Association among sickle cell trait, fitness, and cardiovascular risk factors in CARDIA.

The contribution of sickle cell trait (SCT) to racial disparities in cardiopulmonary fitness is not known, despite concerns that SCT is associated with exertion-related sudden death. We evaluated the association of SCT status with cross-sectional and longitudinal changes in fitness and risk for hypertension, diabetes, and metabolic syndrome over the course of 25 years among 1995 African Americans (56% women, 18-30 years old) in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Overall, the prevalence of SCT was 6.8% (136/1995) in CARDIA, and over the course of 25 years, 46% (738/1590), 18% (288/1631), and 40% (645/1,611) of all participants developed hypertension, diabetes, and metabolic syndrome, respectively. Compared with participants without SCT, participants with SCT had similar baseline measures of fitness in cross-section, including exercise duration (535 vs 540 seconds; P = .62), estimated metabolic equivalent of tasks (METs; 11.6 vs 11.7; P = .80), maximum heart rate (174 vs 175 beats/min; P = .41), and heart rate at 2 minutes recovery (44 vs 43 beats/min; P = .28). In our secondary analysis, there was neither an association of SCT status with longitudinal changes in fitness nor an association with development of hypertension, diabetes, or metabolic syndrome after adjustment for sex, baseline age, body mass index, fitness, and physical activity. SCT is not associated with reduced fitness in this longitudinal study of young African American adults, suggesting the increased risk for exertion-related sudden death in SCT carriers is unlikely related to fitness. SCT status also is not an independent risk factor for developing hypertension, diabetes, or metabolic syndrome.

Validity of Cardiovascular Data From Electronic Sources: The Multi-Ethnic Study of Atherosclerosis and HealthLNK.

BACKGROUND: Understanding the validity of data from electronic data research networks is critical to national research initiatives and learning healthcare systems for cardiovascular care. Our goal was to evaluate the degree of agreement of electronic data research networks in comparison with data collected by standardized research approaches in a cohort study. METHODS: We linked individual-level data from MESA (Multi-Ethnic Study of Atherosclerosis), a community-based cohort, with HealthLNK, a 2006 to 2012 database of electronic health records from 6 Chicago health systems. To evaluate the correlation and agreement of blood pressure in HealthLNK in comparison with in-person MESA examinations, and body mass index in HealthLNK in comparison with MESA, we used Pearson correlation coefficients and Bland-Altman plots. Using diagnoses in MESA as the criterion standard, we calculated the performance of HealthLNK for hypertension, obesity, and diabetes mellitus diagnosis by using International Classification of Diseases, Ninth Revision codes and clinical data. We also identified potential myocardial infarctions, strokes, and heart failure events in HealthLNK and compared them with adjudicated events in MESA. RESULTS: Of the 1164 MESA participants enrolled at the Chicago Field Center, 802 (68.9%) participants had data in HealthLNK. The correlation was low for systolic blood pressure (0.39; P<0.0001). In comparison with MESA, HealthLNK overestimated systolic blood pressure by 6.5 mm Hg (95% confidence interval, 4.2-7.8). There was a high correlation between body mass index in MESA and HealthLNK (0.94; P<0.0001). HealthLNK underestimated body mass index by 0.3 kg/m2 (95% confidence interval, -0.4 to -0.1). With the use of International Classification of Diseases, Ninth Revision codes and clinical data, the sensitivity and specificity of HealthLNK queries for hypertension were 82.4% and 59.4%, for obesity were 73.0% and 89.8%, and for diabetes mellitus were 79.8% and 93.3%. In comparison with adjudicated cardiovascular events in MESA, the concordance rates for myocardial infarction, stroke, and heart failure were, respectively, 41.7% (5/12), 61.5% (8/13), and 62.5% (10/16). CONCLUSIONS: These findings illustrate the limitations and strengths of electronic data repositories in comparison with information collected by traditional standardized epidemiological approaches for the ascertainment of cardiovascular risk factors and events.

Racial Differences in Rates of Change of Childhood Body Mass Index and Blood Pressure Percentiles.

