Skeletal muscle expression of adipose-specific phospholipase in peripheral artery disease.

Flow-limiting atherosclerotic lesions of arteries supplying the limbs are a cause of symptoms in patients with peripheral artery disease (PAD). Musculoskeletal metabolic factors also contribute to the pathophysiology of claudication, which is manifest as leg discomfort that impairs walking capacity. Accordingly, we conducted a case-control study to determine whether skeletal muscle metabolic gene expression is altered in PAD. Calf skeletal muscle gene expression of patients with PAD and healthy subjects was analyzed using microarrays. The top-ranking gene differentially expressed between PAD and controls (FDR < 0.001) was PLA2G16, which encodes adipose-specific phospholipase A2 (AdPLA) and is implicated in the maintenance of insulin sensitivity and regulation of lipid metabolism. Differential expression was confirmed by qRT-PCR; PLA2G16 was downregulated by 68% in patients with PAD (p < 0.001). Expression of Pla2g16 was then measured in control (db/+) and diabetic (db/db) mice that underwent unilateral femoral artery ligation. There was significantly reduced expression of Pla2g16 in the ischemic leg of both control and diabetic mice (by 51%), with significantly greater magnitude of reduction in the diabetic mice (by 79%). We conclude that AdPLA is downregulated in humans with PAD and in mice with hindlimb ischemia. Reduced AdPLA may contribute to impaired walking capacity in patients with PAD via its effects on skeletal muscle metabolism. Further studies are needed to fully characterize the role of AdPLA in PAD and to investigate its potential as a therapeutic target for alleviating symptoms of claudication.

Clinical and Workplace Outcomes From a Virtually Delivered Cognitive Behavioral Therapy Program for Pain.

OBJECTIVES: To evaluate clinical and workplace outcomes from an evidence-based virtual behavioral therapy program for individuals with pain and behavioral health issues. METHODS: This was a retrospective de-identified data analysis among a cohort of 1,086 participants enrolled in a standardized, evidence-based telebehavioral therapy program between September 1, 2016, and August 31, 2017 (mean age 53 ± 11.5 years; 29% male). The program was delivered over approximately 8 weeks by licensed therapists and behavior coaches by telephone or video, and tailored to the pain management and behavioral health goals of each participant. Structured measurements were documented in the electronic clinical record, including demographics, comorbidities, pain severity (Pain Intensity, Enjoyment of Life, General Activity tool), behavioral health symptoms (Depression, Anxiety and Stress Scale short form), and productivity (Work Productivity and Activity Impairment survey). RESULTS: At baseline, participants had high average pain severity (5.8/10 points), high frequencies of behavioral health symptoms (68%), and activity impairment (90%); absenteeism (34%) and presenteeism (75%) were observed among employed individuals. Pain severity and pain interference improved by 17% and 27%, respectively, over 8 weeks (P < 0.0001). Reductions in depression, anxiety, and stress symptoms were significant and associated with reductions in pain interference (P < 0.0001). Absenteeism, presenteeism, and activity impairment ratings each improved by more than 25% (P < 0.0001). DISCUSSION: Participants in a virtually delivered behavioral therapy program for pain experienced significant improvements in pain intensity, pain interference, behavioral health symptoms, and work productivity.

A Nationally Scaled Telebehavioral Health Program for Chronic Pain: Characteristics, Goals, and Psychological Outcomes.

