genetic and environmental factors may play an important role in the development of PAD. However, family history of PAD has not been adequately investigated.
The San Diego Population Study (SDPS) enrolled 2404 ethnically diverse men and women aged 29–91 who attended a baseline visit from 1994–98 to assess PAD and venous disease. Ankle brachial index (ABI) measurement was performed at the baseline clinic examination and family history of PAD was obtained via questionnaire. Family history of PAD was primarily defined as having any 1st degree relative with PAD. Prevalent PAD was defined as ABI ≤ 0.90 and severe prevalent PAD as ABI ≤ 0.70, with both definitions also including any previous leg revascularization. Logistic regression was used to evaluate the association of family history of PAD with prevalent PAD.
The mean (SD) age was 59 (11) years, 66% were women, and 58% were Caucasian with 42% comprising other racial/ethnic groups. Prevalence of PAD was 3.6%, and severe prevalent PAD was 1.9%. In fully adjusted models, family history of PAD was associated with a 1.83-fold higher odds of PAD (95% CI (1.03, 3.26), p=0.04), an association which was stronger for severe prevalent PAD (OR 2.42, 95% CI (1.13, 5.23), p=0.02).
Family history of PAD is independently strongly associated with PAD prevalence and severity. This indicates a role for genetic factors and/or other shared environmental factors contributing to PAD.
family history; peripheral artery disease; ankle brachial index
The purpose of this study was to examine the association of progressive versus stable peripheral arterial disease (PAD) with the risk of future cardiovascular disease (CVD) events.
An independent association between PAD, defined by low values of the ankle-brachial index (ABI), and future CVD risk has been demonstrated. However, the prognostic significance of declining versus stable ABI has not been studied.
We recruited 508 subjects (59 women, 449 men) from 2 hospital vascular laboratories in San Diego, California. ABI and CVD risk factors were measured at Visit 2 (1990 to 1994). ABI values from each subject’s earliest vascular laboratory examination (Visit 1) were abstracted from medical records. Mortality and morbidity were tracked for 6 years after Visit 2 using vital statistics and hospitalization data.
In multivariate models adjusted for CVD risk factors, very low (<0.70) and, in some cases, low (0.70 ≤ ABI <0.90) Visit 2 ABIs were associated with significantly elevated all-cause mortality, CVD mortality, and combined CVD morbidity/mortality at 3 and 6 years. Decreases in ABI of more than 0.15 between Visit 1 and Visit 2 were significantly associated with an increased risk of all-cause mortality (risk ratio [RR]: 2.4) and CVD mortality (RR: 2.8) at 3 years, and CVD morbidity/mortality (RR: 1.9) at 6 years, independent of Visit 2 ABI and other risk factors.
Progressive PAD (ABI decline >0.15) was significantly and independently associated with increased CVD risk. Patients with decreasing ABI may be candidates for more intensive cardiovascular risk factor management.
peripheral vascular disease; cardiovascular diseases; risk factors; morbidity; mortality
Higher levels of inflammation are associated with adverse outcomes in persons with lower extremity peripheral arterial disease (PAD). This study evaluated associations of physical activity during daily life with levels of inflammatory biomarkers, D-dimer, and homocysteine in persons with PAD. Participants were 244 men and women (mean age 74.4 years ± 8.2) with PAD (ankle brachial index (ABI) < .90). C reactive protein (CRP), Interleukin-6 (IL-6), soluble Intracellular Adhesion Molecule-1 (sICAM-1), soluble Vascular Cellular Adhesion Molecule-1 (sVCAM-1), D-dimer, and homocysteine were assessed at study entry. Physical activity was objectively assessed via a vertical accelerometer, which participants wore continuously for 7 days. After adjusting for age, sex, race, body mass index, smoking, comorbidities, ABI, and other potential confounders, higher physical activity levels were associated linearly and significantly with lower levels of all measured circulating biomarkers: sVCAM-1 (p trend = 0.001); D-Dimer (p trend = 0.005); homocysteine (p trend = 0.006); IL-6 (p trend = 0.010); CRP, (p trend = 0.028); sICAM-1 (p trend = 0.033). In conclusion, higher levels of physical activity were associated independently with lower levels of inflammatory markers, homocysteine, and D-dimer in PAD patients.
High-sensitivity C-reactive protein (hsCRP) levels are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP ≥2 mg/L to guide statin therapy; however the association of hsCRP to atherosclerosis, independent of obesity, remains unknown.
Methods and Results
We studied 6,760 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were stratified into 4 groups: non-obese/low hsCRP, non-obese/high hsCRP, obese/low hsCRP, and obese/high hsCRP. Using multivariable logistic and robust linear regression, we described the association with subclinical atherosclerosis, using coronary artery calcium (CAC) and carotid intima-media thickness (cIMT). Mean BMI was 28.3 ± 5.5 kg/m2, and median hsCRP was 1.9 mg/L (0.84 – 4.26). High hsCRP, in the absence of obesity, was not associated with CAC and was mildly associated with cIMT. Obesity was strongly associated with CAC and cIMT independent of hsCRP. When obesity and high hsCRP were both present, there was no evidence of multiplicative interaction. Similar associations were seen among 2,083 JUPITER-eligible individuals.
High hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with cIMT in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independent of hsCRP status.
obesity; hsCRP; high sensitivity C-reactive protein; subclinical atherosclerosis; coronary artery calcium; carotid intima-media thickness
We determined whether persistently high levels of interleukin-6 (IL-6) or soluble vascular adhesion molecule (sVCAM-1) are associated with faster functional decline, compared to fluctuating or persistently low biomarker levels, among 255 participants with peripheral arterial disease (PAD). Participants underwent baseline and at least two annual follow-up measures of IL-6 and sVCAM-1. Participants were categorized as follows: Category 1- annual levels of IL-6 (or sVCAM-1) were in the lowest tertile for at least three study visits. Category 3- annual levels of IL-6 (or sVCAM-1) were in the highest tertile for at least three visits. Category 2- levels of IL-6 (or sVCAM-1) did not meet criteria for Groups 1 or 3. Six-minute walk, fastest paced four meter walking velocity, and the short physical performance battery (SPPB) were measured annually. Results were adjusted for age, sex, race, comorbidities, statins, physical activity, the ankle brachial index, and other confounders. Across IL-6 categories, average annual declines in six minute walk performance were Category 1: -21.4 feet, Category 2:-49.2 feet, and Category 3:-76.8 feet (p trend = 0.013) and average annual declines in the SPPB score were -0.18, -0.45, and -0.62, respectively (p trend = 0.022). Similar associations of IL-6 categories with decline in fastest paced walking velocity were observed (p trend = 0.034). There were no significant associations of sVCAM-1 categories with functional decline. In conclusion, among PAD participants, persistently high IL-6 levels are associated with faster functional decline compared to those with fluctuating or persistently low IL-6 levels.
Inflammation; physical functioning; peripheral arterial disease; intermittent claudication
The clinical significance of magnetic resonance imaged (MRI) plaque characteristics in the superficial femoral artery (SFA) is not well established. We studied associations of the ankle brachial index (ABI) and leg symptoms with MRI-measured plaque area and percent lumen area in the SFA in participants with and without lower extremity peripheral arterial disease (PAD).
Methods and Results
Four hundred twenty-seven participants (393 with PAD) underwent plaque imaging of the first 30 millimeters of the SFA. Twelve 2.5 millimeter cross-sectional images of the SFA were obtained. Outcomes were normalized plaque area, adjusted for artery size (0–1 scale, 1=greatest plaque), and lumen area, expressed as a percent of the total artery area. Adjusting for age, sex, race, smoking, statins, cholesterol, and other covariates, lower ABI values were associated with higher normalized mean plaque area (ABI < 0.50:0.79; ABI 0.50 to 0.69:0.73; ABI 0.70 to 0.89:0.65; ABI 0.90 to 0.99:0.62; ABI 1.00 to 1.09:0.48; ABI 1.10–1.30:0.47 (P trend <0.001)) and smaller mean percent lumen area (P trend<0.001). Compared to PAD participants with intermittent claudication, asymptomatic PAD participants had lower normalized mean plaque area (0.72 vs. 0.65, p=0.005) and larger mean percent lumen area (0.30 vs. 0.36, p=0.01), adjusting for the ABI and other confounders.
Lower ABI values are associated with greater MRI-measured plaque burden and smaller lumen area in the first 30 millimeters of the SFA. Compared to PAD participants with claudication, asymptomatic PAD participants have smaller plaque area and larger lumen area in the SFA.
atherosclerosis; magnetic resonance imaging; peripheral vascular disease; plaque
To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population.
A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation.
In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized β=0.97), male sex (β=1.88), body surface area (standardized β=0.92), current smoking (β=0.42), D-dimer levels (β=0.19) and hypertension (β=0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (β=-0.70) (P<.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (β's= -0.59, -0.49, and -0.52, respectively, all P<.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (β=0.11 to 0.19), associated with larger AD.
Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.
aorta; aneurysm; atherosclerosis; ethnicity; epidemiology
The initiation and acceleration of atherosclerosis is hypothesized as a physiologic mechanism underlying associations between air pollution and cardiovascular effects. Despite toxicologic evidence, epidemiologic data are limited.
In this cross-sectional analysis we investigated exposure to fine particulate matter (PM2.5) and residential proximity to major roads in relation to abdominal aortic calcification a sensitive indicator of systemic atherosclerosis. Aortic calcification was measured by computed tomography among 1147 persons, in 5 U.S. metropolitan areas, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). The presence and quantity of aortic calcification were modeled using relative risk regression and linear regression, respectively, with adjustment for potential confounders.