OBJECTIVE: To assess whether racial differences in rates of change in body mass index (BMI) and blood pressure (BP) percentiles emerge during distinct periods of childhood. STUDY DESIGN: In this retrospective cohort study, we included children aged 5-20 years who received regular outpatient care at a large academic medical center between January 1996 and April 2016. BMI was expressed as age- and sex-specific percentiles and BP as age-, sex-, and height-specific percentiles. Linear mixed models incorporating linear spline functions with 2 breakpoints at 9 and 12 years of age were used to estimate the changes in BMI and BP percentiles over time during age periods: <9, 9-<12, and >12 years of age. RESULTS: Among 5703 children (24.8% black, 10.1% Hispanic), Hispanic females had an increased rate of change in BMI percentile per year relative to white females during ages 5-9 years (+2.94%; 95% CI, 0.24-5.64; P = .033). Black and Hispanic males also had an increased rate of change in BMI percentile per year relative to white males that occurred from ages 5-9 (+2.35% [95% CI, 0.76-3.94; P = .004]; +2.63% [95% CI, 0.31-4.95; P = .026], respectively). There were no significant racial differences in the rate of change of BP percentiles, although black females had higher hypertension rates compared with white females (10.0% vs 5.7%; P < .001). CONCLUSIONS: Childhood patterns in BMI percentiles differ by race. Racial differences in rates of change in BMI percentile emerge early in childhood. Further study of early patterns could help to identify critical periods during childhood where disparities begin to emerge.

Prevalence and progression of subclinical atherosclerosis in younger adults with low short-term but high lifetime estimated risk for cardiovascular disease: the coronary artery risk development in young adults study and multi-ethnic study of atherosclerosis.

BACKGROUND: We hypothesized that individuals with low 10-year but high lifetime cardiovascular disease risk would have a greater burden of subclinical atherosclerosis than those with low 10-year but low lifetime risk. METHODS AND RESULTS: We included 2988 individuals < or = 50 years of age at examination year 15 from the Coronary Artery Risk Development in Young Adults (CARDIA) study and 1076 individuals < or = 50 of age at study entry from the Multi-Ethnic Study of Atherosclerosis (MESA). The 10-year risk and lifetime risk for cardiovascular disease were estimated for each participant, permitting stratification into 3 groups: low 10-year (<10%)/low lifetime (<39%) risk, low 10-year (<10%)/high lifetime risk (> or = 39%), and high 10-year risk (> or = 10%) or diagnosed diabetes mellitus. Baseline levels and change in levels of subclinical atherosclerosis (coronary artery calcium or carotid intima-media thickness) were compared across risk strata. Among participants with low 10-year risk (91% of all participants) in CARDIA, those with a high lifetime risk compared with low lifetime risk had significantly greater common (0.83 versus 0.80 mm in men; 0.79 versus 0.75 mm in women) and internal (0.85 versus 0.80 mm in men; 0.80 versus 0.76 mm in women) carotid intima-media thickness, higher coronary artery calcium prevalence (16.6% versus 9.8% in men; 7.1% versus 2.3% in women), and significantly greater incidence of coronary artery calcium progression (22.3% versus 15.4% in men; 8.7% versus 5.3% in women). Similar results were observed in MESA. CONCLUSIONS: Individuals with low 10-year but high lifetime risk have a greater subclinical disease burden and greater incidence of atherosclerotic progression compared with individuals with low 10-year and low lifetime risk, even at younger ages.

An association between clotting factor VII and carotid intima-media thickness: the CARDIA study.

BACKGROUND AND PURPOSE: To investigate associations of procoagulants (factor VII [FVII], FVIII, von Willebrand factor) with subclinical atherosclerosis, we examined participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: Clotting factor assays were performed in 1254 participants 23 to 37 years of age (baseline) and repeated at ages 38 through 50 (follow-up). Carotid intima-media thickness (IMT) was measured at follow-up. RESULTS: Baseline levels of procoagulants (%), mean (SD) were: FVII, 76 (18); FVIII, 102 (38); and von Willebrand factor, 108 (47). At follow-up, all had increased by 40% to 55%. After age adjustment, mean common carotid IMT increased from the lowest to the highest tertile of FVII in the total group (0.787 to 0.801; P=0.007), in whites (0.772 to 0.790; P=0.002), and in men (0.807 to 0.827; P=0.015). All associations were attenuated by multivariable adjustment. However, participants with FVII values in the highest tertile at one or both examinations, compared with those in the lowest tertile, had greater common carotid IMT after age and multivariable adjustment (0.806 versus 0.778; P<0.05). Baseline FVIII was associated with greater internal carotid IMT in the total group, in whites, and in women after age adjustment but not multivariable adjustment. No associations were seen for von Willebrand factor. CONCLUSIONS: FVII is associated with common carotid IMT in young adults, but the strength of the association is modified by other cardiovascular disease risk factors, such as body mass index. FVIII is associated with internal carotid IMT only in age-adjusted analyses, and no associations were observed for von Willebrand factor.

