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Original Research
Jade S. Hiramoto , Ronit Katz , Steven Weisman , Michael Conte
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Journal of the American Heart Association. 2014; 3: e000651
Jade S. Hiramoto
Division of Vascular and Endovascular Surgery, UCSF, San Francisco, CA (J.S.H., M.C.)
Ronit Katz
Department of Biostatistics, University of Washington, Seattle, WA (R.K.)
Steven Weisman
Innovative Science Solutions, Morristown, NJ (S.W.)
Michael Conte
Division of Vascular and Endovascular Surgery, UCSF, San Francisco, CA (J.S.H., M.C.)

Background Women have high rates of peripheral artery disease (PAD) despite fewer cardiovascular disease (CVD) risk factors, compared to men. We sought to determine the gender-specific prevalence of low ankle brachial index (ABI) and the relationship to C-reactive protein (CRP) levels and CVD risk factors in the Life Line Screening population.

Methods and Results Between April 2005 and August 2011, 133 750 women and 71 996 men had ABI and CRP measured at a Life Line Screening Center. Women were slightly older than men, whereas men were more likely to be current smokers, have diabetes mellitus (DM), and coronary artery disease (CAD) (<0.001 for each). Women were more likely to have ABI≤1.0, compared to men (26.6% versus 14.4%, respectively; <0.001), as well as ABI≤0.9 (4.1% women versus 2.6% men; <0.001). Women had higher median CRP levels (1.94 mg/L; interquartile range [IQR], 0.89, 4.44 mg/L), compared to men (1.35 mg/L; IQR, 0.73, 2.80 mg/L; <0.001). Men and women shared similar risk factors for ABI≤0.9, including older age, black race, smoking, DM, hypertension, hypercholesterolemia, CAD, and elevated CRP levels. In an adjusted model, there were significant interactions between gender and age (<0.001), CRP (<0.001), CAD (=0.03), and DM (=0.06) with ABI as the outcome. The associations between age, CRP, CAD, and DM with ABI≤0.9 were stronger in men than in women.

Conclusions Women participating in the Life Line Screening had higher CRP levels and a higher prevalence of PAD, compared to men. Neither higher CRP levels nor conventional CVD risk factors explained the excess prevalence of PAD in women.

Introduction

Peripheral artery disease (PAD) affects millions of people in the United States and is now recognized as a global pandemic, affecting over 202 million people worldwide. Not only is PAD a major cause of functional impairment and limb loss, but it is also strongly associated with an increased risk of myocardial infarction (MI), stroke, and death. Although not widely recognized by the public or by clinicians, the prevalence and burden of PAD is equal, if not higher, in women compared to men. In addition, women with PAD experience faster functional decline and have poorer outcomes after lower extremity revascularization procedures, compared to men. Because women have a longer life expectancy than men, women will be even more disproportionately affected with PAD in the future as the population ages.

Traditional cardiovascular disease (CVD) risk factors are strongly associated with the development and progression of PAD, and the prevailing paradigm is that the risk factors for PAD are the same for men as they are for women. However, traditional CVD risk factors are more prevalent in men with PAD compared to women with PAD, suggesting that alternative risk factors for PAD may affect women disproportionately. Inflammation is a strong risk factor for PAD, and inflammatory profiles appear to be different in women and men. C-reactive protein (CRP) is an acute-phase protein that is elevated in individuals with PAD, and higher CRP levels are associated with both risk and progression of PAD. In addition, several population studies have demonstrated higher CRP levels in women compared to men. It is not known whether gender differences in CRP levels explain observed differences in the prevalence of PAD in women compared to men.

Although women experience PAD and PAD-related consequences at rates that are at least as high as those observed in men, PAD continues to be understudied in women. Women are under-represented in contemporary PAD studies, contributing to significant gaps in knowledge about PAD risk factors in women. The Life Line Screening (Independence, OH) data set contains extensive records of participants who completed detailed medical questionnaires and had measurements of both ankle brachial index (ABI) and CRP levels. This population is also unique in that women are over-represented (approximately 2:1) compared to men. The aim of this study is to determine the prevalence of abnormal ABI levels in this voluntary screening population of women and men and to compare the gender-specific associations of CVD risk factors and CRP with ABI levels.

