Impaired muscle oxygen use at onset of exercise in peripheral arterial disease

ObjectivesIn patients with peripheral arterial disease (PAD), abnormal muscle metabolism and impaired oxygen delivery distal to the arterial occlusions may contribute to the exercise limitation observed in this population. Muscle tissue hemoglobin saturation (StO2), measured with near-infrared spectroscopy, reflects the relative contributions of oxygen delivery and oxygen use. Thus differences in the kinetics of StO2 in response to exercise may yield important insight into the potential mechanisms associated with the PAD exercise impairment. The purposes of this study were to characterize the muscle oxygenation responses in patients with PAD and in healthy control subjects at the onset of exercise, and to compare the kinetics of StO2 desaturation. We hypothesized that at the onset of exercise the kinetics of StO2 desaturation would be slowed in PAD compared with control responses.Material and methodsSix patients with PAD and 6 healthy control subjects from a university center were examined in a prospective cross-sectional analysis that evaluated the desaturation kinetics of StO2 at the onset of walking exercise. On separate visits subjects performed graded treadmill exercise and 3 constant work rate treadmill tests equivalent to ∼60% (low), ∼80% (medium), and 100% (peak) of their peak exercise work rate. Gastrocnemious muscle StO2 response profiles (InSpectra tissue spectrometer) were measured at rest and across the rest to exercise transition. Muscle StO2 responses were characterized by an exponential mathematical model. The end point value was taken as the time constant of StO2 desaturation after onset of exercise (ie, equivalent to time to reach approximately 63% of StO2 decrease).ResultsThe patients with PAD and the control subjects were of similar age and activity level. The qualitative patterns of StO2 responses at onset of exercise were also similar between patients and control subjects at all work rates. However, the kinetic time constants of StO2 desaturation were prolonged in patients with PAD versus control subjects (averaged time constant across all work rates, 21.9 ± 9.4 seconds vs 4.9 ± 2.2 seconds; P < .01).ConclusionsThe slowed muscle StO2 kinetics in PAD are consistent with an impairment in muscle oxygen use at the onset of walking exercise. Impaired muscle metabolism may contribute to the altered physiologic responses to exercise and to exercise impairment in patients with PAD

Persistent Organic Pollutant in the Venetian coastal environment

The Venetian coastal area is characterized by a strong anthropogenic impact and its quality is very important because of local economical activities, such as tourism or fishing. In the context of the Water Framework Directive (WFD, 2000/60/EC), the aim of the project Q-ALiVe (Qualità dell’Ambiente Litoraneo Veneto) is to check the environmental quality of the Venetian coastal area and whether rivers contamination could influence it. We studied an area going from the mouth of the Adige river to the Malamocco inlet of the Venice lagoon (including the mouth of the Brenta river and the Chioggia lagoon inlet), to distance from the coast of up to about a kilometer. In this work we presented the data relative to Persistent Organic Pollutants (POPs) as PCBs, PBDEs and PAHs, in samples of seawater. Samples were collected during four different sampling campaigns, in different seasons (June 2011, August 2011, September 2011, November 2011); in each sampling campaign we collected 10 samples of surface water. Analytical samples procedures for POPs include liquid-liquid continuous extraction, followed by an automated purification step, with neutral silica columns. Analysis were made by HRGC-HRMS (PCBs) or HRGC-LRMS (PAHs and PBDEs). Quantification was made by isotope dilution. Results suggest a negligible influence of rivers contamination to the quality of the sea facing the city of Chioggia and the Venice lagoon. Funds for this work were provided, in the framework of Q-ALiVe Project, by the Regione del Veneto - L.R. 15/07

Inflammatory Cytokines Associated With Failure of Lower-Extremity Endovascular Revascularization (LER): A Prospective Study of a Population With Diabetes

OBJECTIVE Peripheral artery disease (PAD) is one of the most relevant complications of diabetes. Although several pharmacological and revascularization approaches are available for treating patients with diabetes and PAD, an endovascular approach is often associated with postprocedural complications that can increase the risk for acute limb ischemia or amputation. However, no definitive molecular associations have been described that could explain the difference in outcomes after endovascular treatment in patients with diabetes, PAD, and chronic limb-threatening ischemia (CLTI). RESEARCH DESIGN AND METHODS We evaluated the relationship between the levels of the main cytokines associated with diabetic atherosclerosis and the outcomes after endovascular procedures in patients with diabetes, PAD, and CLTI. RESULTS A total of 299 patients with below-the-knee occlusive disease who were undergoing an angioplasty procedure were enrolled. The levels of key cytokines—osteoprotegerin (OPG), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP)—were measured, and major adverse limb events (MALE) and major adverse cardiovascular events (MACE) were assessed 1, 3, 6, and 12 months after the procedure. There was a linear trend from the lowest to the highest quartile for each cytokine at baseline and incident MALE. A linear association was also observed between increasing levels of each cytokine and incident MACE. Receiver operating characteristics models were constructed using clinical and laboratory risk factors, and the inclusion of cytokines significantly improved the prediction of incident events. CONCLUSIONS We demonstrated that elevated OPG, TNF-α, IL-6, and CRP levels at baseline correlate with worse vascular outcomes in patients with diabetes, PAD, and CLTI undergoing an endovascular procedure

Effects of canagliflozin on amputation risk in type 2 diabetes:the CANVAS Program

Aims/hypothesis The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.Methods The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.Results There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100mg and 300mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.Conclusions/interpretation The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.</p

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease

International audienc

Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication

Background: Claudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K-134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication. Methods: The study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K-134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms. Results: When 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial. Conclusions: In this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population

Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID.

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF