Mortality In Peripheral Artery Disease Research Articles

Secondary calciprotein particle size is associated with patient mortality in peripheral artery disease

Background and aimsSecondary calciprotein particles (CPP-II) induce inflammation and contribute to vascular calcification. CPP-II size is associated with vascular calcification in patients with chronic kidney disease (CKD) and all-cause mortality in hemodialysis patients. Here, we investigate for the first time a possible role of CPP-II size in patients with peripheral artery disease (PAD) without severe CKD. MethodsWe measured the hydrodynamic radius (Rh) of CPP-II by using dynamic light scattering in a cohort of 281 PAD patients. Mortality was evaluated over a period of ten years by central death registry queries. 35% of patients died during the observation period (median of 8.8 (6.2–9.0) years). Cox-regression analyses were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) and to allow for multivariable adjustment. ResultsThe mean CPP-II size was 188 (162-218) nm. Older patients, patients with reduced kidney function, and those with media sclerosis had larger CPP-II (p < 0.001, p = 0.008, and p = 0.043, retrospectively). There was no association between CPP-II size and overall atherosclerotic disease burden (p = 0.551). CPP-II size was independently significantly associated with all-cause (HR 1.33 (CI 1.01–1.74), p = 0.039) and cardiovascular mortality (HR 1.52 (CI 1.05–2.20), p = 0.026) in multivariable regression analyses. ConclusionsLarge CPP-II size is associated with mortality in PAD patients and might be a new feasible biomarker for the presence of media sclerosis in this patient population.

Discovery of four plasmatic biomarkers potentially predicting cardiovascular outcome in peripheral artery disease

Peripheral artery disease (PAD) patients have an increased cardiovascular risk despite pharmacological treatment strategies. Biomarker research improving risk stratification only focused on known atherothrombotic pathways, but unexplored pathways might play more important roles. To explore the association between a broad cardiovascular biomarker set and cardiovascular risk in PAD. 120 PAD outpatients were enrolled in this observational cohort study. Patients were followed for one year in which the composite endpoint (myocardial infarction, coronary revascularization, stroke, acute limb ischemia and mortality) was assessed. Patient data and blood samples were collected upon inclusion, and citrated platelet-poor plasma was used to analyze 184 biomarkers in Olink Cardiovascular panel II and III using a proximity extension assay. Fifteen patients reached the composite endpoint. These patients had more prior strokes and higher serum creatinine levels. Multivariate analysis revealed increased plasma levels of protease-activated receptor 1 (PAR1), galectin-9 (Gal-9), tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) and interleukin 6 (IL-6) to be most predictive for cardiovascular events and mortality. Positive regulation of acute inflammatory responses and leukocyte chemotaxis were identified as involved biological processes. This study identified IL-6, PAR1, Gal-9, TNFRSF11A as potent predictors for cardiovascular events and mortality in PAD, and potential drug development targets.

Lipoprotein (a) and long-term outcome in patients with peripheral artery disease undergoing revascularization

Background and aimsDespite low LDL-C goals, the residual risk for further cardiovascular (CV) events in patients with peripheral artery disease (PAD) remains high. Lipoprotein (a) (Lp(a)) is a known risk factor for PAD incidence, but little is known regarding the outcome in patients with symptomatic PAD. Thus, this study investigates Lp(a) and CV mortality in PAD after endovascular repair. MethodsA total of 1222 patients with PAD in two cohorts according to Lp(a) assay in nmol/L (n = 964, Lip-LEAD-A) or mg/dl (n = 258, Lip-LEAD-B) were followed up for 4.3 (IQR 3.0–5.6) or 7.6 (IQR 3.2–8.1) years. Lp(a) was measured before endovascular repair for either intermittent claudication (IC) or critical limb ischemia (CLI). Outcome information was obtained from the federal death registry. ResultsIn Lip-LEAD-A, 141 CV-deaths occurred (annual calculated CV-death rate 3.4%), whereas 64 CV-deaths were registered in Lip-LEAD-B (annual calculated CV-death rate 3.3%). After adjustment for traditional CV risk factors Lp(a) was neither associated with outcome in Lip-LEAD-A (highest tertile HR 1.47, 95%CI [0.96–2.24]) nor in Lip-LEAD-B (highest tertile HR 1.34 [0.70–2.58]). Subanalyses for IC (HR 1.37 [0.74–2.55]; HR 1.10 [0.44–2.80], CLI (HR 1.55 [0.86–2.80], HR 3.01 [0.99–9.10]), or concomitant coronary artery disease (CAD; HR 1.34 [0.71–2.54]; HR 1.21 [0.46–3.17]) failed to show a significant association between Lp(a) and CV-mortality. ConclusionsIn this large-scale cohort of symptomatic PAD no association of elevated Lp(a) with CV mortality was found over a median observation period of 5 years. Thus, an even longer study including asymptomatic patients is warranted.

