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
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 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
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
To determine whether asymptomatic lower extremity peripheral arterial disease (PAD) and leg symptoms other than intermittent claudication (IC) in PAD are associated with faster functional decline compared to people with both PAD and IC.
Prospective, observational study.
Chicago-area medical center.
415 men and women with PAD followed annually for up to seven years.
At baseline, PAD patients were categorized into symptom categories including IC, leg pain on exertion and rest, pain/carry on (participants walk through exertional leg pain), and always asymptomatic (participants who never experience exertional leg pain, even during the six-minute walk). Outcomes included mobility loss (becoming unable to walk ¼ mile or walk up and down one flight of stairs without assistance) and becoming unable to complete the six minute walk without stopping. Analyses adjust for age, sex, comorbidities, the ankle brachial index (ABI) and other confounders.
Always asymptomatic PAD participants (hazard ratio (HR)=2.94, 95% Confidence Interval (CI)= 1.34-5.42, p=0.005) and those with leg pain on exertion and rest (HR=2.89, 95% CI=1.47-5.68, p=0.002) had increased mobility loss compared to participants with IC. PAD participants with leg pain/carry on were less likely (p=0.047) to become unable to walk for six minutes continuously without stopping, compared to participants with IC.
The ABI identifies asymptomatic PAD patients and those with atypical leg symptoms who are at risk for greater mobility decline than participants without PAD and PAD participants with IC.
intermittent claudication; peripheral vascular disease; physical functioning
To establish associations between leg strength and mortality in men and women with lower extremity peripheral arterial disease (PAD).
Observational, prospective study.
Chicago area medical centers.
Participants were 410 men and women with PAD age 55 and older followed for a mean of 60.0 months.
Isometric knee extension, knee flexion, hip extension, and hip flexion were measured at baseline. Primary outcomes were all-cause and cardiovascular disease mortality. Cox proportional hazards models were used to assess relations between leg strength and all-cause and cardiovascular disease mortality among men and women, adjusting for age, race, comorbidities, smoking, body mass index, and the ankle brachial index.
Among the 246 male participants, poorer baseline strength for knee flexion (P trend = .029), knee extension (P trend =.010), and hip extension (P trend = .013) were each associated independently with higher all-cause mortality. Poorer strength for knee flexion (P trend = .042) and hip extension (P trend = .029) were associated with higher cardiovascular mortality. Compared to those in the fourth (best) baseline knee flexion quartile, Hazard Ratios for all-cause and cardiovascular disease mortality among men in the 1st (poorest) knee flexion quartile were 2.23 (95% Confidence Interval (CI) = 1.02–4.87, P=.045) and 4.20 (95% CI = 1.12–15.79, P=.043), respectively. No significant associations of leg strength and all-cause mortality were identified among women.
Poorer leg strength is associated with increased mortality in men, but not women, with PAD. Future study is needed to determine whether interventions that increase leg strength improve survival in men with PAD.
We studied associations of borderline and low-normal ankle brachial index (ABI) values with functional decline over five-year follow-up.
Associations of borderline and low-normal ABI with functional decline are unknown.
The 666 participants included 412 with peripheral arterial disease (PAD). Participants were categorized as follows: Severe PAD (ABI < 0.50), moderate PAD (ABI 0.50-0.69), mild PAD (ABI 0.70 to 0.89), borderline ABI (0.90 to 0.99), low normal ABI (1.00 to 1.09), and normal ABI (ABI 1.10-1.30). Outcomes were assessed annually for five years. Mobility loss was defined as loss of the ability to walk ¼ mile or walk up and down one flight of stairs without assistance among those without baseline mobility impairment. Becoming unable to walk for six minutes continuously was defined as stopping during the six minute walk at follow-up among those who walked for six minutes continuously at baseline. Results adjust for age, sex, race, comorbidities, and other confounders.
Hazard ratios (HR) for mobility loss according to ABI category were as follows. Severe PAD: HR=4.16 (95% Confidence Interval (CI)=1.58-10.92), moderate PAD: HR=3.82 (95% CI=1.66-8.81), mild PAD: HR=3.22 (95% CI=1.43-7.21), borderline ABI: HR=3.07 (95% CI=1.21-7.84), low normal ABI: HR=2.61 (95% CI=1.08-6.32) (p trend=0.0018). Similar associations were observed for becoming unable to walk six-minutes continuously (p trend<0.0001).
