Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events.

Cardiovascular diseases are associated with gut dysbiosis, but the role of microbe-derived metabolites as biomarkers or modulators of cardiovascular disease are not well understood. This is a targeted metabolomics study to investigate the association of nine microbe-derived metabolites with lower extremity peripheral artery disease (PAD), a form of atherosclerosis, and major adverse cardiac events (MACE). The study cohort consists of individuals with intermittent claudication and ankle-brachial index (ABI) < 0.9 (N = 119) and controls without clinically-apparent atherosclerosis (N = 37). The primary endpoint was MACE, a composite endpoint of myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or cardiac-related death. Plasma metabolite concentrations differed significantly between the PAD and control groups. After adjustment for traditional atherosclerosis risk factors, kynurenine, hippuric acid, indole-3-propionic acid (IPA), and indole-3-aldehyde (I3A) concentrations were negatively associated with PAD, whereas indoxyl sulfate and 3-hydroxyanthranilic acid were positively associated. Hippuric acid, IPA, and I3A correlated with ABI, a surrogate for atherosclerotic disease burden. Those in the highest I3A concentration quartile had significantly improved freedom from MACE during follow-up compared to those in the lowest quartile. This study identifies specific indole- and phenyl-derived species impacted by gut microbial metabolic pathways that could represent novel microbiome-related biomarkers of PAD.

Foundational Considerations for Artificial Intelligence Using Ophthalmic Images.

IMPORTANCE: The development of artificial intelligence (AI) and other machine diagnostic systems, also known as software as a medical device, and its recent introduction into clinical practice requires a deeply rooted foundation in bioethics for consideration by regulatory agencies and other stakeholders around the globe. OBJECTIVES: To initiate a dialogue on the issues to consider when developing a bioethically sound foundation for AI in medicine, based on images of eye structures, for discussion with all stakeholders. EVIDENCE REVIEW: The scope of the issues and summaries of the discussions under consideration by the Foundational Principles of Ophthalmic Imaging and Algorithmic Interpretation Working Group, as first presented during the Collaborative Community on Ophthalmic Imaging inaugural meeting on September 7, 2020, and afterward in the working group. FINDINGS: Artificial intelligence has the potential to improve health care access and patient outcome fundamentally while decreasing disparities, lowering cost, and enhancing the care team. Nevertheless, substantial concerns exist. Bioethicists, AI algorithm experts, as well as the Food and Drug Administration and other regulatory agencies, industry, patient advocacy groups, clinicians and their professional societies, other provider groups, and payors (i.e., stakeholders) working together in collaborative communities to resolve the fundamental ethical issues of nonmaleficence, autonomy, and equity are essential to attain this potential. Resolution impacts all levels of the design, validation, and implementation of AI in medicine. Design, validation, and implementation of AI warrant meticulous attention. CONCLUSIONS AND RELEVANCE: The development of a bioethically sound foundation may be possible if it is based in the fundamental ethical principles of nonmaleficence, autonomy, and equity for considerations for the design, validation, and implementation for AI systems. Achieving such a foundation will be helpful for continuing successful introduction into medicine before consideration by regulatory agencies. Important improvements in accessibility and quality of health care, decrease in health disparities, and lower cost thereby can be achieved. These considerations should be discussed with all stakeholders and expanded on as a useful initiation of this dialogue.

Depression Predicts Non-Home Discharge After Abdominal Aortic Aneurysm Repair.