Association of sleep apnea with outcomes in peripheral artery disease: Insights from the PORTRAIT study.

Sleep apnea is a predictor of adverse cardiovascular outcome in many cardiovascular diseases but whether it is associated with worse health status outcomes or mortality in peripheral artery disease (PAD) is unknown. PORTRAIT is an international (US, Netherlands, Australia) prospective PAD registry that consecutively enrolled patients who presented with new-onset or recent exacerbations of PAD symptoms to any of 16 vascular specialty clinics. Health status was assessed upon presentation and at 12 months with the disease-specific Peripheral Artery Questionnaire (PAQ). Higher PAQ scores indicate better health status. A sequentially-adjusted hierarchical linear regression model examined the association between sleep apnea and 1-year PAQ symptoms, quality of life, and summary scores. Five-year survival curves by comorbid sleep apnea status for US patients were compared using the log-rank test. The mean age of the 1204 PORTRAIT participants was 67.6 ± 9.4 years with 37.5% women and 8.3% (n = 100) having sleep apnea. Patients with sleep apnea were more likely to be from the US, more sedentary, and to have diabetes, obesity, coronary disease, more depressive symptoms and a history of prior peripheral interventions. Paradoxically, they also had higher ankle-brachial indices, but lower PAQ Summary scores at presentation and 12 months (41.2 ± 22.0 vs. 49. 9± 21.6 and 58.6 ± 27.9 vs. 71.3 ± 24.9, respectively, p = <0.05). The association between sleep apnea and 1-year health status persisted after multivariable adjustment, but there were no differences in all-cause mortality over 5 years (28.0% vs. 23.4%, p = 0.76). In patients presenting with PAD, comorbid sleep apnea is independently associated with worse health status over time. Future studies should test whether better treatment of sleep apnea can improve the health status of patients with PAD. NCT01419080.

Trimethylamine-N-Oxide (TMAO) Predicts Cardiovascular Mortality in Peripheral Artery Disease

Peripheral artery disease (PAD) is a major cause of acute and chronic illness, with extremely poor prognosis that remains underdiagnosed and undertreated. Trimethylamine-N-Oxide (TMAO), a gut derived metabolite, has been associated with atherosclerotic burden. We determined plasma levels of TMAO by mass spectrometry and evaluated their association with PAD severity and prognosis. 262 symptomatic PAD patients (mean age 70 years, 87% men) categorized in intermittent claudication (IC, n = 147) and critical limb ischemia (CLI, n = 115) were followed-up for a mean average of 4 years (min 1-max 102 months). TMAO levels were increased in CLI compared to IC (P < 0.001). Receiver operating characteristic (ROC) curves for severity (CLI) rendered a cutoff of 2.26 µmol/L for TMAO (62% sensitivity, 76% specificity). Patients with TMAO > 2.26 µmol/L exhibited higher risk of cardiovascular death (sub-hazard ratios ≥2, P < 0.05) that remained significant after adjustment for confounding factors. TMAO levels were associated to disease severity and CV-mortality in our cohort, suggesting an improvement of PAD prognosis with the measurement of TMAO. Overall, our results indicate that the intestinal bacterial function, together with the activity of key hepatic enzymes for TMA oxidation (FMO3) and renal function, should be considered when designing therapeutic strategies to control gut-derived metabolites in vascular patients.

P1960Endothelial progenitor cells are associated with cardiovascular outcome in patients with peripheral artery disease

Abstract Background and introduction Endothelial dysfunction and associated cells are an important cornerstone in the development and progression of peripheral artery disease (PAD). Endothelial progenitor cells (EPC) are released from the bone marrow and have exhibited the potential for cardiovascular repair. Higher EPC levels have been linked to longer event-free survival in coronary artery disease. Similar evaluation of EPC on mortality in PAD is lacking. Purpose The current study aimed to evaluate the possible association between EPC levels and mortality in PAD patients. Methods EPC were measured in 367 PAD patients (age 69.22±10.3, 66.5% male, Fontaine stage I-II) by flow cytometry using the cell surface marker CD34+ and CD309+. Patients were followed for seven years to assess all cause and cardiovascular mortality. Patients were categorized into quartiles according to EPC levels for further analyses. Statistics included Kaplan-Meier and Cox regression. Results 89 patients died over the observation period. ICD-codes indicated a cardiovascular cause in 58 patients. The group with the highest count of EPC showed a trend towards higher all-cause mortality (p=0.070) and a significant association with cardiovascular mortality (p=0.002). Multivariable adjustment for age, c-reactive protein, systolic blood pressure, renal function (creatinine and urinary albumin), low density lipoprotein cholesterol, HbA1c, and smoking status revealed the EPC quartile to be an independent risk factor for cardiovascular mortality (p=0.016). Conclusion Increased levels of CD34+CD309+ cells are independently associated with long-term cardiovascular mortality in PAD patients.

Arterial stiffness and 5-year mortality in patients with peripheral arterial disease.

Among patients with peripheral arterial disease (PAD) the risk of mortality remains extremely high. We investigated whether arterial stiffness evaluated by aortic Pulse Wave Velocity (aPWV) and Augmentation index normalized for a standard heart rate of 75 bpm (Aix@75), predict cardiovascular disease (CVD) and total mortality in PAD and No-PAD patients. In 231 PAD patients (ankle-brachial index-ABI ≤ 0.9) and 167 No-PAD (ABI ≥ 0.91 < 1.3) the aPWV and Aix @75HR were evaluated using arterial tonometry and ABI values were obtained using an 8-MHz Doppler probe. The CVD and total mortality rates in relation to aPWV and Aix@75HR were analyzed using Cox regression model. During a mean follow-up of 5.4 ± 2 years 39 (16.9%) deaths occurred in PAD patients and 8 (4.8%) in No-PAD. In the population study, the age was a predictor of CVD mortality (HR = 0.143, 95% CI, 0.06-0.23; p = 0.0004) while the aPWV, was a predictor of total mortality (HR = 1.18, 95% CI, 1.07-1.30; p = 0.0008). In the PAD group, the aPWV remained associated with an increased risk for total mortality (HR = 1.14, 95% CI, 1.03-1.27; p = 0.010). An increase of aPWV may be an indicator of total mortality in PAD patients.

Trimethylamine (Tma) And Trimethylamine-N-Oxide (Tmao) As Predictors Of Cardiovascular Mortality In Peripheral Artery Disease

Trimethylamine (Tma) And Trimethylamine-N-Oxide (Tmao) As Predictors Of Cardiovascular Mortality In Peripheral Artery Disease

Impact of diabetes on mortality in peripheral artery disease: a meta‐analysis

There are accumulating studies showing the association between diabetes and all-cause mortality in peripheral vascular disease. However, the results in these studies are conflicting regarding the impact of diabetes on outcome. Diabetes is associated with increased risk of mortality in peripheral artery disease. Using MEDLINE and Scopus, we searched for studies published before January 2016. Additionally, studies were identified by manual search of references of original articles or review studies on this topic. Of the 1072 initially identified records, 21 studies with 15,857 patients were included in the final analysis. Diabetes was associated with a statistically significant increased risk of all-cause mortality (odds ratio: 1.89, 95% confidence interval: 1.51-2.35, P < 0.001), without detected publication bias (Egger bias = 0.75, P = 0.631). The stronger effect on outcome was obtained in patients with critical limb ischemia (odds ratio: 2.38, 95% confidence interval: 1.22-4.63, P < 0.001) as the most severe form of peripheral vascular disease. Diabetes is associated with an increased risk of mortality in peripheral vascular disease, and the effect is even more pronounced in patients with critical limb ischemia.

