Prognosis Of Peripheral Artery Disease Research Articles

Abstract 374: Sexual Dimorphism And Elabela Expression In Peripheral Artery Disease

Introduction: Elabela is a component of the apelinergic system known to regulate immune responses and has a cardiovascular protection role, including atherosclerosis. Peripheral artery disease (PAD) is the narrowing or blockage of larger arteries in the legs. Patients with PAD suffer from poor perfusion to their lower extremities, in addition to increased rates of cardiovascular complications. The role of sexual dimorphism in the immune system in the PAD is poorly understood. Our previous research suggests that Elabela may hold a gender-dependent protective role that can be used as immunotherapeutic. We hypothesized that in patients with PAD, expression of Elabela will be different between males and females, implicating in sexual dimorphism of the immune response, the disease outcome, and treatment. Methods: Blood samples were collected from PAD patients (n=8) and risk factor closely matched controls (n=8). PBMCs were isolated by gradient centrifugation. By flow cytometry, gating strategy on Elabela, and Elabela expressing leukocytes, using FlowJow software for analysis. Results: The results showed that there is a sexual difference in the expression of Elabela in both controls and patients with PAD. In general, males showed a high level of Elabela than females. PAD decreases Elabela expression in both males and females. Regarding Elabela expressing leukocytes, in female controls, there was no significant difference in leukocyte expression of Elabela as compared to PAD patients, while male controls demonstrated increased leukocyte expression of Elabela. Conclusions: Our findings suggest a potential role for Elabela in PAD. Importantly, these results also indicate a difference in Elabela expression based on sex dimorphism. Such differences could potentially be used as a biomarker in the diagnosis and prognosis of PAD along with therapeutic values.

Lipoprotein(a) is a Promising Residual Risk Factor for Long-Term Clinical Prognosis in Peripheral Arterial Disease.

Objectives: We investigated the relationship between plasma lipoprotein(a) [Lp(a)] level and long-term prognosis, cardiovascular events, or pure leg events (LE) in patients with peripheral arterial disease (PAD).Materials and Methods: We prospectively enrolled 1104 PAD patients. The endpoints were LE, cerebrovascular- or cardiovascular-related death (CVRD), all-cause death (ACD), and major adverse cardiovascular events (MACE).Results: The incidences of LE, CVRD, ACD, and MACE were correlated with Lp(a) level (P<0.05). Lp(a) was positively correlated with low-density lipoprotein cholesterol and C-reactive protein (CRP) and negatively correlated with estimated glomerular filtration rate (eGFR). In the Cox multivariate regression analysis, high Lp(a), CRP, age, low ankle-brachial pressure index (ABI), eGFR, albumin, critical limb ischemia (CLI), cerebrovascular disease (CVD), and diabetes were associated with LE; high Lp(a), age, CRP, low ABI, body mass index, eGFR, albumin, CLI, coronary heart disease (CHD), CVD, and diabetes were associated with CVRD; high Lp(a), CRP, age, low ABI, eGFR, albumin, CLI, and CVD were associated with ACD; and high Lp(a), CRP, age, low eGFR, albumin, CLI, CHD, and diabetes were associated with MACE (P<0.05). Statins improved all endpoints (P<0.01).Conclusion: Lp(a) was a significant residual risk factor for LE, CVRD, ACD, and MACE in PAD patients.

Comparative mortality according to peripheral artery disease and coronary heart disease/stroke in the United States

Background and aimsA recent trial reported that patients with peripheral artery disease (PAD) without coronary heart disease or stroke (CHD/stroke) had worse prognosis than those with CHD/stroke without PAD. However, community-based data are lacking. The purpose of this study was to compare mortality according to the status of PAD and CHD/stroke in the general population. MethodsIn 6780 participants (aged ≥40 years) from the National Health and Nutrition Examination Surveys 1999–2004, we compared mortality risk according to PAD (ankle-brachial index ≤0.9) and CHD/stroke (self-report) at baseline using the Kaplan-Meier method and multivariable Cox models accounting for sampling weights. ResultsThe prevalence of having both PAD and CHD/stroke was 1.6%. The prevalence of PAD without CHD/stroke and CHD/stroke without PAD was 4.1% and 8.5%, respectively (85.8% without PAD or CHD/stroke). Over a median follow-up of 12.8 years, 21.2% died. Individuals with both PAD and CHD/stroke had the worst survival (25.5% at 12 years). Those with PAD without CHD/stroke had the second worst prognosis (47.7%), followed by those with CHD/stroke without PAD (53.2%) and those without CHD/stroke or PAD (87.2%). Adjusted hazard ratio of mortality was 2.70 (95% CI, 2.07–3.53) for PAD with CHD/stroke, 1.81 (1.54–2.12) in CHD/stroke without PAD, and 1.68 (1.35–2.08) in PAD without CHD/stroke vs. no CHD/stroke or PAD. ConclusionsIn the US adults, PAD contributed to increased mortality in persons with and without CHD/stroke. The prognosis of PAD without CHD/stroke was no better than that of CHD/stroke without PAD. These results suggest the importance of recognizing the presence of PAD in the community.

Efficacy of high- versus moderate-dose statin therapy on lower extremity artery disease after revascularization

Aim: Statins are one of the most important agents in the treatment of atherosclerotic peripheral arterial disease. We aim to compare high- and moderate-dose statin therapy in patients with lower extremity artery disease (LEAD) who have undergone percutaneous transluminal angioplasty (PTA). Patients and Methods: Ninety-four patients treated with PTA were selected consecutively and retrospectively and were divided into two groups according to the high- or moderate-dose statin treatments they were given. Groups were compared for the absence of restenosis and occlusion as primary patency and the need for reintervention in the treated arterial segment as secondary patency. All patients underwent computed tomography (CT) angiography or duplex scan one year after receiving PTA. Results: Coronary revascularization (p&amp;lt;0.001) and prior statin usage (p:0.02) were more common in the high-dose statin group when compared to the moderate-dose statin group. Lesion characteristics did not differ between the two groups. Primary patency rate was significantly higher (36.1% vs. 27.6%, p 0.01) in the high-dose statin group. Major amputation (4.2% vs. 10.6%, p:0.03) and minor amputation (12.7% vs. 19.1%, p:0.03) rates were significantly lower in the high-dose statin group. Regression analysis revealed that the usage of high-dose statin therapy was an independent predictor of higher primary patency in patients who were treated with prior PTA(Odds ratio:2.208, p&amp;lt;0.001) Conclusion: High-dose long-term statin treatment might have better outcomes on primary patency in patients who underwent prior PTA for infrapopliteal lesions as a subgroup of peripheral artery disease. The administration of the high-dose long-term statin therapy might be important in the prognosis of peripheral arterial disease, especially for those with infrapopliteal lesions.

Lower Extremity Peripheral Artery Disease: Contemporary Epidemiology, Management Gaps, and Future Directions: A Scientific Statement From the American Heart Association.

Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.

Prevalence, Characteristics, and Prognosis of Peripheral Arterial Disease in Patients With Diabetic Charcot Foot

Charcot foot (CF) is a rare complication of diabetes associated with foot deformities and foot ulcers. Peripheral arterial disease (PAD) is a factor of poor prognosis in patients with diabetic foot ulcers (DFUs). However, PAD has infrequently been studied in CF. We aimed to determine the prevalence, the characteristics and the prognosis of PAD in a large group of patients with diabetic CF. We retrospectively compared 56 patients with diabetic CF to 116 patients with diabetic foot without CF. The prevalence of PAD in patients with CF was 66.1%. Compared to patients without CF, patients with CF had similar risks to have PAD (OR 0.98, 95%CI 0.50-1.94, p= .97) and neuro-ischemic DFUs (OR 1.19, 95%CI 0.57-2.49, p=.65), more risk to have lesions of distal arteries (OR 4.17, 95%CI 1.76-9.94, p=.001) and less risk to need revascularization (OR 0.14, 95%CI 0.06-0.36, p< .001). In patients with CF, PAD was strongly predicted by DFUs (OR 24.55, 95%CI 1.80-334.43, p=.016) and coronary artery disease (OR 17.11, 95%CI 1.75-167.43, p=.015). Survival rate and limb salvage rate in patients with CF were not worsened by PAD and by neuro-ischemic DFUs, respectively. In conclusion, we show that PAD should not be overlooked in patients with diabetic CF, especially in those having DFUs or coronary artery disease. PAD in patients with CF differed from that of patients without CF since it predominated in distal arteries and required less often revascularization.

