Development Of Critical Limb Ischemia Research Articles

Lipoprotein(a) and the risk of major adverse limb events in patients with stable atherosclerotic vascular disease

Abstract Background/Introduction Patients with atherosclerotic vascular disease are at heightened risk of ischemic events, including adverse limb events. The pathobiology of adverse limb events ranges from events that are predominantly thrombotic such as acute limb ischemia (ALI) to those that are due primarily to progressive atherosclerosis such as worsening functional imitation requiring elective peripheral revascularization and development of critical limb ischemia (CLI). Evolving data suggest that lipoprotein(a) [Lp(a)] may be associated with the risk of adverse limb events; however, which type of events are related to Lp(a) has not been well described. Purpose To evaluate the association between Lp(a) and specific limb outcomes in patients with stable atherosclerotic vascular disease. Methods Data from two randomized clinical trials including patients with stable atherosclerotic vascular disease were combined: TRA2P-TIMI 50 and FOURIER. We measured Lp(a) in baseline samples in the TIMI Clinical Trials Laboratory. Major adverse cardiovascular events (CV death, myocardial infarction (MI), or stroke) were the primary or key secondary outcomes of the trials. Peripheral revascularization procedures occurring during follow up were investigator reported. Adverse limb events, including CLI and ALI, were categorized through the review of safety data by two blinded vascular specialists. MALE was defined as the composite of peripheral revascularization, CLI, or ALI. The association of Lp(a) as a continuous variable and MALE was assessed and adjusted for randomized therapy in each trial, age, sex, race, region, prior MI, prior stroke, peripheral artery disease, hypertension, diabetes mellitus, smoking status, and statin use. Results A total of 28,892 patients were included in the combined analysis population. The median Lp(a) was 36 nmol/L (IQR 12 – 159). A total of 1336 MALE events occurred during follow-up, including 1307 peripheral revascularizations (1237 elective, 173 urgent), 259 CLI events, and 148 ALI events. Lp(a) was associated with an increased risk of MALE (Adj HR 1.07 per SD, 95% CI 1.02 – 1.13, p=0.007, Figure Panel A) with the risk of a similar magnitude for that of MACE (Adj HR 1.05 per SD, 95% CI 1.01 – 1.10, p=0.020). The association of Lp(a) and MALE was driven by peripheral revascularizations including elective revascularization (Adj. HR 1.07, 95% CI 1.02 – 1.13, p=0.010) with a consistent trend for CLI; however, a relationship with ALI was unclear (Figure Panel B). Conclusion In patients with stable atherosclerotic vascular disease, Lp(a) is associated with MALE with the relationship driven by peripheral revascularization and a consistent trend for CLI. Any relationship with ALI, a primarily thrombotic event, is less clear. Overall, these data support the relationship of Lp(a) and progression of lower extremity atherosclerosis.Figure Panel AFigure Panel B

Impaired angiogenesis in diabetic critical limb ischemia is mediated by a miR-130b/INHBA signaling axis.

Patients with peripheral artery disease (PAD) and diabetes compose a high-risk population for development of critical limb ischemia (CLI) and amputation, although the underlying mechanisms remain poorly understood. Comparison of dysregulated microRNAs from diabetic patients with PAD and diabetic mice with limb ischemia revealed the conserved microRNA, miR-130b-3p. In vitro angiogenic assays demonstrated that miR-130b rapidly promoted proliferation, migration, and sprouting in endothelial cells (ECs), whereas miR-130b inhibition exerted antiangiogenic effects. Local delivery of miR-130b mimics into ischemic muscles of diabetic mice (db/db) following femoral artery ligation (FAL) promoted revascularization by increasing angiogenesis and markedly improved limb necrosis and amputation. RNA-Seq and gene set enrichment analysis from miR-130b-overexpressing ECs revealed the BMP/TGF-β signaling pathway as one of the top dysregulated pathways. Accordingly, overlapping downregulated transcripts from RNA-Seq and miRNA prediction algorithms identified that miR-130b directly targeted and repressed the TGF-β superfamily member inhibin-β-A (INHBA). miR-130b overexpression or siRNA-mediated knockdown of INHBA induced IL-8 expression, a potent angiogenic chemokine. Lastly, ectopic delivery of silencer RNAs (siRNA) targeting Inhba in db/db ischemic muscles following FAL improved revascularization and limb necrosis, recapitulating the phenotype of miR-130b delivery. Taken together, a miR-130b/INHBA signaling axis may provide therapeutic targets for patients with PAD and diabetes at risk of developing CLI.

Medical Management of Peripheral Arterial Disease

Peripheral arterial disease is a condition associated with high rates of cardiovascular morbidity and mortality, increased risk of adverse limb events, including development of critical limb ischemia and amputation, and also with decreased quality of life. This manuscript provides an overview of the medical management of patients with peripheral arterial disease. We discuss contemporary therapies that decrease major adverse cardiovascular and limb events among patients with peripheral arterial disease, and also therapies that improve the patient's ability to walk and quality of life in general.