Semiquantitative assessment of tibial artery calcification by computed tomography angiography and its ability to predict infrapopliteal angioplasty outcomes

Tibial artery calcification (TAC) is associated with increased risk of amputation and mortality in peripheral artery disease. We sought to investigate whether the severity of TAC based on semiquantitative analysis of computed tomography angiography (CTA) can predict outcomes of endovascular therapy in patients with critical limb ischemia. We reviewed medical records of 124 patients who underwent lower extremity CTA before intervention. Based on CTA, TAC severity was categorized into three groups: minimal calcification (MC; n= 43), intermediate calcification (IC;n= 36), or extensive calcification (EC; n= 45). Immediate and late outcomes of infrapopliteal interventions were compared, and predictors of the outcomes were investigated. The categorized severity of target TAC correlated with the log-transformed TAC score (r= 0.873; P< .001). The EC group was younger and had more diabetes and chronic kidney disease compared with the MC or IC group (all P< .001). The technical success was lower in the EC group (71.1%) than in the MC (95.3%) or IC (91.7%) group (P= .001). The survival free of unplanned amputations at 2years was significantly lower in the EC group (58.9%) than in the MC (79.0%) or IC (95.3%) group (P< .001). Extensive TAC was an independent predictor of technical success (hazard ratio, 0.02; 95%confidence interval, 0.00-0.45; P= .014) and unplanned amputation (hazard ratio, 9.90; 95% confidence interval, 2.05-47.75; P= .004). The categorized severity of TAC by semiquantitative analysis of CTA correlated with TAC score, and extensive TAC was associated with a lower technical success rate of angioplasty and an increased incidence of unplanned amputation.

Community walking speed, sedentary or lying down time, and mortality in peripheral artery disease.

We studied whether slower community walking speed and whether greater time spent lying down or sleeping were associated with higher mortality in people with lower extremity peripheral artery disease (PAD). Participants with an ankle-brachial index (ABI) < 0.90 were identified from Chicago medical centers. At baseline, participants reported their usual walking speed outside their home and the number of hours they spent lying down or sleeping per day. Cause of death was adjudicated using death certificates and medical record review. Analyses were adjusted for age, sex, race, comorbidities, ABI, and other confounders. Of 1314 PAD participants, 189 (14.4%) died, including 63 cardiovascular disease (CVD) deaths. Mean follow-up was 34.9 months ± 18.1. Relative to average or normal pace (2-3 miles/hour), slower walking speed was associated with greater CVD mortality: no walking at all: hazard ratio (HR) = 4.17, 95% confidence interval (CI) = 1.46-11.89; casual strolling (0-2 miles/hour): HR = 2.24, 95% CI = 1.16-4.32; brisk or striding (>3 miles/hour): HR = 0.55, 95% CI = 0.07-4.30. These associations were not significant after additional adjustment for the six-minute walk. Relative to sleeping or lying down for 8-9 hours, fewer or greater hours sleeping or lying down were associated with higher CVD mortality: 4-7 hours: HR = 2.08, 95% CI = 1.06-4.05; 10-11 hours: HR = 4.07, 95% CI = 1.86-8.89; ⩾ 12 hours: HR = 3.75, 95% CI = 1.47-9.62. These associations were maintained after adjustment for the six-minute walk. In conclusion, slower walking speed outside the home and less than 8 hours or more than 9 hours lying down per day are potentially modifiable behaviors associated with increased CVD mortality in patients with PAD.

The association between ischemic and jeopardized myocardia and all-cause mortality in patients with peripheral artery disease.

Peripheral artery disease (PAD) is associated with increased mortality and concomitant coronary artery disease (CAD). However, it is unclear whether uncovering the presence of functional coronary ischemia by single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) would further help stratifying that excess risk. From January 2000 to 2009, 4294 individuals underwent cardiac stress testing within 180 days of ankle-brachial index (ABI) measurements. Of these, 645 had PAD and SPECT MPI stress testing. Abnormal ABI was defined as ⩽ 0.9 or prior lower extremity arterial revascularization. Myocardial ischemic burden and total jeopardized myocardium were represented by the summed difference score (SDS) and summed stress score (SSS), respectively. Univariate and multivariable Cox proportional hazard analyses were used to study the impact of SDS and SSS on all-cause mortality. Additionally, using a hierarchical approach, we examined the step-wise addition of post-stress test coronary and lower extremity arterial revascularizations as time-varying covariates on outcomes. We found no significant difference in all-cause mortality between patients with ischemic myocardium (SDS > 0) and those without (SDS = 0) (adjusted HR: 0.94, 95% CI: 0.53-1.69; p = 0.84). Similarly, the presence of jeopardized myocardium (SSS > 0) did not have a significant impact on mortality (adjusted HR: 1.16, 95% CI: 0.67-2.00; p = 0.59). Moreover, adjustment for post-testing coronary and lower extremity arterial revascularizations did not affect our results. In conclusion, ischemic and jeopardized myocardia are not predictors of all-cause mortality in PAD; thus, SPECT MPI does not appear to be a useful risk stratification tool in these patients.