Eicosapentaenoic acid levels predict prognosis of peripheral artery disease caused by aortoiliac artery lesions

Background and aimEicosapentaenoic acid (EPA) has been reported to improve clinical outcome of high-risk atherosclerotic patients. We investigated whether endogenous EPA values predict prognosis of peripheral artery disease (PAD) patients. Methods and resultsThis retrospective study included 166 consecutive patients who had received endovascular therapy (EVT) for PAD caused by aortoiliac artery lesions. Patients were divided into 2 groups using median preoperative EPA value (57 μg/ml): LOW EPA (n = 83) and HIGH EPA (n = 83). We compared differences between the 2 groups in prevalence of major adverse limb events (MALE) which included target lesion revascularization (TLR), non-TLR, and major amputation, and major adverse events (MAE) which included MALE and all cause death. At a median follow-up period of 20 months, MALE had occurred in 24 LOW EPA patients (28.9%) and in 12 HIGH EPA patients (14.5%) (p = 0.04), and MAE had occurred in 41 LOW EPA patients (49.4%) and in 21 HIGH EPA patients (25.3%) (p < 0.01). Kaplan–Meier analysis showed prevalence of MALE and MAE was significantly higher in LOW EPA than in HIGH EPA (long-rank test χ2 = 8.5, p < 0.01, log-rank test χ2 = 13.2, p < 0.01, respectively). Multivariate Cox regression revealed preoperative EPA value < 57 μg/ml was an independent predictor for MALE (hazard ratio [HR]: 2.70; 95% CI: 1.35 to 5.4; p < 0.01) and MAE (HR: 2.86; 95% CI: 1.67 to 4.91; p < 0.01). ConclusionsEndogenous EPA value seems to be associated with risk of MALE and MAE after EVT in patients with PAD caused by aortoiliac artery lesions.

Development of a Novel Risk Score for Predicting Prognosis of Peripheral Arterial Disease