Evaluation of Perfusion Index as a Screening Tool for Developing Critical Limb Ischemia.

Objective: The perfusion index (PI) is a physiological marker for evaluating the peripheral circulation. We explored the possibility of using PI as a screening tool for development of critical limb ischemia in peripheral artery disease (PAD).Method: We measured the PI in 79 limbs of 70 PAD patients. Data were analyzed to find a correlation between the PI and PAD severity.Result: The PI tended to be lower as PAD became severer. Especially, there were significant differences between the Fontaine 1 and Fontaine 4 groups in average PI and minimum PI, and between Fontaine 1 and two other groups (Fontaine 2 and Fontaine 4 groups) in maximum PI. A mild correlation was found between PI and the ankle brachial index. These data were used to calculate an average PI of 0.27 as a cut-off value for critical limb ischemia (CLI). In 65 asymptomatic PAD patients and claudication, significantly more patients with a PI value greater than the cut-off value developed CLI than those with a PI lower than the cut-off.Conclusion: The PI can be a useful tool for evaluating the development of CLI in mild PAD patients, and patients tended not to progress to CLI when their average PI was higher than 0.27. (This is a translation of Jpn J Vasc Surg 2020; 29: 103–108.)

Total thrombus-formation analysis system (T-TAS) can predict target lesion revascularization in patients undergoing endovascular therapy for critical limb ischemia

Abstract Background Despite of the development of endovascular therapy (EVT), the frequency of target lesion revascularization (TLR) after EVT in patients with critical limb ischemia (CLI) is still high. Recent histrogical study suggested the possibility of thromboembolic phenomenon in the development of CLI; however, there is few monitoring system of total thrombogenicity in perioperative period of EVT in CLI patients. The total thrombus-formation analysis system (T-TAS), a novel system for quantitatively analyzing thrombus formation using microchips with thrombogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip), is validated and can evaluate the total thrombogenicity. Purpose To investigate the utility of T-TAS parameters in predicting TLR after EVT in CLI patients. Methods We analyzed 27 CLI patients (45 lesions; aortoiliac 20%, femoropopliteal 40%, infrapopliteal 40%) who underwent EVT at our institution between January 2018 and December 2020. Patients undergoing hemodialysis were excluded. Blood sample was collected on the day of EVT and was used in T-TAS to compute the thrombus formation area under the curve (AUC; AUC for the first 30 minutes for AR tested at flow rate of 10 lL/min [AR10-AUC30]). We investigated the relationship between the AR10-AUC30 level and the occurrence of clinically-driven TLR, and the predictors of TLR among CLI patients. Results Study population had a mean age of 77 years, and 56% were male. During the follow-up period (mean 1.0±0.7 years), 11 lesions (24%) required clinically-driven TLR. The AR10-AUC30 level was significantly higher in patients requiring TLR than those without TLR (1783±121 vs. 1587±205; p<0.01). The frequency of TLR significantly increased in association with a tertile of the AR10-AUC30 level (Figure 1, p for trend=0.003). As shown in Figure 2, univariate logistic regression analysis demonstrated male sex and the third tertile of the AR10-AUC30 level compared to its first or second tertiles were significantly associated with TLR in patients with CLI, whereas platelet count, PT-INR, APTT, and atherosclerotic risk factors including glycated hemoglobin, low-density lipoprotein cholesterol, and renal function were not. Multivariate logistic regression analysis also revealed that the AR10-AUC30 level ≥1707 (=its third tertile) as an independent predictor for TLR, even after adjusted by age and sex (OR=6.28, 95% CI=1.18–33.3, p=0.03). Conclusions In patients with CLI, the AR10-AUC30 level measured by the T-TAS may be a potential predictor to identify the high-risk patients requiring TLR after EVT. This finding suggests the hypercoagulability in CLI patients and that an anticoagulant agent following EVT may be useful in preventing a restenosis in CLI patients. Further study with a larger sample size is warranted to validate this finding. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Targeted Delivery of a Matrix Metalloproteinases-2 Specific Inhibitor Using Multifunctional Nanogels to Attenuate Ischemic Skeletal Muscle Degeneration and Promote Revascularization.