BACKGROUND: Mental health's impact on vascular surgical patients has long been overlooked. While outside the expertise of most surgeons, understanding the role that depression plays in the postoperative course could provide additional insight into opportunities to improve surgical outcomes and healthcare value. Additionally, non-home discharge (NHD) to a rehabilitation or skilled nursing facility after surgery is associated with impaired quality of life and higher postdischarge complications, readmissions, and mortality. We hypothesized that depression would be associated with an increased risk for NHD following abdominal aortic aneurysm (AAA) repair. METHODS: Nonruptured AAA repair cases were identified from the National Inpatient Sample (NIS) using ICD-9 codes between 2005 and 2014. Depression, comorbidities, postoperative complications, and discharge destination were evaluated using statistical tests as appropriate to the data. A hierarchical multivariable logistic regression controlling for hospital level variation was used to examine the independent association between depression, and the primary outcome of NHD controlling for median income and confounders meeting P < 0.05 on univariate analysis. RESULTS: There were 99,934 total cases analyzed, of which 4,755 (4.8%) were diagnosed with depression and 10,618 (11.9%) required NHD. Patients with depression were younger, more likely to be women, white, have diabetes, chronic obstructive pulmonary disease, hypertension, tobacco use, and more likely to experience a postoperative complication. On adjusted multivariable analysis, patients with depression were more likely to require NHD (odds ratio [OR] 1.87, 95% confidence interval [CI]: 1.68-2.08, c-statistic = 0.82). On stratified analysis by operative approach, depression had a larger effect estimate in endovascular repair (OR 2.19; 95% CI: 1.90-2.52) versus open repair (OR 1.60; 95% CI: 1.38-1.87). CONCLUSIONS: In a nationally representative sample, patients with depression were more likely to require NHD after AAA repair. This study highlights the importance that depression plays in postoperative outcomes after AAA repair. Furthermore, addressing mental health preoperatively has the potential to improve outcomes in patients undergoing AAA repair.

Patients with depression are less likely to go home after critical limb revascularization.

BACKGROUND: Although often overlooked during the preoperative evaluation, recent evidence has suggested that depression in patients with peripheral artery disease is associated with increased postoperative complications, including decreased primary and secondary patency after revascularization and an increased risk of major amputation and mortality. Postoperative nonhome discharge (NHD) is an important outcome for patients and has also been associated with other adverse outcomes; however, the effect that depression has on NHD after vascular surgery has remained unexplored. We hypothesized that depression would be associated with an increased risk of NHD after revascularization for chronic limb threatening ischemia (CLTI). METHODS: Endovascular, open, and hybrid (combined open and endovascular) cases of revascularization for CLTI were identified from the 2012 to 2014 National (Nationwide) Inpatient Sample. CLTI, diagnoses of depression, and medical comorbidities were defined using the corresponding International Classification of Diseases, Ninth Revision, Clinical Modification codes. A hierarchical multivariable binary logistic regression controlling for hospital level variation and for confounders meeting P <.01 on bivariate analysis was used to examine the association between depression and NHD. A sensitivity analysis after coarsened exact matching for baseline characteristics that differed between the two groups was performed to reduce any imbalance. RESULTS: A total of 64,817 cases were identified, of which 5472 (8.4%) included a diagnosis of depression and 16,524 (25.5%) NHD. The patients with depression were younger and more likely to be women and white, have multiple comorbidities and a nonelective admission, and experience a postoperative complication (P <.05). On unadjusted analyses, patients with depression had an 8% absolute increased risk of requiring NHD (32.1% vs 24.9%; P <.001). On multivariable analysis, patients with depression had an increased odds for NHD (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.40-1.61; c-statistic, 0.81) compared with those without depression. After stratification by operative approach, depression had a larger effect estimate in endovascular revascularization (OR, 1.57; 95% CI, 1.42-1.74) compared with open (OR, 1.45; 95% CI, 1.30-1.62). A test for interaction between depression and gender identified that men with depression had greater odds of NHD compared with women with depression (OR, 1.68; 95% CI, 1.51-1.88; vs OR, 1.37; 95% CI, 1.25-1.51; interaction P <.01). A sensitivity analysis after coarsened exact matching confirmed these findings. CONCLUSIONS: To the best of our knowledge, the present study is the first to identify an association between depression and NHD after revascularization for CLTI. These results provide further evidence of the negative effects that comorbid depression has on patients undergoing revascularization for CLTI. Future studies should examine whether treating depression can improve the outcomes in this patient population.

Treatment With a Marine Oil Supplement Alters Lipid Mediators and Leukocyte Phenotype in Healthy Patients and Those With Peripheral Artery Disease.

Background Peripheral artery disease (PAD) is an advanced form of atherosclerosis characterized by chronic inflammation. Resolution of inflammation is a highly coordinated process driven by specialized pro-resolving lipid mediators endogenously derived from omega-3 fatty acids. We investigated the impact of a short-course, oral, enriched marine oil supplement on leukocyte phenotype and biochemical mediators in patients with symptomatic PAD and healthy volunteers. Methods and Results This was a prospective, open-label study of 5-day oral administration of an enriched marine oil supplement, assessing 3 escalating doses in 10 healthy volunteers and 10 patients with PAD. Over the course of the study, there was a significant increase in the plasma level of several lipid mediator families, total specialized pro-resolving lipid mediators, and specialized pro-resolving lipid mediator:prostaglandin ratio. Supplementation was associated with an increase in phagocytic activity of peripheral blood monocytes and neutrophils. Circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers (cluster of differentiation 18, 163, 54, and 36, and chemokine receptor 2). Similarly, transcriptional profiling of monocyte-derived macrophages displayed polarization toward a reparative phenotype postsupplementation. The most notable cellular and biochemical changes over the study occurred in patients with PAD. There were strong correlations between integrated biochemical measures of lipid mediators (specialized pro-resolving lipid mediators:prostaglandin ratio) and phenotypic changes in circulating leukocytes in both healthy individuals and patients with PAD. Conclusions These data suggest that short-term enriched marine oil supplementation dramatically remodels downstream lipid mediator pathways and induces a less inflammatory and more pro-resolution phenotype in circulating leukocytes and monocyte-derived macrophages. Further studies are required to determine the potential clinical relevance of these findings in patients with PAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02719665.

Association of comorbid depression with inpatient outcomes in critical limb ischemia.

There is a growing body of evidence that peripheral artery disease (PAD) may be impacted by depression. The objective of this study is to determine whether outcomes, primarily major amputation, differ between patients with depression and those without who presented to hospitals with critical limb ischemia (CLI), the end-stage of PAD. A retrospective cohort of patients hospitalized for CLI during 2012 and 2013 was identified from the National Inpatient Sample (NIS) using ICD-9 codes. The primary outcome was major amputation and secondary outcomes were length of stay and other complications. The sample included 116,008 patients hospitalized for CLI, of whom 10,512 (9.1%) had comorbid depression. Patients with depression were younger (64 ± 14 vs 67 ± 14 years, p < 0.001) and more likely to be female (55% vs 41%, p < 0.001), white (73% vs 66%, p < 0.001), and tobacco users (46% vs 41%, p < 0.001). They were also more likely to have prior amputations (9.8% vs 7.9%, p < 0.001). During the hospitalization, the rate of major amputation was higher in patients with comorbid depression (11.5% vs 9.1%, p < 0.001). In multivariable analysis, excluding patients who died prior to/without receiving an amputation (n = 2621), comorbid depression was associated with a 39% increased odds of major amputation (adjusted OR 1.39, 95% CI 1.30, 1.49; p < 0.001). Across the entire sample, comorbid depression was also independently associated with a slightly longer length of stay (ß = 0.199, 95% CI 0.155, 0.244; p < 0.001). These results provide further evidence that depression is a variable of interest in PAD and surgical quality databases should include mental health variables to enable further study.

Predicting the effects of supplemental EPA and DHA on the omega-3 index.

BACKGROUND: Supplemental long-chain omega-3 (n-3) fatty acids (EPA and DHA) raise erythrocyte EPA + DHA [omega-3 index (O3I)] concentrations, but the magnitude or variability of this effect is unclear. OBJECTIVE: The purpose of this study was to model the effects of supplemental EPA + DHA on the O3I. METHODS: Deidentified data from 1422 individuals from 14 published n-3 intervention trials were included. Variables considered included dose, baseline O3I, sex, age, weight, height, chemical form [ethyl ester (EE) compared with triglyceride (TG)], and duration of treatment. The O3I was measured by the same method in all included studies. Variables were selected by stepwise regression using the Bayesian information criterion. RESULTS: Individuals supplemented with EPA + DHA (n = 846) took a mean ± SD of 1983 ± 1297 mg/d, and the placebo controls (n = 576) took none. The mean duration of supplementation was 13.6 ± 6.0 wk. The O3I increased from 4.9% ± 1.7% to 8.1% ± 2.7% in the supplemented individuals ( P < 0.0001). The final model included dose, baseline O3I, and chemical formulation type (EE or TG), and these explained 62% of the variance in response (P < 0.0001). The model predicted that the final O3I (and 95% CI) for a population like this, with a baseline concentration of 4.9%, given 850 mg/d of EPA + DHA EE would be ∼6.5% (95% CI: 6.3%, 6.7%). Gram for gram, TG-based supplements increased the O3I by about 1 percentage point more than EE products. CONCLUSIONS: Of the factors tested, only baseline O3I, dose, and chemical formulation were significant predictors of O3I response to supplementation. The model developed here can be used by researchers to help estimate the O3I response to a given EPA + DHA dose and chemical form.

Peripheral Artery Disease Is Associated with a Deficiency of Erythrocyte Membrane n-3 Polyunsaturated Fatty Acids.

Population-based data suggest that individuals who consume large dietary amounts of n-3 polyunsaturated fatty acids (PUFA) have lower odds of peripheral artery disease (PAD); however, clinical studies examining n-3 PUFA levels in patients with PAD are sparse. The objective of this study is to compare erythrocyte membrane fatty acid (FA) content between patients with PAD and controls. We conducted a cross-sectional study of 179 vascular surgery outpatients (controls, 34; PAD, 145). A blood sample was drawn and the erythrocyte FA content was assayed using capillary gas chromatography. We calculated the ratio of the n-3 PUFA eicosapentaenoic acid (EPA) to the n-6 PUFA arachidonic acid (ARA) as well as the omega-3 index (O3I), a measure of erythrocyte content of the n-3 PUFA, EPA, and docosahexaenoic acid (DHA), expressed as a percentage of total erythrocyte FA. Compared with controls, patients with PAD smoked more and were more likely to have hypertension and hyperlipidemia (p < 0.05). Patients with PAD had a lower mean O3I (5.0 ± 1.7% vs 6.0 ± 1.6%, p < 0.001) and EPA:ARA ratio (0.04 ± 0.02 vs 0.05 ± 0.05, p < 0.001), but greater mean total saturated fats (39.5 ± 2.5% vs 38.5 ± 2.6%, p = 0.01). After adjusting for several patient characteristics, comorbidities, and medications, an absolute decrease of 1% in the O3I was associated with 39% greater odds of PAD (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.03-1.86, and p = 0.03). PAD was associated with a deficiency of erythrocyte n-3 PUFA, a lower EPA:ARA ratio, and greater mean total saturated fats. These alterations in FA content may be involved in the pathogenesis or development of poor outcomes in PAD.

Leptinemia is Associated With Peripheral Artery Disease.

BACKGROUND: Leptin, adiponectin, and resistin are in a class of hormones called adipokines that are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. We examined the association between adipokine levels and peripheral artery disease (PAD), hypothesizing that after adjusting for fat mass, leptin and resistin would be higher, whereas adiponectin would be lower, in patients with PAD. METHODS: A cross-sectional sample of 179 predominately male (97%) vascular surgery outpatients was recruited from the San Francisco Veterans Affairs Medical Center (SFVAMC). PAD was defined as either an ankle-brachial index < 0.9 plus symptoms of claudication or prior revascularization for symptomatic PAD (n = 141). Controls had an ankle-brachial index ≥0.9 and no history of atherosclerotic disease (n = 38). Adipokines were assayed using commercially available ELISA kits and values were log-transformed. Fat mass was measured using bioelectrical impedance. RESULTS: In an analysis adjusting for body mass index (BMI) and atherosclerotic risk factors, higher serum leptin was associated with PAD (OR 2.54, 95% CI 1.07-6.01, P = 0.03), whereas high molecular weight adiponectin was inversely associated, though not significantly (OR 0.60, 95% CI 0.33-1.08, P = 0.09). Resistin was not associated with PAD. Sensitivity analyses using fat mass/height2 rather than BMI yielded similar results. CONCLUSIONS: These results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes.

Fish Oil Increases Specialized Pro-resolving Lipid Mediators in PAD (The OMEGA-PAD II Trial).

BACKGROUND: N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). MATERIALS AND METHODS: The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. RESULTS: Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil: 0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking impairment questionnaire, or 6-min walk test in the fish oil group. CONCLUSIONS: Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine whether these early changes translate to clinical improvements in patients with PAD.

Serum resistin is associated with impaired endothelial function and a higher rate of adverse cardiac events in patients with peripheral artery disease.

OBJECTIVE: Resistin is a hormone that has been associated with metabolic syndrome and cardiovascular disease. The role of resistin in patients with peripheral artery disease (PAD) has not been fully explored. This study seeks to understand the relationship between serum resistin, vascular function, and cardiovascular outcomes in patients with PAD. METHODS: There were 106 patients with PAD who were recruited between 2011 and 2016. Patients attended a baseline visit during which a comprehensive vascular physiology assessment including medical and surgical history, radial artery tonometry, and flow mediated-vasodilation (FMD) was completed. A blood sample was drawn, and serum resistin was assayed using enzyme-linked immunosorbent assay kits. Using the time of study enrollment as the time of origin, incident major adverse cardiac events (MACEs) were identified by subsequent chart review and defined as a composite end point of myocardial infarction, coronary revascularization, transient ischemic attack, stroke, or death from a cardiac cause. RESULTS: Patients had a mean age of 68 ± 8 years, were largely white (75%), and had comorbidities commonly associated with PAD including hypertension (92%), hyperlipidemia (87%), coronary artery disease (37%), and diabetes mellitus (38%). After stratification by resistin quartile, higher resistin quartiles were significantly associated with an older age, a greater number of pack-years smoked, and a lower estimated glomerular filtration rate. Despite similar comorbidities and medication use, endothelial function, as measured by FMD, was significantly lower with increasing resistin quartile (I, 9.1% ± 3.3%; II, 7.1% ± 3.5%; III, 5.8% ± 4.0%; IV, 5.6% ± 3.5%; P = .002). In multivariable linear regression, higher resistin quartiles (III and IV) were associated with lower FMD relative to quartile I after adjusting for several patient characteristics, medications, and comorbidities (III, -2.26 [95% confidence interval (CI), -4.51 to -0.01; P = .05]; IV, -2.53 [95% CI, -4.87 to -0.20; P = .03]). During a median follow-up period of 36 months (interquartile range, 29-45 months), 21 patients experienced the primary end point. In a Cox proportional hazards model adjusted for smoking status, coronary artery disease, and age, each 1 ng/mL increase in resistin was associated with a 10% increased risk of MACEs (hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04). CONCLUSIONS: In patients with PAD, higher levels of resistin were associated with impaired endothelial function and an increased rate of MACEs. These results suggest that resistin may be a marker or effector of impaired vascular physiology and adverse cardiac outcomes in patients with PAD. Further research is needed to determine the potential mechanisms by which resistin may impair endothelial function and increase MACEs in this population.

Scoping review of frailty in vascular surgery.

OBJECTIVE: This review sought to describe the current state of knowledge of the impact of frailty on perioperative clinical outcomes in patients undergoing vascular interventions. METHODS: A scoping review of the literature from both PubMed and Ovid Embase databases was conducted to identify relevant English- and French-language articles published from inception to May 31, 2018. Patients undergoing vascular surgery interventions were included. RESULTS: Twenty-three studies have addressed the prevalence or prognostic impact of frailty in patients undergoing vascular surgery procedures. The prevalence of frailty ranged from 20% to 60%, and notably 14 different frailty assessments were used in these studies. Frailty was associated with increased comorbid status, prolonged length of stay, discharge to assisted living facility, loss of independence, postoperative morbidity, and all-cause mortality. CONCLUSIONS: There are a variety of heterogeneous tools to measure frailty in patients undergoing vascular surgery interventions. The prevalence of frailty varies by the scale used to measure it, as does its predictive value. Clinicians and surgeons should be sensitized to the importance of assessing frailty preoperatively in older adults undergoing vascular surgery and using it to assist in the decision-making process and allocation of surgical resources.

Depression severity is associated with increased inflammation in veterans with peripheral artery disease.

The present study examines the association between depressive symptoms and inflammatory markers in peripheral artery disease (PAD) to better understand the mechanistic relationship between depression and PAD. A cross-sectional sample of 117 patients with PAD (97% male, 76% Caucasian) was recruited from the San Francisco Veterans Affairs Medical Center. Patients were categorized into three subgroups based upon current depressive symptom severity, as defined by Patient Health Questionnaire-8 scores: no symptoms (score of 0-4, n = 62), mild symptoms (score of 5-9, n = 33), and moderate/severe symptoms (score ≥ 10, n = 22). Serum levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor-alpha (TNF-α) were assayed and log-transformed for multivariable analysis. To decrease the possibility of Type 1 errors, inflammatory markers were standardized and summed to create a total inflammatory score. In a multivariable analysis controlling for demographics, PAD severity, and atherosclerotic risk factors, mild and moderate/severe depressive symptoms were predictive of a higher total inflammatory score when compared to the group with no symptoms (mild symptoms p = 0.04, moderate/severe symptoms p = 0.007). Exploratory multivariable analyses of individual inflammatory markers found IL-6 levels were significantly higher in the moderate/severe symptoms group ( p = 0.006) than in the no symptoms group. Moreover, hs-CRP and ICAM-1 trended upwards with increasing depression severity. TNF-α was not associated with depression severity. We conclude that depressive symptom severity was independently associated with greater inflammation in PAD. Future research should examine the strength and directionality of this association through larger prospective cohort studies, as well as investigate the pathophysiological mechanisms responsible.

Review of biologic and behavioral risk factors linking depression and peripheral artery disease.

The incidence of depression has been rising rapidly, and depression has been recognized as one of the world's leading causes of disability. More recently, depression has been associated with an increased risk of symptomatic atherosclerotic disease as well as worse perioperative outcomes in patients with cardiovascular disease. Additionally, recent studies have demonstrated an association between depression and peripheral artery disease (PAD), which has been estimated to affect more than 200 million people worldwide. These studies have identified that depression is associated with poor functional and surgical outcomes in patients with PAD. Although the directionality and specific mechanisms underlying this association have yet to be clearly defined, several biologic and behavioral risk factors have been identified to play a role in this relationship. These factors include tobacco use, physical inactivity, medical non-adherence, endothelial and coagulation dysfunction, and dysregulation of the hypothalamic-pituitary-adrenal axis, autonomic system, and immune system. In this article, we review these potential mechanisms and the current evidence linking depression and PAD, as well as future directions for research and interventional strategies. Understanding and elucidating this relationship may assist in preventing the development of PAD and may improve the care that patients with PAD and comorbid depression receive.