At five-year follow-up, persons with borderline ABI values have a higher incidence of mobility loss and becoming unable to walk for six minutes continuously compared to persons with a normal baseline ABI. A low normal ABI is associated with an increased incidence of mobility loss compared to persons with a normal ABI.
We studied associations of borderline and low-normal ABI values with functional decline over five-year follow-up among 666 participants, including 412 with lower extremity peripheral arterial disease (PAD). At five year follow-up, participants with borderline ABI values at baseline (ABI 0.90 to 0.99) had significantly greater mobility loss and were more likely to become unable to walk for six-minutes continuously compared to those with a normal baseline ABI. Participants with low normal ABI values (ABI 1.00 to 1.09) had significantly greater mobility loss compared to those with a normal baseline ABI.
ankle brachial index; physical functioning; peripheral arterial disease; intermittent claudication
The purpose of this study was to examine the association of both a low and a high ankle-brachial index (ABI) with incident cardiovascular events in a multi-ethnic cohort.
Abnormal ankle-brachial indices (ABIs), both low and high, are associated with elevated cardiovascular disease (CVD) risk. However, it is unknown whether this association is consistent across different ethnic groups, and whether it is independent of both newer biomarkers and other measures of subclinical atherosclerotic CVD.
6647 non-Hispanic white, African-American, Hispanic, and Chinese men and women aged 45–84 years from free-living populations in six United States field centers and free of clinical CVD at baseline had extensive measures of traditional and newer biomarker risk factors, and measures of subclinical CVD, including the ABI. Incident CVD, defined as coronary disease, stroke, or other atherosclerotic CVD death, was determined over a mean follow-up of 5.3 years.
Both a low (<1.00) and a high (≥ 1.40) ABI were associated with incident CVD events. Gender- specific and ethnic-specific analyses showed consistent results. Hazard ratios were 1.77 (p<.001) for a low and 1.85 (p=.050) for a high ABI after adjustment for both traditional and newer biomarker CVD risk factors, and the ABI significantly improved risk discrimination. Further adjustment for coronary artery calcium score, common and internal carotid intimal medial thickness, and major ECG abnormalities only modestly attenuated these hazard ratios.
In this study both a low and a high ABI were associated with elevated CVD risk in persons free of known CVD, independent of standard and novel risk factors, and independent of other measures of subclinical CVD. Further research should address the cost-effectiveness of measuring the ABI in targeted population groups.
peripheral arterial disease; ankle-brachial index; cardiovascular events; risk factors; subclinical atherosclerosis
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
subclavian artery; blood pressure; atherosclerosis; epidemiology
A higher serum phosphorus level is associated with cardiovascular disease (CVD) events among community-living populations. Mechanisms are unknown. The ankle-brachial index (ABI) provides information on both atherosclerosis and arterial stiffness. In this cross-sectional study (2000–2002), the authors evaluated the association of serum phosphorus levels with low (<0.90) and high (≥1.40 or incompressible) ABI as compared with intermediate ABI in 5,330 older US men, among whom the mean serum phosphorus level was 3.2 mg/dL (standard deviation, 0.4), 6% had a low ABI, and 5% had a high ABI. Each 1-mg/dL increase in serum phosphorus level was associated with a 1.6-fold greater prevalence of low ABI (95% confidence interval (CI): 1.2, 2.1; P < 0.001) and a 1.4-fold greater prevalence of high ABI (95% CI: 1.0, 1.9; P = 0.03) in models adjusted for demographic factors, traditional CVD risk factors, and kidney function. However, the association of phosphorus with high ABI differed by chronic kidney disease (CKD) status (in persons with CKD, prevalence ratio = 2.96, 95% CI: 1.61, 5.45; in persons without CKD, prevalence ratio = 1.14, 95% CI: 0.81, 1.61; interaction P = 0.04). In conclusion, among community-living older men, higher phosphorus levels are associated with low ABI and are also associated with high ABI in persons with CKD. These associations may explain the link between serum phosphorus levels and CVD events.