Peripheral arterial disease (PAD) patients have a poor prognosis due to the various comorbidities. It is important to decide revascularization procedure (endovascular or surgical) for PAD patients with consideration of life prognosis. However, the evaluation method for life prognosis of PAD patients had not been established yet. The objective of this research is to develop a novel risk score for predicting prognosis of PAD. This study was a single-center study, and consisted of two parts. First, we developed a novel prognostic score in a retrospective study. Second, we examined the usefulness of the evaluation score prospectively. From January 2009 to July 2017, PAD patients underwent revascularization procedures in our institution were enrolled in the retrospective study. Patients were divided in two groups according to 2-year prognosis (survival group, n = 96; death group, n = 53). Risk factors for atherosclerosis (body mass index, smoking, hypertension, hyperlipidemia, diabetes mellitus, hemodialysis), past histories (coronary artery diseases, cerebrovascular disease), Rutherford classification, WIfI stage, Society for Vascular Surgery/American Association for Vascular Surgery (SVS/AAVS) score, psoas muscle index (PMI) = psoas muscle area (at the level of L3 on CT)/height (m2), and Geriatric Nutrition Risk Index (GNRI) = 14.89 × serum albumin (g/dL) + 41.7 × body mass index/22 were investigated retrospectively. Significant differences were observed in SVS/AAVS score, WIfI stage, PMI, and GNRI. We established PAD-SVS/AAVS score using these items and calculated PAD-SVS/AAVS score (=SVS/AAVS score + WIfI status × 2 + PMI status × 2 + GNRI status ×1) (Table). The cut-off value for 2-year prognosis was 22 (sensitivity, 77.4%; specificity, 76.0%). Then, from August 2017 to December 2019, PAD patients underwent revascularization procedures in our institution were enrolled in the prospective study. Patients were divided in two groups according to PAD-SVS/AAVS score (low-risk group with a score of <21, n = 45; high-risk group with a score of >22, n = 31). The primary end point was prognosis after revascularization procedure, and follow-up was performed until January 2019. Kaplan-Meier and log-rank tests were used to estimate and compare between the two groups. In the prospective study, the mean follow-up period was 348.9 days, mean estimated survival time was 905 days in the low-risk group and 428 days in the high-risk group, and significant difference was observed in survival probability (P < .001) (Figure). We developed the novel prognosis score; the PAD-SVS/AAVS score and showed the usefulness. PAD-SVS/AAVS score enables to predict prognosis of PAD patients and to decide revascularization procedure with consideration of life prognosis.Table IPeripheral artery disease-Society for Vascular Surgery/American Association for Vascular Surgery (PAD-SVS/AAVS) scoreScoreDescription of scoreMajor components Cardiac status Pulmonary statusSame as original SVS/AAVS score Renal statusMinor components HypertensionSame as original SVS/AAVS score AgePAD components WIfI status 0Stage 1 1Stage 2 2Stage 3 3Stage 4PMI status 0Male, >6.36; female, >3.92 1Male, 4.77-6.36; female, 3.51-3.92 2Male, 3.88-4.76; female, 2.81-3.50 3Male, ≤3.87; female, ≤2.80GNRI status 0>98 192-98 282-92 3<82GNRI, Geriatric Nutrition Risk Index; PMI, psoas muscle index.PAD-SVS/AAVS score = SVS/AAVS score + WIfI status × 2 + PMI status × 2 + GNRI status × 1. Open table in a new tab

Elevated Preoperative Neutrophil-lymphocyte Ratio is Asociated with Poor Patency and Major Adverse Limb Events After Infrainguinal Bypass Surgery Revascularization

Introduction: High neutrophyl-lympochyte ratio (NLR) is associated with the pro-inflammatory status that surrounds atherosclerosis. NLR has also been related to the clinical severity and prognosis of peripheral arterial disease. Our aim is to analyse the influence of this pro-atherosclerotic marker on infrainguinal bypass surgery patency and clinical outcomes. Methods: Retrospective analysis of 150 infrainguinal bypasses. The clinical indication was critical limb ischemia in n=100 (66’7%) procedures. A preoperative blood sample of each patient was obtained 24 hours before the procedure was performed. These samples were used to calculate NLR. Our cohort was stratified in 4 group according to NLR interquartile ranges. (Quartile 1 [Q1] n=37; Quartile 2 [Q2] n=38; Quartile 3 [Q3] n=38: Quartile 4 [Q4] n=37). Patency and amputation rates at 30 days were compared between groups using the Chi-Square test. Patency, limb salvage and overall survival at 24 months were calculated by means of Kaplan-Meier test. Freedom from “major adverse limb events” (MALE) and from “major adverse cardiovascular events” (MACE) at 24 months were also analysed. Comparisons between groups were performed using Log-Rank test for a P < .05 in 2-tailed test. Results: Patency and amputation rate at 30 days were similar between the studied groups. Primary patency of the Q4 group at 24 months was inferior to the primary patency observed in the rest of the cohort (47% vs. 67%; p=0.01). We also found a tendency towards a lower assisted-primary patency at 24 months in the Q4 group (62% vs. 75%; p=0.08). Limb salvage (70% vs. 85%; p=.03) and freedom from MALE (62% vs. 79%; p=0.01) at 24 months were inferior in the Q4 group. Freedom from MACE and overall survival rates were similar between groups. Conclusion: Preoperative NLR is associated with major adverse limb events and lower long term patency rates after infrainguinal bypass surgery revascularization. Future prospective studies are required to determine its clinical utility.