Characterizing the relationship between flow-mediated vasodilation and radial artery tonometry in peripheral artery disease.

BACKGROUND: Arterial stiffness, measured by the augmentation index (AIX) from radial artery tonometry, and endothelial dysfunction, measured by brachial-artery flow-mediated vasodilation (FMD), have each been associated with increased risk of cardiovascular events. However, their interrelationship in peripheral artery disease (PAD) patients is poorly understood. MATERIALS AND METHODS: In a cross-sectional analysis of 123 vascular surgery outpatients, the association between FMD and AIX was examined in controls with atherosclerotic risk factors (n = 32) and patients with PAD (n = 91). PAD was defined as claudication symptoms with an ankle-brachial index of <0.9 or a history of revascularization for symptomatic PAD. Controls had an ankle-brachial index ≥0.9 and no history of atherosclerotic vascular disease. RESULTS: Compared to controls, patients with PAD had lower FMD (6.3 ± 3.8 versus 8.4 ± 3.7, P = 0.008), while central AIX normalized to 75 beats per minute (25.5 ± 9.0 versus 19.3 ± 8.6, P = 0.001) and peripheral AIX (91.3 ± 14.5 versus 81.3 ± 11.4, P = 0.001) were higher. FMD was not significantly correlated with either central or peripheral AIX (central AIX: P = 0.58; peripheral AIX: P = 0.89) across the entire cohort, or in either the patients with PAD (central AIX: P = 0.48; peripheral AIX: P = 0.23) or controls (central AIX: P = 0.43; peripheral AIX: P = 0.92). In a multivariate model including FMD, higher AIX remained independently associated with PAD. CONCLUSIONS: In an analysis of vascular surgery outpatients, no correlation between FMD and AIX was detected. Larger prospective studies are needed to determine whether the inclusion of both parameters improves predictive models for the early identification and potential risk stratification of PAD patients.

The association of comorbid depression with mortality and amputation in veterans with peripheral artery disease.

OBJECTIVE: Peripheral artery disease (PAD) is an increasing health concern with rising incidence globally. Previous studies have shown an association between PAD incidence and depression. The objective of the study was to determine the association of comorbid depression with PAD outcomes (amputation and all-cause mortality rates) in veterans. METHODS: An observational retrospective cohort of 155,647 patients with incident PAD (2003-2014) from nationwide U.S. Veterans Health Administration hospitals was conducted using the national Veterans Affairs Corporate Data Warehouse. Depression was measured using concurrent International Classification of Diseases, Ninth Revision diagnosis codes 6 months before or after PAD diagnosis. The main outcomes were incident major amputation and all-cause mortality. Crude associations were assessed with Kaplan-Meier plots. The effects of depression adjusted for covariates were analyzed using Cox proportional hazards models. RESULTS: Depression was present in 16% of the cohort, with the occurrence of 9517 amputations and 63,287 deaths (median follow-up, 5.9 years). Unadjusted hazard ratios (HRs) of comorbid depression for amputations and all-cause mortality were 1.32 (95% confidence interval [CI], 1.25-1.39) and 1.02 (95% CI, 0.99-1.04), respectively. After adjustment for covariates in Cox regression models, a diagnosis of comorbid depression at the time of PAD diagnosis was associated with a 13% higher amputation (HR, 1.13; 95% CI, 1.07-1.19) and 17% higher mortality (HR, 1.17; 95% CI, 1.14-1.20) risk compared with patients with no depression. On stratification by use of antidepressants, depressed patients not taking antidepressants had a 42% higher risk of amputation (HR, 1.42; 95% CI, 1.27-1.58) compared with those without depression. Patients taking antidepressants for depression still had increased risk of amputation but only 10% higher compared with those without depression (HR, 1.10; 95% CI, 1.03-1.17). Interestingly, patients taking antidepressants for other indications also had a higher risk of amputation compared with those not having depression or not taking antidepressants (HR, 1.08; 95% CI, 1.03-1.14). Having any diagnosis of depression or the need for antidepressants increased the mortality risk by 18% to 25% in the PAD cohort compared with those without depression and not taking antidepressants for any other indication. CONCLUSIONS: PAD patients with comorbid depression have a significantly higher risk of amputation and mortality than PAD patients without depression. Furthermore, untreated depression was associated with an increased amputation risk in the PAD population, more so than depression or other mental illness being treated by antidepressants. The underlying mechanisms for causality, if any, remain to be determined. The association of antidepressant treatment use with amputation risk should prompt further investigations into possible mechanistic links between untreated depression and vascular dysfunction.