Long Term Risk for Peripheral Arterial Disease Patients is Higher Among Men

Introduction: The introduction of modern cardiovascular risk preventive therapy and new endovascular treatment options may have influenced the long term mortality and morbidity in patients with peripheral arterial disease (PAD). The aim of this study was to determine long-term survival and incidence of leg revascularizations in subjects with PAD with special focus on gender differences. Methods: A cohort study was started 2004 by randomly selecting 8000 subjects, aged 59–89 years, from the population. A total of 5080 subjects participated and underwent ankle brachial index measurements (ABI). Data was also collected for risk factors and concomitant diseases. The cohort was re-examined 2015 covering data from national governmental registries on survival and surgical interventions for PAD. Results: The point-prevalence of PAD in 2004 was 11 % (95% CI, 9–13) for subjects having only asymptomatic PAD (APAD), 7% (6.5 –7) for intermittent claudication (IC) and 1.2 % (1 –1.5) for those with severe limb ischemia(SLI). Among the 4926 subjects who were available for follow up at 10 years the mortality rates were 50% for APAD, 59% for IC and 72% for SLI. Subjects without PAD had a rate of 24%. Mortality was higher among men (age adjusted 35.9% 95% CI: 34.2–37.6) than women (26.1% 95% CI: 24.7–27.6) likewise in PAD subjects with diabetes mellitus (68% vs. 52% without, p < 0.001). Factors significantly related to increased mortality were for men and women, respectively; SLI (HR 1.87 and 1.87), congestive heart failure (HR 1.69 vs. 2.44), renal failure (HR 1.4. vs. 2.2) and diabetes (HR 1.51 vs. 1.65). Fifty one subjects underwent revascularization because of chronic leg ischemia in the cohort during the ten years. In the reference group the rate was 0.4%, while it was 1.9 % of APAD subjects, 5.8 % of the IC and 6.2% of the SLI group. Conclusion: The mortality is still high in patients with PAD, and half of patients with APAD are dead within 10 years which is comparable with IC patients. The mortality is higher in men than in women. In a population based cohort like this, very few patients were revascularized, and surprisingly few patients with IC and SLI are offered vascular surgery. Overall, more focus on mortality in PAD is needed and there is still a need for information about vascular surgery to GP's offices and awareness among PAD subjects.

Coronary Artery Disease Severity and Cardiovascular Biomarkers in Patients with Peripheral Artery Disease

Cardiovascular mortality in peripheral artery disease (PAD) patients is higher in critical limb ischemia (CLI) than in intermittent claudication (IC). We sought to evaluate differential characteristics of coronary artery disease (CAD) severity and prognostic biomarkers for cardiovascular events between CLI and IC patients. Coronary angiography was performed on 242 PAD patients (age 73 ± 8 years) with either CLI or IC. High-sensitivity troponin T (hs-TnT), eicosapentaenoic acid-arachidonic acid ratio (EPA/AA), and lipoprotein(a), as biomarkers for prognostic factors, were measured from blood samples. The study patients were divided into a CLI-group (n = 42) and IC-group (n = 200). The Gensini score as an indicator of coronary angiographic severity was higher in the CLI-group than in the IC-group (39.1 ± 31.2 vs. 8.5 ± 8.3, p < 0.0001). Hs-TnT and lipoprotein(a) values were higher in the CLI-group than in the IC-group (0.152 ± 0.186 ng/mL vs. 0.046 ± 0.091, p < 0.0001, 45.9 ± 23.3 mg/dL vs. 26.2 ± 27.7, p = 0.0002, respectively) and EPA/AA was lower in the CLI-group than in the IC-group (0.22 ± 0.11 vs. 0.38 ± 0.29, p = 0.0049, respectively). Greater CAD severity, higher hs-TnT, and lipoprotein(a), and lower EPA/AA were observed in the CLI-group, which may explain higher cardiovascular events in patients with CLI.

Vitamin D status, functional decline, and mortality in peripheral artery disease

Associations of vitamin D levels with prospectively measured functional decline and mortality in people with lower extremity peripheral artery disease (PAD) are unknown. We determined whether lower baseline vitamin D levels are associated with a faster decline in functional performance and higher mortality among people with and without PAD. A total of 658 participants (395 with PAD) underwent baseline measurement of 25-hydroxyvitamin D (DiaSorin radioimmunoassay), a 6-minute walk test, 4-meter walking velocity and the Short Physical Performance Battery (SPPB), and were followed annually for up to 4 years. Analyses were adjusted for age, sex, race, body mass index, comorbidities, the ankle-brachial index, and other confounders. Among participants with PAD, lower baseline vitamin D levels were associated with a faster decline in the 6-minute walk (vitamin D < 30 nmol/L: -70.0 feet/year; vitamin D 30 to < 50 nmol/L: -72.3 feet/year; vitamin D 50 to < 75 nmol/L: -35.5 feet/year; vitamin D 75 to < 120 nmol/L: -35.9 feet/year; p trend=0.012). PAD participants with vitamin D < 30 nmol/L had a faster decline in the SPPB and 6-minute walk compared to those with levels of 50 to < 75 (p=0.034 and p=0.04, respectively). Among participants without PAD, lower vitamin D was associated with a faster decline in the fast 4-meter walking velocity (p trend=0.003). There were no significant associations of baseline vitamin D levels with all-cause or cardiovascular disease mortality in PAD or non-PAD participants. In conclusion, among individuals with and without PAD, low vitamin D status was associated with a faster decline in some measures of functional performance but was not related to mortality.

Mortality in Patients with Pad with Respect to Glycaemic Status: A Review

Peripheral arterial disease (PAD) is a manifestation of atherosclerosis. Atherosclerosis is a chronic inflammatory process and nonenzymatic glycation is a process of major interest in relation to how risk factors promote atherogenesis. A strong association between diabetes mellitus (DM) and PAD has been established, and the association is related to the duration of DM. Previous studies have revealed a higher prevalence of DM in patients with PAD compared to general populations and populations at risk of developing DM. The typical dyslipidaemia found in patients with PAD is similar to that found in patients with insulin resistance, and an association of HbA1c with atherogenic dyslipidaemia is described. HbA1c has been described as a predictor for DM and of micro and macrovascular disease. 5-year all-cause mortality in PAD is 19–37% and 10-year all-cause mortality is 42-54%. The mortality in PAD increases with age, with the severity of the peripheral vascular disease, and with the coexistence of PAD with coronary artery disease and DM. Patients with DM, defined by glucose criteria, and PAD have an increased mortality compared with patients with PAD alone. Recent studies have shown an association of HbA1c levels with vascular complications and death in patients with DM. No studies could be found that aimed to validate HbA1c against glucose criteria as a predictor for mortality in patients with PAD. Further studies on patients with PAD and DM are needed to identify which is the best diagnostic method to predict mortality in PAD with respect to glycaemic status: the glucose parameters or the HbA1c.

Abstract 298: Microfibrillar Protein 4 is an Integrin avß3/5 Ligand Involved in Vascular Remodeling

Arterial injury stimulates remodeling responses that, when overexuberant, leads to stenosis. This response is influenced by specific integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is a matricellular integrin ligand localized to the vascular wall. We hypothesized that systemic MFAP4 (sMFAP4) associates to vascular remodeling processes and that MFAP4 enhances integrin dependent VSMC activation and vasculoproliferative disease-associated remodeling. We explored the hypotheses using a prospective human cohort with symptomatic obstructive peripheral arterial disease (PAD), VSMC culture studies, and produced MFAP4 deficient mice for studying neointima formation. We demonstrate that the highest tertile of sMFAP4 was significantly associated with primary patency after vascular reconstruction, and the overall need for vascular reconstruction and mortality in 343 PAD patients. MFAP4 mediated the adhesion, migration, and proliferation of VSMCs in an integrin αVβ3/5-dependent manner in vitro. These effects were inhibited by MFAP4-blocking antibodies. MFAP4-deficient mice displayed delayed neointimal formation when challenged with carotid artery ligation, but the compensatory outward remodeling of vessel diameter was reduced. In conclusion, sMFAP4 has the potential to serve as a systemic marker morbidity and mortality in PAD. MFAP4 regulates integrin αVβ3/5 signaling and pathological remodeling in vivo, and may have therapeutic implications in vasculoproliferative diseases.