Treatment of Critical Limb Ischemia by pIRES/VEGF165/HGF Administration

Prognosis of peripheral artery disease (PAD), especially critical limb ischemia (CLI), is very poor despite the development of endovascular therapy and bypass surgery. Many patients result in having leg amputation. We decided to investigate the safety and efficacy of plasmid of internal ribosome entry site/vascular endothelial growth factor (VEGF) 165/hepatocyte growth factor (HGF) gene therapy (GT) in patients suffered from CLI. Administration of plasmid of internal ribosome entry site/VEGF165/HGF was performed in 12 limbs of 12 patients with rest pain and ischemic ulcers due to CLI. Plasmid was injected into the muscles of the ischemic limbs. The levels of VEGF in serum and the ankle-brachial index (ABI) were measured before and after treatment. Mean (±SD) plasma levels of VEGF increased nonsignificantly from 258±81 pg/L to 489±96 pg/L (P>0.05) 2weeks after therapy, and the ABI improved significantly from 0.27±0.20 to 0.50±0.22 (P<0.001) 3months after therapy. Ischemic ulcers healed in 9 limbs. Amputation was performed in 3 patients because of advanced necrosis and wound infection. However, the level of amputations was lowered below knee in these cases. Complications were limited to transient leg edema in 3 patients and fever in 2 patients. Intramuscular administration of plasmid of internal ribosome entry site/VEGF165/HGF is safe, feasible, and effective for patients with critical leg ischemia.

Role of Ligands of Receptor for Advanced Glycation End Products (RAGE) in Peripheral Artery Disease

Atherosclerotic cardiovascular disease, including peripheral artery disease (PAD), is more common and severe in diabetic patients compared with nondiabetic individuals. Indeed, diabetes is associated with the increased risk of limb amputation and all-cause mortality in patients with symptomatic PAD. Proteins and lipids are nonenzymatically modified by sugars, resulting in the formation and accumulation of advanced glycation end products (AGEs), whose process is accelerated under diabetic conditions, especially patients with a long duration of diabetes. Accumulating evidence shows that nonenzymatic modification by sugars alters the structural integrity of collagens and lipoproteins in large vessels, thereby being involved in vascular stiffness and atherosclerotic plaque instability. Furthermore, engagement of receptor for AGEs (RAGE) with its ligands, such as AGEs, high mobility group box 1, and S100A proteins evokes inflammatory and thrombotic reactions, thus playing a central role in the development and progression of atherosclerotic cardiovascular disease. In this article, we review the pathophysiological role of RAGE ligands in PAD and discuss the clinical utility of measurement of plasma, serum, or tissue RAGE ligands for assessment of the severity and prognosis of PAD. This review suggests that RAGE ligands may be a novel biomarker and also a therapeutic target of PAD, especially in patients with diabetes.

Medial Arterial Calcification: An Overlooked Player in Peripheral Arterial Disease.

Peripheral arterial disease (PAD) is a global health issue that is becoming more prevalent in an aging world population. Diabetes mellitus and chronic kidney disease are also on the increase, and both are associated with accelerated vascular calcification and an unfavorable prognosis in PAD. These data challenge the traditional athero-centric view of PAD, instead pointing toward a disease process complicated by medial arterial calcification. Like atherosclerosis, aging is a potent risk factor for medial arterial calcification, and accelerated vascular aging may underpin the devastating manifestations of PAD, particularly in patients prone to calcification. Consequently, this review will attempt to dissect the relationship between medial arterial calcification and atherosclerosis in PAD and identify common as well as novel risk factors that may contribute to and accelerate progression of PAD. In this context, we focus on the complex interplay between oxidative stress, DNA damage, and vascular aging, as well as the unexplored role of neuropathy.

The role of inflammation in cardiovascular diseases: the predictive value of neutrophil-lymphocyte ratio as a marker in peripheral arterial disease.