ankle brachial index; cardiovascular diseases; kidney diseases; phosphorus
The aim of this study was to determine the associations between the presence and extent of calcified atherosclerosis in multiple vascular beds and systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, isolated systolic hypertension, and hypertension. 9,510 patients (42.5% women) underwent electron beam computed tomography scanning as part of a routine health maintenance screening. At the same visit, blood pressure was measured with the participant in the seated position using a mercury sphygmomanometer. Mean age was 58±11.4 years and body mass index was 27.1±4.5. The prevalence of any calcification in the carotids, coronaries, subclavians, thoracic aorta, abdominal aorta, and iliacs were 31.9, 57.2, 31.7, 37.0, 54.3, and 48.8% respectively. In separate multivariable logistic models containing traditional cardiovascular disease risk factors, pulse pressure and systolic blood pressure were significantly associated with presence of calcification in all vascular beds except the iliacs and subclavians, respectively, with pulse pressure having stronger magnitudes of the associations for most of the vascular beds. Age stratified analyses indicated that these associations were stronger in those over 60 years of age, compared to subjects less than 60 years of age, and gender stratified analyses demonstrated that men had a greater association compared to women. Also, the magnitudes of the associations for isolated systolic hypertension were, in general, larger than those for hypertension. Pulse pressure and isolated systolic hypertension are robust and important correlates for calcified atherosclerosis in different vascular beds. Isolated systolic hypertension may be clinically relevant in diagnosing or preventing calcified atherosclerosis.
Pulse Pressure; Isolated systolic hypertension; Systolic Blood Pressure; Calcification; Atherosclerosis; Hypertension; Vascular beds
In persons with coronary artery disease (CAD), low body mass index is associated with greater mortality, however it is uncertain if low muscle mass is a risk factor for mortality in this setting.
Methods and Results
903 individuals with CAD provided 24-hour urine collections. We measured urine creatinine and volume, and calculated creatinine excretion rate (CER), a marker of muscle mass. Cox proportional hazards models evaluated the association of CER with mortality risk during follow-up. Two-hundred thirty-two participants (26%) died over a median follow-up of 6.0 years. Compared to the highest sex-specific CER tertile, the lowest tertile (< 1,068 mg/day in men, < 766 mg/day in women) was associated with > 2-fold risk of mortality (hazard ratio [HR] 2.30; 95% confidence interval [CI] 1.51–3.51) in models adjusted for age, sex, race, cystatin C-based eGFR, body mass index, traditional CVD risk factors, and C-reactive protein levels. The association was essentially unaltered with further adjustment for physical fitness, left ventricular (LV) mass, LV ejection fraction, or fasting insulin and glucose levels.
Lower CER is strongly associated with mortality in outpatients with CAD, independent of conventional measures of body composition, kidney function, and traditional CAD risk factors. Future studies should determine whether low CER may be a modifiable risk factor for mortality among persons with CAD, potentially through resistive exercise training or nutrition interventions.
Cardiovascular disease; mortality; lean mass; muscle mass; creatinine
The authors aimed to determine differences in the prevalence of peripheral arterial disease (PAD) and its associations with cardiovascular disease (CVD) risk factors, using different methods of calculating the ankle-brachial index (ABI). Using measurements taken in the bilateral brachial, dorsalis pedis, and posterior tibial arteries, the authors calculated ABI in 3 ways: 1) with the lowest ankle pressure (dorsalis pedis artery or posterior tibial artery) (“ABI-LO”), 2) with the highest ankle pressure (“ABI-HI”), and 3) with the mean of the ankle pressures (“ABI-MN”). For all 3 methods, the index ABI was the lower of the ABIs calculated from the left and right legs. PAD was defined as an ABI less than 0.90. Among 6,590 subjects from a multiethnic cohort (baseline examination: 2000–2002), in comparison with ABI-HI, the relative prevalence of PAD was 3.95 times higher in women and 2.74 times higher in men when ABI-LO was used. The relative magnitudes of the associations were largest between PAD and both subclinical atherosclerosis and CVD risk factors when ABI-HI was used, except when risk estimates for PAD were less than 1.0, where the largest relative magnitudes of association were found using ABI-LO. PAD prevalence and its associations with CVD risk factors and subclinical atherosclerosis measures depend on the ankle pressure used to compute the ABI.
ankle brachial index; cardiovascular diseases; continental population groups; ethnic groups; peripheral vascular diseases