Declining Walking Impairment Questionnaire Scores Are Associated With Subsequent Increased Mortality in Peripheral Artery Disease

This study determined whether greater 2-year declines in Walking Impairment Questionnaire (WIQ) stair climbing, distance, or speed scores were associated with higher all-cause and cardiovascular disease (CVD) mortality among men and women with lower extremity peripheral artery disease (PAD). Associations of decline in the WIQ with mortality among people with PAD are unknown. Participants were 442 men and women with PAD identified from Chicago area medical centers. The WIQ was completed at baseline and at 2-year follow-up. Cox proportional hazard models were used to assess associations across categories of 2-year changes in WIQ stair climbing, WIQ distance, and WIQ speed scores with subsequent all-cause and CVD mortality, adjusting for age, sex, race, ankle-brachial index, body mass index, smoking, comorbidities, and other covariates. One hundred twenty-three participants (27.8%) died during a median follow-up of 4.7 years after the 2-year change in WIQ score measurements. Forty-five participants died from CVD. Adjusting for covariates, participants with WIQ score declines ≥20.0 points had higher all-cause mortality (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.01 to 3.68 for WIQ stair climbing; HR: 2.34, 95% CI: 1.15 to 4.75 for WIQ distance; and HR: 3.55, 95% CI: 1.57 to 8.04 for WIQ speed, respectively) compared with participants with ≥20.0 point improvement in each of the corresponding WIQ categories. Participants with ≥20.0 point declines in the WIQ distance score had higher CVD mortality (HR: 4.56, 95% CI: 1.30 to 16.01) compared with those with ≥20.0 point improvement in the WIQ distance score. Patients with PAD who experienced ≥20.0 point declines in the WIQ stair climbing, distance, and speed scores had a higher rate of all-cause mortality compared with those with less declines in each WIQ score.

Peripheral arterial disease: a literature review

Peripheral arterial disease (PAD) is a common vascular condition that affects both quality of life and life expectancy with an increased risk of cardiovascular events. A literature search was carried out of Pub-Med, MEDLINE, the Cochrane Library and Google Scholar from the establishment of these databases up to February 2012. The search was performed by using the keywords 'peripheral arterial disease' and one of the following words: 'management', 'investigations', 'risk factors', 'epidemiology', 'revascularization', 'cryoplasty', 'atherectomy' and 'gene therapy'. Studies were limited to those published in English language. Aggressive risk factors modification is needed to reduce cardiovascular-related mortality in PAD patients. Choice of endovascular or surgical intervention remains controversial in an ever-evolving field. There is a rapid expansion of endovascular technologies aiming to improve the effectiveness of this modality. The advances in the fields of gene therapy and therapeutic angiogenesis mean these are potential future treatments. Tissue engineering is a developing area and aims to produce grafts with similar patency and infection profiles to those of autologous material. Further elucidation of the pathophysiology of atherosclerosis is required to provide new targets for pharmacotherapy.

Abstract 198: Oxidative Stress Mediates the Augmented Muscle Mechanoreflex in Peripheral Arterial Disease Patients

Background Exaggerated blood pressure (BP) responses to dynamic exercise predict cardiovascular mortality in peripheral arterial disease (PAD) patients. However, the underlying mechanisms are unclear and no attempt has been made to attenuate this response using antioxidants. Methods Three physiological studies were conducted in PAD patients and controls. In Protocol 1, subjects underwent four minutes of low-intensity (0.5-2.0 kg), rhythmic plantar flexion in the supine posture. In Protocol 2, PAD patients received high dose ascorbic acid intravenously prior to exercise. In Protocol 3, involuntary exercise was conducted via electrical stimulation of the tibial nerve. The primary outcome measure was the change in mean arterial pressure (ΔMAP) during the first 20 seconds of exercise (i.e. when mechanoreceptors within skeletal muscle activate the sympathetic nervous system). Results Compared to controls, PAD patients had significantly greater ΔMAP during plantar flexion, particularly at 0.5 kg of the most affected leg (11±2 vs. 2±1 mmHg) as well as the least affected leg (7±1 vs. 1±1 mmHg). This augmented response occurred before the onset of claudication pain and was attenuated by ∼50% (i.e. 6 mmHg) in the presence of ascorbic acid. Electrically evoked exercise also elicited larger hemodynamic changes in the PAD patients compared to controls. Further, the ΔMAP during 0.5 kg plantar flexion inversely correlated with the ankle-brachial index, indicating that patients with more severe resting limb ischemia had a larger BP response to exercise. Conclusions The BP response to low intensity exercise was enhanced in PAD. Chronic limb ischemia may sensitize muscle afferents and potentiate the autonomic response to muscle contraction in a dose-dependent manner.