We observed a slightly elevated risk of aortic calcification (RR = 1.06; 95% confidence interval = 0.96–1.16) with a 10-μg/m3 contrast in PM2.5. The PM2.5-associated risk of aortic calcification was stronger among participants with long-term residence near a PM2.5 monitor (RR = 1.11; 1.00–1.24) and among participants not recently employed outside the home (RR = 1.10; 1.00–1.22). PM2.5 was not associated with an increase in the quantity of aortic calcification (Agatston score) and no roadway proximity effects were noted. There was indication of PM2.5 effect modification by lipid-lowering medication use, with greater effects among users, and PM2.5 associations were observed most consistently among Hispanics.
Although we did not find persuasive associations across our full study population, associations were stronger among participants with less exposure misclassification. These findings support the hypothesis of a relationship between particulate air pollution and systemic atherosclerosis.
Associations of decline in functional performance with clinically-important outcomes in patients with peripheral arterial disease (PAD) are unknown.
We hypothesized that greater two-year decline in office-based functional performance measures would be associated with greater mobility loss and mortality in people with PAD.
440 men and women with PAD completed the six-minute walk test and measures of walking velocity at baseline and annually for two years. Participants were categorized into tertiles according to their functional decline between baseline and two-year follow-up and were followed annually after the functional change assessment. Cox proportional hazard models were used to assess relations between the two-year change in functional performance with later mortality and mobility loss, adjusting for age, sex, race, the ankle brachial index, comorbidities, and other confounders.
One hundred two participants (23.2%) died during a median follow-up of 44.5 months after functional change was assessed. Of 319 participants without baseline mobility disability, 60 (18.8%) developed mobility loss after functional change was assessed. Participants in the tertile with greatest six-minute walk decline had the highest subsequent mobility loss (Hazard Ratio (HR)=3.50, 95% Confidence Interval (CI)=1.56–7.85, p=0.002), all-cause mortality (HR=2.16, 95% CI=1.28–3.64, p=0.004), and cardiovascular disease (CVD) mortality (HR=2.45, 95% CI=1.08–5.54, p=0.031), compared to those with the smallest six-minute walk decline. Greater declines in fastest paced four-meter walking velocity were associated with higher mobility loss (P trend=0.018), all-cause mortality (P trend=0.01) and CVD mortality (P trend=0.004).
PAD participants with declining functional performance are at increased risk for later mobility loss and mortality.
peripheral vascular disease; mortality; physical functioning
Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.
Among 1,812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.
AAC prevalence ranged from 34% in those aged 45–54 to 94% in those aged 75–84 (p<0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p<0.0001). CAC prevalence, mean maximum CIMT ≥ 1 mm, and ABI<0.9 was greater in those with vs. without AAC: CAC 60% vs 16%, CIMT 38% vs 7%, and ABI 5% vs 1% for women and CAC 80% vs 37%, CIMT 43% vs 16%, and ABI 4% vs 2% for men (p<0.01 for all except p<0.05 for ABI in men). The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women and 30% in men (p<0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45–54 to 53% in those aged 75–84 (p<0.01 to p<0.001). Finally, increased AAC was associated with 2 to 3-fold relative risks for the presence of increased CIMT, low ABI, or CAC.
AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
atherosclerosis; calcification; cardiovascular disease; epidemiology
Associations of pathophysiologic calf muscle characteristics with functional decline in people with lower extremity peripheral arterial disease (PAD) are unknown.
METHODS AND RESULTS
Three hundred seventy participants with PAD underwent baseline measurement of calf muscle area, density, and percent fat using computed tomography. Participants were followed annually for two years. The outcome of mobility loss was defined as becoming unable to walk ¼ mile or walk up and down one flight of stairs without assistance, among those without baseline mobility limitations. Additional outcomes were ≥ 20% decline in six-minute walk distance and becoming unable to walk for six minutes continuously among participants who walked continuously for six minutes at baseline. Adjusting for age, sex, race, body mass index, the ankle brachial index, smoking, physical activity, relevant medications, and comorbidities, lower calf muscle density (p trend < 0.001) and lower calf muscle area (p trend =0.039) were each associated with increased mobility loss rates. Compared to participants in the highest baseline tertiles, participants in the lowest tertile of calf muscle percent fat had a hazard ratio of 0.18 for incident mobility loss (95% CI = 0.06–0.55, p=0.003), and participants in the lowest tertile of muscle density had a 3.50 hazard ratio for incident mobility loss (95% CI= 1.28–9.57, p=0.015). No significant associations of calf muscle characteristics with six-minute walk outcomes were observed.
Our findings suggest that interventions to prevent mobility loss in PAD should focus on reversing pathophysiologic findings in calf muscle.
Intermittent claudication; mobility; peripheral arterial disease; physical functioning