BACKGROUND: Millions of U.S. adults suffer from chronic pain with a high prevalence of comorbid mental health issues. Telehealth-delivered behavioral therapy for chronic pain has been evaluated in the research setting. The purpose of this study was 1) to describe a nationally scaled, standardized, telebehavioral therapy program for patients with chronic pain and behavioral comorbidities, and 2) evaluate characteristics, goals, and psychosocial outcomes among program participants. MATERIALS AND METHODS: This was mixed-methods retrospective cohort analysis among consecutive program graduates (mean age 53y; 24% male). The 8-week program was delivered by a licensed therapist and a behavior coach through telephone/secure video and tailored to each participant's behavioral health needs and goals. Participant chief complaints, behavioral goals, and mood triggers were abstracted by deidentified clinical record review using structured qualitative research methods. Depression, anxiety, and stress symptom data were collected at baseline and program graduation using the validated Depression Anxiety Stress Scales 21. RESULTS: Back pain (42%) and hip/leg/knee pain (28%) comprised the most common chief complaints. Pain management (44%) and weight loss (43%) were the most frequently cited goals. At baseline, approximately half of participants had elevated depression (59%), anxiety (54%), and/or stress (48%) scores. Triggers for depressed, anxious, or stressed mood included severe pain (47%), health concerns (46%), and interpersonal relationship challenges (45%). At graduation, significant improvement in median depression (-54%), anxiety (-50%), and stress (-33%) symptom scores was observed among those with non-normal baseline values (p < 0.001); degree of improvement did not vary by participant age or sex. CONCLUSIONS: Participants in a nationally scaled telebehavioral health program for chronic pain experienced significant improvement in depression, anxiety, and stress symptoms and shared several complaints, goals, and mood triggers.

A Tele-Behavioral Health Intervention to Reduce Depression, Anxiety, and Stress and Improve Diabetes Self-Management.

BACKGROUND: Depression is prevalent among individuals with diabetes and associated with suboptimal self-management. Little is known about the feasibility and potential impact of tele-behavioral therapy to improve depressive symptoms and self-management among diabetes patients. METHODS: This was a retrospective observational study of consecutive graduates enrolled in a national 8-week diabetes behavioral telehealth program between August 1, 2014, and January 31, 2015 (N = 466; mean age 56.8 ± 5.0 years; 56% female). Participant characteristics (demographics, comorbidities) were obtained by standardized questionnaire. Depression, anxiety, and stress symptoms (DASS; validated Depression Anxiety and Stress Scale 21 survey), and glucose self-testing frequency and values (point-of-care monitor) were measured at program start and completion. Changes in DASS severity and glucose self-testing frequency were assessed by chi-square tests. Changes in DASS and blood glucose levels were evaluated by paired t-tests. RESULTS: At baseline, approximately one in three participants had elevated depression (32%), anxiety (33%), or stress (31%) scores. Significant reductions in average DASS, depression (-8.8), anxiety (-6.9), and stress (-9.9), scores were observed at graduation among those with elevated baseline scores (p < 0.0001); most (≥80%) improved to less severe depression, anxiety, or stress categories. Improved glucose self-testing frequency (69% vs. 60% tested ≥once per week; p = 0.0005) and significant reductions in mean morning glucose levels (-12.3 mg/dL; p = 0.0002) were observed from baseline to graduation. Participants with normal versus non-normal depression scores were more likely to have lower (

An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells.

Complex organisms may coordinate molecular responses to hypoxia by specialized avenues of communication across multiple tissues, but these mechanisms are poorly understood. Plasma-based, extracellular microRNAs have been described, yet their regulation and biological functions in hypoxia remain enigmatic. We found a unique pattern of release of the hypoxia-inducible microRNA-210 (miR-210) from hypoxic and reoxygenated cells. This microRNA is also elevated in human plasma in physiologic and pathologic conditions of altered oxygen demand and delivery. Released miR-210 can be delivered to recipient cells, and the suppression of its direct target ISCU and mitochondrial metabolism is primarily evident in hypoxia. To regulate these hypoxia-specific actions, prolyl-hydroxylation of Argonaute 2 acts as a molecular switch that reciprocally modulates miR-210 release and intracellular activity in source cells as well as regulates intracellular activity in recipient cells after miR-210 delivery. Therefore, Argonaute 2-dependent control of released miR-210 represents a unique communication system that integrates the hypoxic response across anatomically distinct cells, preventing unnecessary activity of delivered miR-210 in normoxia while still preparing recipient tissues for incipient hypoxic stress and accelerating adaptation.

Association of monocyte tumor necrosis factor α expression and serum inflammatory biomarkers with walking impairment in peripheral artery disease.