Life Line Screening Background

The Life Line Screening program began in 1993 and was designed to provide community-based screening services to help make people aware of unrecognized health problems. The study cohort consists of self-referred individuals who paid for vascular screening tests, which were performed at over 20 000 sites across the United States. Each individual completed a detailed questionnaire before undergoing the screening procedure, which included information on demographics, smoking, CVD risk factors, and medical comorbidities. No information was collected on socioeconomic factors (such as education level or yearly income) or specific names of medications (ie, statin use for hypercholesterolemia). Life Line Screening utilizes laboratories that are certified by the Clinical Laboratory Improvement Amendments by the U.S. government's Division of Laboratory Services. All Life Line Screening sites across the United States utilize identical procedural protocols. Institutional Review Board approval was not required for this study because this research involved unidentifiable, coded data without access to a key to decipher the code.

Participants

Because the purpose of this study was to determine the gender-specific associations between CVD risk factors and CRP with ABI, only participants with measurement of both ABI and CRP, as well as complete information on 3 specific CVD risk factors (hypercholesterolemia, hypertension, and smoking) were included in this study. Between April 2005 and August 2011, 133 750 women and 71 996 men had measurement of ABI and CRP performed at a Life Line Screening center in the United States and had no missing information on age, gender, race, hypercholesterolemia, hypertension, and smoking, which was extracted from detailed questionnaires completed at the time of their screening. For those who underwent multiple screenings, only the first screening during this time period was used. Any participant who reported a previous procedure to treat lower-extremity PAD was excluded from the analysis.

Ankle Brachial Index Measurement

Blood pressures were measured using standard blood pressure cuffs, an aneroid sphygmomanometer, and an 8-MHz Doppler ultrasound probe. Systolic pressures were measured in both arms (bilateral brachial arteries) and both ankles (bilateral posterior tibial [PT] and dorsalis pedis [DP] arteries). The left ABI was calculated by dividing the highest of the left PT or DP systolic pressure by the highest of the brachial pressures. Similarly, the right ABI was calculated by dividing the highest of the right PT or DP systolic pressure by the highest of the brachial pressures. The lower value between the 2 legs was used in the analysis. Participants who could not have the lower-extremity arteries occluded before 300 mm Hg were recorded as having noncompressible arteries and included in the ABI≥1.30 category.

Measurement of CRP, Glucose, and Lipids

CRP, glucose, total cholesterol, high-density lipoprotein (HDL), and triglycerides (TGs) were measured using the Cholestech LDX system ( http://www.cholestech.com ). CRP was measured using reflectance photometry, with a measurement range of 0.3 to 10 mg/L. Total cholesterol and HDL cholesterol were measured by enzymatic methods. TGs were measured by an enzymatic method based on the hydrolysis of TGs by lipase to glycerol and free fatty acids. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation (LDL-cholesterol=Total cholesterol−HDL cholesterol−TGs). Glucose was measured by an enzymatic method that uses glucose oxidase to catalyze the oxidation of glucose to gluconolactone and hydrogen peroxide. The measurement ranges (mg/dL) were: total cholesterol, 100 to 500; HDL cholesterol, 15 to 100; TGs, 45 to 650; and glucose, 50 to 500.

Medical Comorbidities

A diagnosis of hypertension was based on either a self-reported diagnosis of hypertension or the use of antihypertensive medications. Diabetes mellitus (DM) was defined as self-report of DM or use of DM medications. Hypercholesterolemia was defined as a self-report of hypercholesterolemia or use of lipid/cholesterol-lowering medications. Participants reported being never, former, or current smokers. A diagnosis of coronary artery disease (CAD) was based on the participant answering yes to a wide range of questions, such as: “Have you ever had a heart attack?”; “Have you ever had angina, a heart attack, angioplasty, or bypass surgery?”; and “Do you have coronary artery disease?”