Frailty Is Associated with an Increased Risk of Major Adverse Cardiac Events in Patients with Stable Claudication.

BACKGROUND: Frailty, a syndrome characterized by decreased physiologic reserves and resistance to stressors, is associated with disability, poor surgical outcomes, and mortality. We evaluated the impact of frailty on cardiovascular disease (CVD) events in peripheral arterial disease (PAD) patients with intermittent claudication. METHODS: We conducted a retrospective review of patients with stable intermittent claudication enrolled in the OMEGA-PAD study between 2010 and 2015. The modified frailty index (mFI) is a retrospectively validated index of frailty derived from the Canadian Study of Health and Aging and was used in this study to categorize frailty as low, medium, or high. Our outcome was time to occurrence of a major adverse cardiac event (MACE), defined as a composite endpoint of myocardial infarction, coronary revascularization, stroke, or CVD-related death. Cox proportional hazards models were used to calculate relative hazards ratio. RESULTS: There were 129 subjects with a mean age of 67 years, 97% were men, 36% were diabetic, and 33% had known coronary heart disease. When the mFI criteria were applied, 38 subjects were "low" frailty, 72 were "medium" frailty, and 19 were "high" frailty. During the median follow-up period of 34 months (interquartile range: 25-43), 29 subjects experienced a MACE. When compared to the lowest mFI, patients with medium frailty were 2.8 times more likely to have an event (95% confidence interval [CI]: 0.95-8.46, P = 0.06), whereas patients with a high mFI were 4.8 times as likely (95% CI: 1.43-15.8, P = 0.01). In a model adjusted for age, smoking status, and presence of diabetes, those with a medium mFI were 4.3 times more likely to have an event (95% CI: 1.37-13.7, P = 0.01) and those with a high mFI were 9.2 times as likely (95% CI: 2.6-32.4, P = 0.001). CONCLUSIONS: Higher mFI category is associated with a significantly increased risk of MACE in PAD patients with stable claudication. Frailty may serve as a useful adjunct for assessment of overall cardiac risk, particularly as treatment options are being contemplated.

Increased circulating blood cell counts in combat-related PTSD: Associations with inflammation and PTSD severity.

Inflammation is reported in post-traumatic stress disorder (PTSD). Few studies have investigated circulating blood cells that may contribute to inflammation. We assessed circulating platelets, white blood cells (WBC) and red blood cells (RBC) in PTSD and assessed their relationship to inflammation and symptom severity. One-hundred and sixty-three male combat-exposed veterans (82 PTSD, 81 non-PTSD) had blood assessed for platelets, WBC, and RBC. Data were correlated with symptom severity and inflammation. All cell counts were significantly elevated in PTSD. There were small mediation effects of BMI and smoking on these relationships. After adjusting for these, the differences in WBC and RBC remained significant, while platelet count was at trend level. In all subjects, all of the cell counts correlated significantly with inflammation. Platelet count correlated with inflammation only in the PTSD subjects. Platelet count, but none of the other cell counts, was directly correlated with PTSD severity ratings in the PTSD group. Combat PTSD is associated with elevations in RBC, WBC, and platelets. Dysregulation of all three major lineages of hematopoietic cells in PTSD, as well as their significant correlation with inflammation, suggest clinical significance of these changes.