OBJECTIVE: Inflammation contributes to the development of peripheral artery disease (PAD) and may contribute to intermittent claudication by adversely affecting vascular and skeletal muscle function. We explored the association of inflammation to maximal walking time (MWT) in patients with claudication. METHODS: Circulating inflammatory biomarkers, including tumor necrosis factor α (TNF-α), C-reactive protein (CRP), interleukin-6 (IL-6), and soluble intercellular adhesion molecule 1 (sICAM), were measured in 75 subjects with intermittent claudication as well as in 43 healthy subjects. Real-time polymerase chain reaction was used to quantify mRNA expression of TNF-α, IL-6, interferon-γ, and CD36 from peripheral blood monocytes. Treadmill testing was performed in PAD subjects to assess MWT. RESULTS: Compared with healthy subjects, PAD subjects had higher levels of circulating TNF-α (P < .0001), CRP (P = .003), sICAM (P < .0001), and IL-6 (P < .0001). Expression of both IL-6 (P = .024) and CD36 (P = .018) was greater in PAD subjects than in healthy subjects. Among subjects with PAD, higher gene expression of TNF-α was associated inversely with MWT (P = .01). MWT was also associated inversely with greater levels of circulating TNF-α (P = .028), CRP (P = .024), IL-6 (P = .03), and sICAM (P = .018). CONCLUSIONS: Systemic inflammation, as indicated by TNF-α inflammatory gene expression in peripheral blood monocytes and by circulating biomarker levels, is associated with impairment in walking time in patients with PAD and intermittent claudication.

Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation.

Anemia and vitamin D deficiency are conditions that both result in significant morbidity and increase with age. The potential relationship between them remains poorly understood, particularly in the elderly. We used the Third National Health and Nutrition Examination Survey to examine the association of vitamin D deficiency with anemia subtypes in persons aged ≥ 60 years. Vitamin D deficiency was defined as serum levels < 20 ng/mL, and anemia was defined according to World Health Organization criteria. Vitamin D deficiency was associated with anemia prevalence independent of age, sex, or race/ethnicity (odds ratio, 1.47; 95% confidence interval, 1.06-2.05; P = .02) and varied significantly by anemia subtype (P overall = .003). The prevalence of vitamin D deficiency was 33.3% in the nonanemic population, 56% in anemia of inflammation (AI; P = .008), and 33.0% in unexplained anemia (P = .55). Non-Hispanic blacks had a 7-fold increased risk of AI compared with whites, and this was partially attenuated after adjusting for vitamin D deficiency. These data show that vitamin D deficiency is associated with specific subtypes of anemia in the elderly, especially in those with AI. Vitamin D may suppress inflammatory pathways, and studies to determine whether vitamin D supplementation ameliorates AI are warranted.

TGF-ß1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization.

Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-ß1-responsive Krüppel- like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼ 60-fold higher than in progenitors lacking PAC markers. KLF10(-/-) mice present with marked defects in PAC differentiation, function, TGF-ß responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10(-/-) PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-ß1(+/-) CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-ß1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.

Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004.

BACKGROUND: Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease. METHODS AND RESULTS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index ≤0.90. Of 7458 eligible participants ≥40 years, weighted PAD prevalence was 5.9±0.3% (mean±SE), corresponding to ≈7.1 million US adults with PAD. Statin use was reported in only 30.5±2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9±1.9%, and aspirin use in 35.8±2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9; P<0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1±2.1%) than subjects without PAD or cardiovascular disease (4.1±0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8; P=0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86; P=0.02). CONCLUSIONS: Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality.

Impaired skeletal muscle glucose uptake by [18F]fluorodeoxyglucose-positron emission tomography in patients with peripheral artery disease and intermittent claudication.