Race and ethnic variation in excessive daytime sleepiness: the multi-ethnic study of atherosclerosis.

This cross-sectional study utilized data from the Multi-Ethnic Study of Atherosclerosis (MESA). The sample included 5,173 older adults (mean age = 66.4 years) recruited from 6 field centers in the United States. Excessive daytime sleepiness (EDS) was evaluated using two measures: self-report of feeling excessively sleepy ≤ 5 days per month and the Epworth Sleepiness Scale (ESS) > 12. White participants were more likely than other groups to report EDS ≤ 5 days per month. After controlling for covariates, African American and Hispanic participants remained less likely to report EDS ≤ 5 days per month. African Americans were more likely to score > 12 on the ESS than White participants. Odds ESS > 12 in African American participants were attenuated but remained significant after controlling for covariates. Results indicate measurement of race/ethnic differences in EDS may result in conflicting estimates of race/ethnic variation. Furthermore, attenuation of differences in ESS < 12 suggests this measure has a stronger association with current health.

Coronary Artery Calcium Progression Among the US and Japanese Men.

Background The risk of coronary heart disease remains low in Japan, although distributions of several coronary risk factors have become comparable with those in the United States. We prospectively compared coronary atherosclerosis burden, measured with coronary artery calcium (CAC) progression, between men in the 2 countries. Methods In 2 population-based samples of 1712 US White, Black, Hispanic, Chinese men (baseline, 2000-2002) and 697 Japanese men in Japan (2006-2008) aged 45-74 years without clinical cardiovascular disease, we quantified CAC progression by serial computed tomography with medians of 3.4 and 5.2 years between scans, respectively. Results Among White, Black, Hispanic, Chinese, and Japanese men free of baseline CAC, CAC incidence was observed in 35.2%, 26.9%, 29.2%, 18.9%, and 29.2%, respectively. After adjustment for times between scans, demographics, behaviors, coronary risk factors, and their changes between scans, White men had significantly higher CAC incidence than Japanese men (relative risk, 1.68; 95% CI, 1.13-2.50). Among those with detectable baseline CAC, after similar adjustments, all the US race/ethnic groups had significantly greater annual changes in CAC score (mean [95% CI]: 39.4 [35.2-43.6] for White, 26.9 [21.4-32.4] for Black, 30.6 [24.7-36.5] for Hispanic, and 30.2 [22.6-37.8] for Chinese men) than Japanese men (15.9 [10.1-21.8]). Conclusions We found a higher CAC incidence among US White men and greater increases in existing CAC among all the US race/ethnic groups than among Japanese men in Japan. These differences persisted despite adjustment for differences in coronary risk factors.

Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood. Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population. Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017. Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6. Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF. Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF. Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

Predictors and outcomes of heart failure with mid-range ejection fraction.

AIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community. METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78). CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

Does lower-extremity arterial disease predict future falling among older men and women?

The purpose of this study was to determine whether lower-extremity peripheral arterial disease (PAD) is an independent risk factor for falls among older persons. Men and women 55 years old and older participated. Subjects with PAD (n = 86) were identified from a noninvasive vascular laboratory and a general medicine practice. Randomly selected controls without PAD (n = 82) were identified from the same medicine practice. Subjects were categorized into PAD (ankle brachial index, <0.90) or controls (ankle brachial index, 0.90 to 1.50). Subjects underwent a comprehensive baseline evaluation for fall risk. Prospective fall data were obtained using monthly mail-in postcards and structured telephone interviews over a mean follow-up of 9.6 +/- 2.9 months. Two independent investigators blinded to PAD status reviewed each fall incident for its eligibility. A total of 37 subjects (22%) had at least 1 eligible fall. In an unadjusted Cox regression model, the relative risk of falling was lower among PAD subjects than among controls (relative risk, 0.54; 95% confidence interval, 0.28 to 1.06). After adjustment for age, gender, history of frequent falls in the last year, number of comorbidities, and balance and gait abnormalities, PAD was significantly associated with a lower risk of falling (relative risk, 0.43; 95% confidence interval, 0.21 to 0.87) as compared with controls. PAD is associated with a lower risk of falling as compared with persons without PAD among older men and women. Future study is needed to determine whether reduced levels of physical activity among patients with PAD account for the lower rate of falling observed here.

Gravidity is not associated with telomere length in a biracial cohort of middle-aged women: The Coronary Artery Risk Development in Young Adults (CARDIA) study.