Statistical Analysis

Baseline characteristics of male and female participants were evaluated for statistical significance using a -test, chi-square test, or Wilcoxon's signed-rank test, where appropriate. Demographic characteristics of male and female participants were also evaluated across different categories of ABI (≤0.9, 0.91 to 1.0, 1.01 to 1.29, and ≥1.3). We used a multinomial logistic regression to model the nominal outcome variable (ABI categories, where the referent category of the outcome included ABI values between 1.01 and 1.29). The log odds of the outcomes were modeled as a linear combination of the predictor variables. Gender interactions for risk factors and ABI were tested. Associations of ABI categories with risk factors were evaluated separately for men and women in fully adjusted (age, race, hypertension, smoking, CRP, prevalent CAD, cholesterol/HDL ratio, and DM) models. All analyses were performed using S-Plus (release 8.0; Insightful Inc, Seattle, WA) and SPSS statistical software (release 16.0.1; SPSS, Inc., Chicago, IL).

The majority of the participants were white (91%), and the women were slightly older than the men in this cohort (mean age, 62.1 versus 60.9 years, respectively; P <0.001). Men were more likely than women to have DM, higher glucose levels, a history of CAD, and to be current or former smokers ( P <0.001 for each) (Table 1 ). Although men were more likely than women to have a history of hypercholesterolemia, women had higher total cholesterol levels (207±50 versus 192±46 mg/dL; P <0.001). Overall, women had a higher median CRP level (1.94 mg/L; interquartile range [IQR], 0.89, 4.44 mg/L), compared to men (1.35 mg/L; IQR, 0.73, 2.80 mg/L; P <0.001), and had higher CRP values within each subgroup of ABI categories.

Our hunt for inner work life triggers led us to the progress principle. When we compared our research participants’ best and worst days (based on their overall mood, specific emotions, and motivation levels), we found that the most common event triggering a “best day” was any progress in the work by the individual or the team. The most common event triggering a “worst day” was a setback.

Consider, for example, how progress relates to one component of inner work life: overall mood ratings. Steps forward occurred on 76% of people’s best-mood days. By contrast, setbacks occurred on only 13% of those days. (See the exhibit “What Happens on a Good Day?”)

Progress—even a small step forward—occurs on many of the days people report being in a good mood.

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Two other types of inner work life triggers also occur frequently on best days: Catalysts , actions that directly support work, including help from a person or group, and nourishers , events such as shows of respect and words of encouragement. Each has an opposite: Inhibitors , actions that fail to support or actively hinder work, and toxins , discouraging or undermining events. Whereas catalysts and inhibitors are directed at the project, nourishers and toxins are directed at the person. Like setbacks, inhibitors and toxins are rare on days of great inner work life.

Events on worst-mood days are nearly the mirror image of those on best-mood days (see the exhibit “What Happens on a Bad Day?”). Here, setbacks predominated, occurring on 67% of those days; progress occurred on only 25% of them. Inhibitors and toxins also marked many worst-mood days, and catalysts and nourishers were rare.

Events on bad days—setbacks and other hindrances—are nearly the mirror image of those on good days.

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Read more

This is the progress principle made visible: If a person is motivated and happy at the end of the workday, it’s a good bet that he or she made some progress. If the person drags out of the office disengaged and joyless, a setback is most likely to blame.

When we analyzed all 12,000 daily surveys filled out by our participants, we discovered that progress and setbacks influence all three aspects of inner work life. On days when they made progress, our participants reported more positive emotions . They not only were in a more upbeat mood in general but also expressed more joy, warmth, and pride. When they suffered setbacks, they experienced more frustration, fear, and sadness.

Motivations were also affected: On progress days, people were more intrinsically motivated—by interest in and enjoyment of the work itself. On setback days, they were not only less intrinsically motivated but also less extrinsically motivated by recognition. Apparently, setbacks can lead a person to feel generally apathetic and disinclined to do the work at all.

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