OBJECTIVE: Reduced limb perfusion from arterial stenosis does not adequately account for intermittent claudication symptoms in peripheral artery disease (PAD). Insulin resistance is associated with PAD and may contribute to claudication by impairing skeletal muscle metabolism. We aimed to determine whether skeletal muscle glucose uptake, assessed by [(18)F]fluorodeoxyglucose positron emission tomography, is reduced in patients with claudication. METHODS AND RESULTS: Thirty-seven subjects with PAD and claudication and 11 healthy controls underwent [(18)F]fluorodeoxyglucose-positron emission tomography imaging of the legs during hyperinsulinemic-euglycemic clamp. Calf glucose uptake was quantified by graphical Patlak analysis, and whole-body insulin sensitivity was assessed as the glucose disposal rate (M) from the insulin clamp. Compared with healthy controls, PAD subjects were insulin resistant (M=3.4 mg/kg per minute [interquartile range, 2.7 to 4.8] versus 5.0 [3.7 to 6.6], P=0.019). Calf muscle glucose uptake was significantly lower in PAD compared with healthy subjects (48.6±2.6 µmol/kg per minute versus 62.9±6.5 µmol/kg per minute, P=0.009) and correlated with systemic insulin sensitivity (r=0.37, P=0.03) in PAD subjects. These abnormalities persisted even after exclusion of PAD subjects with diabetes. CONCLUSIONS: Patients with claudication have impaired calf muscle glucose uptake. Future studies are required to assess whether calf muscle insulin resistance contributes to exercise limitation in patients with intermittent claudication.

Approach to lipid therapy in the patient with atherosclerotic vascular disease.

OPINION STATEMENT: Hyperlipidemia increases the incidence of atherosclerotic vascular disease and is associated with greater rates of recurrent cardiovascular events among individuals with established vascular disease. Several large population studies have confirmed the link between all cholesterol components (including elevated low-density lipoprotein [LDL] cholesterol, total cholesterol, and triglyceride levels, and reduced high-density lipoprotein [HDL] levels) with coronary heart disease and other manifestations of systemic atherosclerosis. In addition, landmark clinical trials have clearly established that lowering LDL cholesterol levels with statins (HMG-CoA reductase inhibitors) can lower recurrent cardiovascular events by nearly 25%. The benefits of altering non-LDL cholesterol levels (eg, triglycerides and HDL) are less clear, but several other medications are often used in conjunction with statins for cholesterol lowering. First-line therapy for lipid lowering in patients with atherosclerotic vascular disease includes statins and a recommendation for lifestyle changes (including diet and exercise). Second-line options for lowering cholesterol include fibrates, nicotinic acid, bile acid sequestrants, and ezetimibe. Therapeutic goals for patients with vascular disease are to achieve an LDL cholesterol level < 100 mg/dL, or <70 mg/dL in individuals at particularly high risk.

Aspirin-triggered lipoxin and resolvin E1 modulate vascular smooth muscle phenotype and correlate with peripheral atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the vessel wall. Recent evidence suggests that chronic vascular inflammation ensues as an imbalance between pro- and anti-inflammatory mediators. Recently identified lipid mediators (eg, lipoxins and resolvins) play active roles in promoting the resolution of inflammation. Alterations in vascular smooth muscle cell (VSMC) phenotype, which manifest as a loss of contractile protein expression and increased proliferation and migration, are prominent mechanistic features of both atherosclerosis and restenosis following various interventions (eg, angioplasty and bypass grafting). We sought to determine whether human atherosclerosis is associated with a "resolution deficit" and whether lipoxins and resolvins influence VSMC phenotype. Here we report that plasma levels of aspirin-triggered lipoxin are significantly lower in patients with symptomatic peripheral artery disease than in healthy volunteers. Both aspirin-triggered lipoxin and resolvin E1 block platelet-derived growth factor-stimulated migration of human saphenous vein SMCs and decrease phosphorylation of the platelet-derived growth factor receptor-ß. Importantly, receptors for aspirin-triggered lipoxin and resolvin E1 (ALX and ChemR23, respectively) were identified in human VSMCs. Overall, these results demonstrate that stimulatory lipid mediators confer a protective phenotypic switch in VSMCs and elucidate new functions for these mediators in the regulation of SMC biology. These results also suggest that peripheral artery disease is associated with an inflammation-resolution deficit and highlight a potential therapeutic opportunity for the regulation of vascular injury responses.

Evaluation of a Commercial Mobile Health App for Depression and Anxiety (AbleTo Digital+): Retrospective Cohort Study.