OBJECTIVE: Having experienced 2-3 births is associated with reduced mortality versus women with <2 or ≥4 births. The effect of 2-3 births on lifespan may be associated with delayed cellular aging. We hypothesized telomere length, a marker of cellular aging, would be longer in women who had 2-3 pregnancies. METHODS: Leukocyte telomere length was measured using quantitative real-time polymerase chain reaction in 620 women in CARDIA at the year 15 and 20 exams, expressed as the ratio of telomere repeat copy number to single-copy gene copy number (T/S). Number of pregnancies at the time of telomere length measurement was obtained (mean age = 41±0.1 years, average gravidity = 2.64±0.1 pregnancies). Participants were divided into 4 groups by number of pregnancies: 0, 1, 2-3, and ≥4, to test for differences in telomere length by gravidity group. RESULTS: The mean and SD for telomere length was 0.98 ± 0.20 T/S in the whole cohort. There were no differences in mean telomere length between groups; 0.98±0.02 T/S in women with 0 pregnancies, 1.01±0.02 T/S in women with 1 pregnancy, 0.97±0.01 T/S in women with 2-3 pregnancies, and 0.99±0.02 T/S in women with ≥4 pregnancies (p = 0.51). We defined high-risk (shorter) telomere length as ≤25th percentile, and low-risk (longer) telomere length as ≥75 percentile. There were no differences in the prevalence of high-risk or low-risk telomere length between gravidity groups. CONCLUSIONS: Gravidity was not associated with telomere length in early middle age; the protective association of 2-3 births may act through other mechanisms.

Discordance Between Apolipoprotein B and LDL-Cholesterol in Young Adults Predicts Coronary Artery Calcification: The CARDIA Study.

BACKGROUND: High levels of apolipoprotein B (apoB) have been shown to predict atherosclerotic cardiovascular disease (CVD) in adults even in the context of low levels of low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C). OBJECTIVES: This study aimed to quantify the associations between apoB and the discordance between apoB and LDL-C or non-HDL-C in young adults and measured coronary artery calcium (CAC) in midlife. METHODS: Data were derived from a multicenter cohort study of young adults recruited at ages 18 to 30 years. All participants with complete baseline CVD risk factor data, including apoB and year 25 (Y25) CAC score, were entered into this study. Presence of CAC was defined as having a positive, nonzero Agatston score as determined by computed tomography. Baseline apoB values were divided into tertiles of 4 mutually exclusive concordant/discordant groups, based on median apoB and LDL-C or non-HDL-C. RESULTS: Analysis included 2,794 participants (mean age: 25 ± 3.6 years; body mass index: 24.5 ± 5 kg/m(2); and 44.4% male). Mean lipid values were as follows: total cholesterol: 177.3 ± 33.1 mg/dl; LDL-C: 109.9 ± 31.1 mg/dl; non-HDL-C: 124.0 ± 33.5 mg/dl; HDL-C: 53 ± 12.8 mg/dl; and apoB: 90.7 ± 24 mg/dl; median triglycerides were 61 mg/dl. Compared with the lowest apoB tertile, higher odds of developing Y25 CAC were seen in the middle (odds ratio [OR]: 1.53) and high (OR: 2.28) tertiles based on traditional risk factor-adjusted models. High apoB and low LDL-C or non-HDL-C discordance was also associated with Y25 CAC in adjusted models (OR: 1.55 and OR: 1.45, respectively). CONCLUSIONS: These data suggest a dose-response association between apoB in young adults and the presence of midlife CAC independent of baseline traditional CVD risk factors.

Predicting Heart Failure With Preserved and Reduced Ejection Fraction: The International Collaboration on Heart Failure Subtypes.

BACKGROUND: Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF). METHODS AND RESULTS: Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95% CI, 0.77-0.82 and external: 0.76; 95% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80-0.84) and validation samples (internal: 0.80; 95% CI, 0.78-0.83 and external: 0.76; 95% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison ≤0.02). CONCLUSIONS: We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.

Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease.