Peripheral arterial disease (PAD) is an important manifestation of atherosclerosis, with increasing prevalence worldwide. A growing body of evidence shows that the systemic inflammatory response is closely related to the development, progression, and prognosis of atherosclerosis. In the last decade, several studies have suggested the role of measured inflammatory biomarkers as predictors of severity and prognosis in PAD in an effort to stratify the risk of these patients, to improve treatment selection, and to predict the results after interventions. A simple inflammatory marker, more available than any other, is the neutrophil–lymphocyte ratio (NLR), which can be easily obtained in clinical practice, based on the absolute count of neutrophils and lymphocytes from the differential leukocytes count. Many researchers evaluated vigorously the NLR as a potential prognostic biomarker predicting pathological and survival outcomes in patients with atherosclerosis. In this work, we aim to present the role of NLR as a prognostic marker in patients with PAD through a thorough review of the literature.

Significance of red blood cell distribution width in diagnosis and prognosis of peripheral arterial disease

Significance of red blood cell distribution width in diagnosis and prognosis of peripheral arterial disease

Peripheral arterial disease and critical limb ischaemia: still poor outcomes and lack of guideline adherence.

Only few and historic studies reported a bad prognosis of peripheral arterial disease (PAD) and critical limb ischaemia (CLI). The contemporary state of treatment and outcomes should be assessed. From the largest public health insurance in Germany, all in- and outpatient diagnosis and procedural data were retrospectively obtained from a cohort of 41 882 patients hospitalized due to PAD during 2009-2011, including a follow-up until 2013. Patients were classified in Rutherford categories 1-3 (n = 21 197), 4 (n = 5353), 5 (n = 6916), and 6 (n = 8416). The proportions of patients with classical risk factors such as hypertension, dyslipidaemia, and smoking declined with higher Rutherford categories (each P < 0.001) while diabetes, chronic kidney disease, and chronic heart failure increased (each P < 0.001). Angiographies and revascularizations were performed less often in advanced PAD (each P < 0.001). In-hospital amputations increased continuously from 0.5% in Rutherford 1-3 to 42% in Rutherford 6, as also myocardial infarctions, strokes, and deaths (each P < 0.001). Among 4298 amputated patients with CLI, 37% had not received any angiography or revascularization neither during index hospitalization nor the 24 months before. During follow-up (mean 1144 days), 7825 patients were amputated and 10 880 died. Kaplan-Meier models projected 4-year mortality risks of 18.9, 37.7, 52.2, and 63.5% in Rutherford 1-3, 4, 5, and 6, and for amputation of 4.6, 12.1, 35.3, and 67.3%, respectively. In multivariable Cox regression models, PAD categories were significant predictors of death, amputation, myocardial infarction, and stroke (each P < 0.001). Length of in-hospital stay (5.8 ± 6.7 days, 10.7 ± 11.1days, 15.2 ± 13.8 days and 22.1 ± 20.3 days; P < 0.001) and mean case costs (3662 ± 3186 €, 5316 ± 6139 €, 6021 ± 4892 €, and 8461 ± 8515 €; P < 0.001) increased continuously in Rutherford 1-3, 4, 5, and 6. While only 49% of the patients suffered from CLI, these produced 65% of in-hospital costs (141 million €), and 56% during follow-up (336 million €). Regardless of recent advances in PAD treatment, current outcomes remain poor especially in CLI. Despite overwhelming evidence for reduction of limb loss by revascularization, CLI patients still received significantly less angiographies and revascularizations.