BACKGROUND: Digital solutions, such as web-based and mobile interventions, have the potential to streamline pathways to mental health services and improve access to mental health care. Although a growing number of randomized trials have established the efficacy of digital interventions for common mental health problems, less is known about the real-world impact of these tools. AbleTo Digital+, a commercially available mental health app for depression and anxiety, offers a unique opportunity to understand the clinical impact of such tools delivered in a real-world context. OBJECTIVE: The primary aim of this study is to examine the magnitude of change in depression and anxiety symptoms among individuals who used AbleTo Digital+ programs. The secondary aim is to evaluate Digital+ module completion, including the use of 1:1 coaching. METHODS: In this retrospective cohort study, we analyzed previously collected and permanently deidentified data from a consecutive cohort of 1896 adults who initiated using one of the three Digital+ eight-module programs (depression, generalized anxiety, or social anxiety) between January 1 and June 30, 2020. Depression, generalized anxiety, and social anxiety symptoms were assessed within each program using the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, and the Social Phobia Inventory, respectively. Linear mixed effects models were built to assess the association between module completion and symptom change among users who completed at least four modules and had at least mild baseline symptom elevations, controlling for age, gender, and baseline symptom severity. Digital+ use, including module completion, 1:1 coaching calls, and in-app coach messaging, was also evaluated. RESULTS: Significant effects were observed among depression (Cohen d=1.5), generalized anxiety (Cohen d=1.2), and social anxiety (Cohen d=1.0) program participants who completed at least four modules and had mild baseline elevations (n=470). Associations between module completion and change in depression (ß=-1.2; P<.001), generalized anxiety (ß=-1.1; P<.001), and social anxiety (ß=-2.4; P<.001) symptom scores retained significance with covariate adjustment. Participants completed an average of 2.6 (SD 2.7) modules. The average total length of app use was 52.2 (SD 83.5) days. Approximately two-thirds of the users engaged in at least 1 coaching call (66.82%, 1267/1896) or in-app text messaging (66.09%, 1253/1896). Participants who completed at least four modules participated in significantly more coaching calls per module (mean 1.1, SD 0.7) than users who completed fewer than four modules (mean 1.0, SD 1.2; t1407=-2.1; P=.03). CONCLUSIONS: This study demonstrated that AbleTo Digital+ users experienced significant reductions in depression, generalized anxiety, and social anxiety symptoms throughout the program.

Comparison of DASS-21, PHQ-8, and GAD-7 in a virtual behavioral health care setting.

BACKGROUND: Validated depression and anxiety symptom screeners are commonly used in clinical settings. How results from different brief depression and anxiety symptom assessment tools compare to each other is not well established, especially in real world healthcare settings. This study aimed to compare the Depression Anxiety Stress Scales 21 Depression scale (DASS-Depression) and Anxiety (DASS-Anxiety) scale to the Patient Health Questionnaire 8 (PHQ-8) and Generalized Anxiety Disorder 7 (GAD-7) respectively, in a real-world virtual behavioral healthcare setting. METHODS: This was a retrospective comparison study of clinical data from a population of adults who completed a consultation via telephone or secure video with a licensed therapist as part of a standardized, evidence-based, virtual behavioral therapy program for individuals with comorbid medical and behavioral health conditions. The joint distributions and correlations between scores yielded by each depression and anxiety scale were assessed using descriptive and Spearman correlation statistics. RESULTS: The DASS-Depression and PHQ-8 were highly correlated (r = .71; p=<.001); the DASS-Anxiety and GAD-7 correlation was also high (r = .61; p=<.001). The PHQ-8 categorized more individuals as having above-threshold depression scores versus the DASS-Depression (71.5% vs. 43.5%; p < .001). The GAD-7 categorized more individuals as having above-threshold anxiety scores versus the DASS-Anxiety (59.0% vs. 45.0%; p < .001). LIMITATIONS: This study compared results yielded by validated screeners, precluding conclusions related to the validity of screener results. CONCLUSIONS: The DASS-Depression and PHQ-8 and the DASS-Anxiety and GAD-7 similarly ranked symptom severity. The PHQ-8 and GAD-7 were more likely than the DASS-21 Depression or Anxiety scales to classify individuals as having above-threshold symptom severity.

A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication.