BACKGROUND: We determined whether statin use (versus nonuse) is associated with superior lower-extremity functioning independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease. METHODS AND RESULTS: Participants included 392 men and women with an ankle brachial index (ABI) <0.90 and 249 with ABI 0.90 to 1.50. Functional outcomes included 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ABI, comorbidities, education level, medical insurance status, cholesterol, and other confounders, participants taking statins had better 6-minute walk performance (1276 versus 1218 feet, P=0.045), faster walking velocity (0.93 versus 0.89 m/s, P=0.006), and a higher summary performance score (10.2 versus 9.4, P<0.001) than participants not taking statins. Positive associations were attenuated slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity and the summary performance score. We did not find significant associations between lower-extremity functioning and aspirin, ACE inhibitors, vasodilators, or beta-blockers. CONCLUSIONS: Statin use is associated with superior leg functioning compared with no statin use, independent of cholesterol levels and other potential confounders. These data suggest that non-cholesterol-lowering properties of statins may favorably influence functioning in persons with and without peripheral arterial disease.

D-dimer, inflammatory markers, and lower extremity functioning in patients with and without peripheral arterial disease.

BACKGROUND: We determined whether higher levels of D-dimer, C-reactive protein (CRP), fibrinogen, and serum amyloid A are associated independently with functional impairment in patients with and without peripheral arterial disease (PAD). METHODS AND RESULTS: Participants were 370 men and women with PAD (ankle brachial index <0.90) and 231 without PAD. Functional outcomes were 6-minute walk distance and 4-meter walking velocity. A summary performance score combined performance in walking speed, standing balance, and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 (12=best). Adjusting for age, sex, ankle brachial index, comorbidities, and other potential mediators and confounders, D-dimer levels were associated independently and inversely with performance on all 3 functional measures in the entire cohort and among patients with and without PAD, respectively. Adjusting for known and potential confounders, CRP levels were associated independently with 6-minute walk distance and the summary performance score among participants with PAD. No significant associations were observed between CRP and the functional measures among participants without PAD. Fibrinogen and SAA levels were not associated independently with the functional measures. CONCLUSIONS: Higher D-dimer levels are associated with poorer functioning among individuals with and without PAD. Higher CRP levels were associated with poorer 6-minute walk performance and a lower summary performance score among participants with PAD but not among those without PAD. Additional study is needed to determine whether D-dimer and CRP are involved in the pathophysiology of functional impairment or whether they are simply sensitive markers of the extent of systemic atherosclerosis.

The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study.

BACKGROUND: The ankle brachial index (ABI) is a noninvasive, reliable measure of lower-extremity ischemia. However, the relationship between ABI and lower-extremity function has not been well studied. OBJECTIVE: To describe the association between the ABI and lower-extremity function. DESIGN: Cross-sectional study. SETTING: 3 academic medical centers in the Chicago area. PARTICIPANTS: 740 men and women (460 with peripheral arterial disease). MEASUREMENTS: Accelerometer-measured physical activity over 7 days, 6-minute walk, 4-m walking velocity, standing balance, and ABI. RESULTS: 33% of participants with peripheral arterial disease had intermittent claudication. Fewer than 40% of participants with an ABI less than 0.40 walked continuously for 6 minutes compared with more than 95% of participants with an ABI between 1.00 and 1.50. Compared with an ABI of 1.10 to 1.50, an ABI less than 0.50 was associated with shorter distance walked in 6 minutes (beta-regression coefficient = -523 ft [95% CI, -592 to -454 ft]; P < 0.001), less physical activity (beta = -514.8 activity units [CI, -657 to -373 activity units]; P < 0.001), slower 4-m walking velocity (beta = -0.21 m/s [CI, -0.27 to -0.15 m/s]; P < 0.001), and less likelihood of maintaining a tandem stand for 10 seconds (odds ratio, 0.37 [CI, 0.18 to 0.76]; P = 0.007), after adjustment for typical confounders. Associations between ABI and function were stronger than associations between leg symptoms and function. CONCLUSIONS: The ABI, a noninvasive test that can be performed in a medical office, is more closely associated with leg function in persons with peripheral arterial disease than is intermittent claudication or other leg symptoms. These data support the use of the ABI to identify abnormal lower-extremity function.

Peripheral artery disease, diabetes, and reduced lower extremity functioning.