Clinical Application of Vascular Regenerative Therapy for Peripheral Artery Disease

Prognosis of peripheral artery disease (PAD), especially critical limb ischemia, is very poor despite the development of endovascular therapy and bypass surgery. Many patients result in leg amputation and, therefore, vascular regenerative therapy is expected in this field. Gene therapy using vascular endothelial growth factor is the first step of vascular regenerative therapy, but did not confirm effectiveness in a large-scale randomized comparative study. Based on animal experiments, bone marrow mononuclear cells (MNCs), peripheral blood MNCs were used as the cell source for regenerative therapy. Those cells were confirmed to be effective to decrease rest pain and ulcer size, but its effect was not fully satisfied. Mesenchymal stem cells (MSCs) are expected as an effective cell source for vascular regeneration and clinical studies are ongoing, because the cells are able to differentiate into various cell types and produce a significant amount of vascular growth factors. Of vascular regeneration therapy, peripheral MNCs and bone marrow MNCs were recognized as advanced medical technology but do not attain to the standard therapy. However, clinical use of MSCs have already started, and induced pluripotent stem cells are surely promising tool for vascular regeneration therapy although further basic studies are required for clinical application.

The role of nutrition and body composition in peripheral arterial disease

Peripheral arterial disease (PAD) has not been as extensively investigated as other cardiovascular diseases. However, the available data suggest that nutrition-based treatment strategies have the potential to reduce the cost-economic burden of PAD substantially. Abdominal obesity is associated with PAD and prospective and cross-sectional studies have shown that a low dietary intake of folate and reduced synthesis of vitamin D are associated with an increased risk of PAD and severe walking impairment in patients who have the disease. However, dietary patterns that are associated with decreased cardiovascular risk might protect against PAD. A small number of clinical trials have provided evidence that increased intakes of niacin and insoluble fiber might be associated with decreased levels of LDL cholesterol and thrombogenic biomarkers, as well as increased serum levels of HDL cholesterol in patients with PAD. However, little evidence that antioxidants, vitamins B(6) and B(12), or essential fatty acid supplements improve clinical outcomes in these patients exists. Overall, data on the effects of nutrition, body composition, and nutritional supplementation on the risk, progression, and prognosis of PAD are scarce. Further research into these areas is required to allow the development of evidence-based nutritional guidelines for the prevention and treatment of the disease.

Activated Protein C-Protein C Inhibitor Complex in Peripheral Arterial Disease

Thrombin activation measured by the levels of the complex between activated protein C (APC) and the protein C inhibitor (PCI) is elevated in several atherosclerotic disorders. The aim of this study was to evaluate whether levels of the APC-PCI complex are related to the prognosis in peripheral arterial disease (PAD). Longitudinal study performed at the Vascular Centre, Malmö University Hospital, Sweden. APC-PCI complex levels were analyzed in 268 consecutive patients hospitalized for PAD and in 42 healthy controls (median age, 74 years). Patients (n = 35) with warfarin treatment less than 4 weeks before APC-PCI sampling were excluded from analysis. Data-based medical records of all 233 remaining patients (median age, 72 [64-79] years) were searched for vascular events such as hospitalization because of atherosclerotic disease, operative or endovascular recanalization of peripheral arteries, transtibial or transfemoral amputation because of PAD, acute coronary syndrome, stroke, or death. Median duration of follow-up was 16 months (interquartile range, 12-23 months). APC-PCI complex levels were higher in PAD patients than in controls (0.240 [0.180-0.320] microg/L vs. 0.140 [0.190-0.220] microg/L; p < 0.0001) but not associated with an increased risk for death (p = 0.2054) or events during follow-up (p = 0.2850). Independent predictors of future events were low b-hemoglobin (p = 0.0084), high b-leukocytes (p = 0.0034), and history of a previous vascular event (p = 0.0032). Age (p = 0.0286), high p-creatinine (p = 0.0165), and history of a previous event (p = 0.0311) were independent predictors of death. APC-PCI complex levels were higher in PAD patients than in controls, but did not predict the clinical outcome. The effect of a possible prethrombotic state, as reflected in increased APC-PCI levels, on prognosis and severity of atherosclerotic disease has to be further investigated.