Pharmacologic therapy for intermittent claudication in patients with peripheral artery disease (PAD) is limited. We aimed to determine the durability of cilostazol treatment response over time, treatment effects in various subpopulations, and long-term safety. This analysis pooled original data from nine randomized, controlled trials evaluating cilostazol in intermittent claudication, including 1258 subjects treated with cilostazol 100 mg bid. Analysis of covariance was used to compare differences in walking distance, and a pooled random-effects weighted mean difference in maximal walking distance (MWD) was determined. Temporal effects were analyzed by compiling data at 4-week intervals in studies of 24 weeks in duration. Cilostazol was associated with a 50.7% improvement from baseline in MWD compared with placebo (24.3%), with an absolute improvement of 42.1 meters greater than the improvement with placebo (p < 0.001) over a mean follow-up period of 20.4 weeks. Continued increases were demonstrated over the 24-week treatment period. These benefits were seen in all subgroups, after stratifying by age, sex, smoking status, duration of PAD, diabetes, hypertension, prior myocardial infarction, or beta-blocker use. Cilostazol did not increase the risk of all-cause mortality (RR 0.95 [0.68-1.35]). In conclusion, treatment with cilostazol achieves benefits in walking distance that are sustained at 24 weeks and observed irrespective of baseline clinical characteristics. Cilostazol demonstrated no increased risk of all-cause mortality.

Association of insulin resistance and inflammation with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999 to 2004.

BACKGROUND: Although the role of inflammation in the pathophysiology of peripheral arterial disease (PAD) is well established, the contribution of insulin resistance (IR) to PAD is less clear. We hypothesized that IR is associated with PAD and that the presence of IR would influence the association between C-reactive protein (CRP) and PAD, an association established predominantly in healthy individuals. METHODS AND RESULTS: We analyzed data from 3242 adults in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 who underwent measurement of ankle brachial index, CRP, and fasting glucose and insulin, enabling calculation of homeostasis model of IR (HOMA-IR). Odds ratios (ORs) and 95% CIs were estimated by logistic regression. The mean prevalence of PAD (defined as an ankle brachial index 3 mg/L) also was strongly associated with PAD (OR, 2.2; 95% CI, 1.3 to 3.6; P=0.003 versus CRP <1 mg/L). Stratifying subjects on the basis of median HOMA-IR, we found that CRP >3 mg/L was no longer significantly associated with PAD in subjects with IR (OR, 1.3; 95% CI, 0.8 to 2.1; P=0.3, P for interaction=0.08). CONCLUSIONS: These findings demonstrate that IR is strongly and independently associated with PAD. Furthermore, IR modifies the association of inflammation with PAD. These data establish a role of IR in PAD and highlight the relative importance of inflammation in patients with and without IR.

Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004.

BACKGROUND: Bilirubin, with recently recognized antioxidant and antiinflammatory activity, has emerged as a candidate for atheroprotection. We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD). METHODS AND RESULTS: We analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors in the National Health and Nutrition Examination Survey (1999 to 2004), a nationally representative cross-sectional examination of the United States population. A 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [95% CI 0.90 to 0.98]) after adjustment for age, gender, race/ethnicity, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease, CRP, and homocysteine. This result was not dependent on bilirubin levels above the reference range, liver disease, or alcohol intake. The inverse association of bilirubin with PAD tended to be stronger among men (OR 0.90 [95% CI 0.85 to 0.96]) compared with women (OR 0.97 [95% CI 0.91 to 1.04]; P(interaction)=0.05), and was stronger among active smokers (OR 0.81 [95% CI 0.73 to 0.90]) compared with nonsmokers (OR 0.97 [95% CI 0.93 to 1.02]; P(interaction)<0.01). CONCLUSIONS: Increased serum total bilirubin level is associated with reduced PAD prevalence. This result is consistent with the hypothesis that bilirubin is protective from PAD.

Using Telehealth to Implement Cognitive-Behavioral Therapy.

Behavioral health issues are common among patients with comorbid medical conditions but often go unrecognized or untreated, resulting in worse clinical outcomes and avoidable medical expenditures. This column describes an innovative telehealth solution that includes proactive and targeted patient identification and engagement and nationwide delivery of a technology-enabled, standardized, and evidence-based behavioral health program delivered via phone or video. A retrospective before-after evaluation of the program demonstrated national reach, high patient satisfaction, and significant reductions in symptoms of depression, anxiety, and stress.