OBJECTIVE: To characterize lower extremity function and dysfunction in peripheral artery disease (PAD) patients with and without diabetes. RESEARCH DESIGN AND METHODS: In this cross-sectional study, 460 men and women with PAD (147 with diabetes) were recruited from three academic medical centers. Assessments included ankle brachial index (ABI), neuropathy score, 6-min walk distance, 4-m walking velocity, Walking Impairment Questionnaire (0-100 scale, 100 = best), and summary performance score (SPS) (0-12 scale, 12 = best). RESULTS: The mean ABI was similar in PAD patients with and without diabetes. PAD patients with diabetes were younger, had a higher BMI, had a worse neuropathy score, and had a greater number of cardiovascular comorbidities compared with those without diabetes. Participants with diabetes were less likely to report classical symptoms of intermittent claudication and more likely to report exertional leg pain, which sometimes started at rest. After adjusting for age, those with diabetes had a shorter mean 6-min walk distance (1,040 vs. 1,168 feet, P < 0.001), slower fast-pace 4-m walk velocity (0.83 vs. 0.90 m/sec, P < 0.001), and a lower SPS (7.3 vs. 8.6, P < 0.001) than those without diabetes. Patients with diet-controlled diabetes performed better than those on diabetes medications. Differences in lower extremity functioning between patients with and without diabetes were largely attenuated but not abolished for SPS and fast-pace 4-m walk velocity after adjustment for type of exertional leg pain, neuropathy score, and number of cardiovascular comorbidities. CONCLUSIONS: Subjects with PAD and diabetes have poorer lower extremity function than those with PAD alone. This difference in functioning appears to be largely explained by diabetes-associated neuropathy, differences in exertional leg symptoms, and greater cardiovascular disease in patients with diabetes.

Metabolic syndrome and incident peripheral artery disease - the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: We evaluated whether metabolic syndrome (MetS) is associated with an increased incidence of lower extremity peripheral artery disease (PAD) in community dwelling people free of clinical cardiovascular disease at baseline. We assessed whether higher levels of inflammatory biomarkers may mediate the association of MetS with incident PAD. METHODS: MetS was defined at baseline as the presence of three or more of the following components: elevated waist circumference, triglycerides ≥150 mg/dL, reduced high-density lipoprotein (HDL) cholesterol, blood pressure ≥130/85 mm Hg or taking blood pressure medication, and fasting glucose ≥100 mg/dL and <126 mg/dL. People with diabetes were excluded. Incident New PAD was defined among people with a normal ankle brachial index (ABI) at baseline (i.e. baseline ABI of 0.90 to 1.40) and consisted of one of the following outcomes during 3-year follow-up: ABI decline to < 0.90 combined with a decline ≥0.15 or medical record confirmed PAD outcome. Multivariable Poisson regression was used to estimate the association between MetS and incident PAD. RESULTS: Among 4817 participants without PAD at baseline, 1382 (29%) had MetS. Adjusting for age, sex, race, smoking, physical activity, low-density lipoprotein cholesterol, baseline ABI, and other confounders, 23/1382 (1.7%) people with MetS developed PAD vs. 30/3435 (0.87%) people without MetS (risk ratio = 1.78 [95% Confidence Interval (CI), 1.04 to 2.82], P = 0.031). Adjusting for C-reactive protein, fibrinogen, or interleukin-6 did not attenuate this association. CONCLUSION: People free of clinical cardiovascular disease with MetS are at increased risk for PAD. Our findings suggest that this association is not mediated by inflammation.

Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index.

Associations between hemostatic and inflammatory markers relative to the ankle brachial index (ABI), an indicator of the presence and severity of peripheral arterial disease (PAD), are not fully understood. We studied relations among selected hemostatic factors, inflammatory markers, and the ankle brachial index (ABI) in patients with and without peripheral arterial disease (PAD). Participants were 370 men and women with ABI <0.90 and 231 patients with ABI 0.90 to 1.50 identified from noninvasive vascular laboratories and general medicine practice. Blood factors were D-dimer, prothrombin 1.2, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), and inflammatory markers (high-sensitivity C-reactive protein [CRP], fibrinogen, and serum amyloid A [SAA]). Among patients without a history of cardiac or cerebrovascular disease, the ABI was significantly inversely associated with log D-dimer (p <0.001), log prothrombin 1.2 (p = 0.001), log CRP (p <0.001), and log fibrinogen (p = 0.005) in unadjusted analyses. In multivariable regression analyses adjusting for all blood factors as well as potential confounders, D-dimer was associated independently with ABI in participants with a history of cardiac or cerebrovascular disease (p = 0.003) and in participants without a history of cardiac or cerebrovascular disease (p = 0.017). In these analyses, CRP was associated independently with ABI among participants with a history of cardiac or cerebrovascular disease (p = 0.026). CRP was not associated independently with ABI in participants without a history of cardiac or cerebrovascular disease. We conclude that D-dimer levels may be more sensitive than other blood markers for measuring the extent of atherosclerosis in lower extremity arteries.