Abstract 5560: Association of 47 Candidate Proteomic Markers of Vascular Disease With the Ankle Brachial Index: The Mayo Clinic Proteomic Markers of Arteriosclerosis Study

Objectives: We investigated the association of 47 candidate proteomic markers in pathways of inflammation, thrombosis, lipoprotein metabolism, vascular remodeling, and vasoregulation, with the ankle-brachial index (ABI) and peripheral arterial disease (PAD) in a bi-ethnic cohort of African Americans (AA) and non-Hispanic Whites (NHW). Methods: Multiple assay platforms were used to measure 47 candidate proteomic markers in 1324 AA and 1237 NHW participants belonging to hypertensive sibships. ABI was measured using a standard protocol, with values &gt;1.4 excluded and PAD defined as ABI &lt;0.9. Multivariable regression analyses (with generalized estimating equations) were employed to identify markers independently associated with ABI and PAD after adjusting for age, BMI, smoking, hypertension, diabetes, history of heart attack and stroke, medication use, total and HDL cholesterol, and estimated GFR as well as physical activity, alcohol consumption and education level. Results: Higher circulating levels of CRP, myeloperoxidase, NT-proBNP, osteoprotegerin, D-Dimer and fibrinogen were each associated with lower ABI in both AA and NHW. Additional markers significantly associated with lower ABI were; in AA - serum amyloid A, ICAM, IL-6, TNFR-I, TNFR-II, MCP-1, Lp(a), pro-atrial natriuretic peptide, pro-arginine vasopressin, pro-adrenomedullin, pro-endothelin, osteonectin, Factor VIII; and in NHW- Hsp27, ox-LDL and resistin. Markers associated with presence of PAD were: in AA - CRP, NT-proBNP, Lp(a), pro-arginine vasopressin and osteoprotegerin; in NHW -CRP, NT-proBNP, Hsp27, myeloperoxidase, oxidized-LDL, Factor VIII, and D-Dimer. When the significant markers were included in a final model, the R 2 for ABI increased from 15.9 to 19.4 for AA and from 18.1 to 22.1 for NHW; the c-statistic for PAD increased from 0.791 to 0.833 inAA and from 0.841 to 0.866 in NHW. Conclusions: Novel protein markers significantly add to prediction of ABI and PAD in both AA and NHW and may have clinical utility in diagnosis and prognosis of PAD as well as in identifying new therapies for atherosclerotic vascular disease.

Depression and Screening Cardiovascular Events

To the Editor: —Peripheral arterial disease (PAD) remains an under-treated disease1, and information about risk factors and prognosis is poorly disseminated in the population2. Nevertheless, PAD and coronary artery disease (CAD) patients share the same risk factors, and risks of future cardiovascular events in PAD patients are comparable with those in CAD patients3. Depression may adversely impact prognosis in CAD patients4, but little is known about depression and prognosis in PAD. Therefore, we read with great interest the work of Cherr and colleagues5 on the relation between psychological factors and cardiovascular events in PAD. Their study generated interesting findings, but there are also a number of issues we would like to address here. First, the screening method the authors used probably led to an overestimation of depression rates. The General Health Questionnaire is not a depression scale, but rather was developed to assess non-specific psychological distress in community samples6, and a higher cut-off score (≥8) has been recommended to screen for depressive symptoms in patients with chronic somatic disease7. Second, 80% of depressed patients received antidepressant therapy. Analyses were not adjusted for type of antidepressant, while studies warn against the use tricyclic antidepressants in cardiovascular populations because they are associated with an increased risk of myocardial infarction8,9. Therefore, we cannot rule out the influence of antidepressant use on adverse outcomes in depressed patients. Finally, in the adjusted analyses, only a rough parameter of disease severity was included (indication for intervention). Table 2 shows us that the group that underwent revascularization was very heterogeneous in terms of disease severity; indication for intervention ranged from claudication to critical leg ischemia and gangrene or tissue loss. It would have been more appropriate to include the lowest ankle-brachial index in the adjusted analyses due to its strong prognostic value for adverse cardiovascular events in PAD10. Likewise, in CAD, the relation between depression and increased risk of mortality seems to be confounded by cardiac disease severity or left ventricular dysfunction11. Future studies examining the link between psychological factors and prognosis in PAD need to take into account reliable indices of disease severity.