Critical limb ischemia (CLI) is a severe form of peripheral artery disease (PAD). It is featured by degenerated skeletal muscle and poor vascularization. During the development of CLI, the upregulated matrix metalloproteinase-2 (MMP-2) degrades muscle extracellular matrix to initiate the degeneration. Meanwhile, MMP-2 is necessary for blood vessel formation. It is thus hypothesized that appropriate MMP-2 bioactivity in ischemic limbs will not only attenuate muscle degeneration but also promote blood vessel formation. Herein, we developed ischemia-targeting poly(N-isopropylacrylamide)-based nanogels to specifically deliver an MMP-2 inhibitor CTTHWGFTLC (CTT) into ischemic limbs to tailor MMP-2 bioactivity. Besides acting as an MMP-2 inhibitor, CTT promoted endothelial cell migration under conditions mimicking the ischemic limbs. The nanogels were sensitive to the pH of ischemic tissues, allowing them to largely aggregate in the injured area. To help reduce nanogel uptake by macrophages and increase circulation time, the nanogels were cloaked with a platelet membrane. An ischemia-targeting peptide CSTSMLKA (CST) was further conjugated on the platelet membrane for targeted delivery of nanogels into the ischemic area. CTT gradually released from the nanogels for 4 weeks. The nanogels mostly accumulated in the ischemic area for 28 days. The released CTT preserved collagen in the muscle and promoted its regeneration. In addition, CTT stimulated angiogenesis. Four weeks after CLI, the blood flow and vessel density of the ischemic limbs treated with the nanogels were remarkably higher than the control groups without CTT release. These results demonstrate that the developed nanogel-based CTT release system has the potential to stimulate ischemic limb regeneration.

P1486CHRONIC DIALYSIS IN ELDERLY PATIENTS: FUNCTIONAL PERFORMANCE STATUS AND TREATMENT OUTCOMES - A SINGLE-CENTER STUDY

Abstract Background and Aims The presence of multiple comorbid conditions and different geriatric impairments in elderly patients leads to a certain specificity in the management of this cohort of patients. The aim was to assess changes in functional performance status and treatment outcomes in elderly patients on chronic dialysis. Method A single-center longitudinal prospective study was conducted, which included 48 patients aged 65 years and older who underwent dialysis (hemodialysis and continuous ambulatory peritoneal dialysis) for more than 3 months. Participants’ functional performance status was measured by the Frailty Scale of Rockwood (FSR) at baseline and after a year of treatment. Functional performance status decline was defined as deterioration by 1 or more positions on the FSR, stable was defined as no difference between baseline and follow-up, and improvement was defined as a gain of 1 or more positions. At baseline, all participants were assessed by the Charlson Comorbidity Index (CCI) and standard lab tests were carried out. All data are presented as median and quartiles (25%; 75%). Results The median of age was 69 (67; 74) and 39.6% were women. The main causes of end-stage renal disease were hypertension (33.3%) and diabetes (31.3%). There were 83.3% hemodialysis patients and 31.3% received dialysis up to 1 year. At baseline 16.7% of patients were frail, 54.2% - pre-frail and 29.1% were fit. Among frail patients at the 1-year follow-up, 62.5% died, 12.5% had received a kidney transplant (KT), 25% showed a further functional performance status decline. Among pre-frail patients, almost half (46.2%) experienced functional decline and 15.4% died; the functional status remained unchanged in 30.8% of patients and 3.8% was transplanted; 1 patient (3.8%) had an improvement in functional performance status. Among fit patients, over half (57.2%) showed stable functional status, a functional decline was observed in 21.4% of patients (all of them became frail), 7.1% died and 14.3% had received a KT. All patients, who had stable functional performance status after a year of treatment, had target values of kt/v, albumin, and phosphorus at baseline. All deceased patients (20.8%) had CCI ≥ 6, 60% of them had high serum phosphorus level. Most functional performance status decline among participants was associated with a loss of mobility, which was most often caused by the progression of chronic heart failure (both independently and after heart attack) or chronic arterial failure (diabetic, due to obliterating atherosclerosis of the lower extremities), including the development of critical limb ischemia, especially in patients on hemodialysis. The distribution of patients according to the FSR in the initial assessment and re-assessment are presented in the table below. Conclusion Functional decline is highly prevalent in elderly patients on chronic dialysis, the risk is higher among frail and pre-frail patients. In most cases, functional performance status decline is associated with a loss of mobility due to the progression of chronic heart or arterial failure. Death probability is higher among frail patients and those with high serum phosphorus level (because of inadequate dialysis due to the initially severe condition of these patients) and high CCI. Achievement in the complex of the target values of kt/v, serum albumin, and phosphorus levels can help to maintain the functional status stable.

Kidney Transplantation Reduces the Risk of Critical Limb Ischemia and/or Amputation Among Patients With End-stage Renal Disease on Hemodialysis

Introduction: The objective of the study was to analyze the risk of critical limb ischemia and/or amputation among patients with end-stage renal disease (ESRD) entering a hemodialysis (HD) program and to evaluate the possible protective effect associated with kidney transplantation. Methods: Retrospective cohort including all ESDR patients that started on HD program at our institution between 2000 and 2010. Collected variables included baseline characteristics (pre-entry in hemodialysis), time on HD program, kidney transplantation and the development of critical limb ischemia and/or need for minor or major amputation. Patients with previous symptomatic peripheral arterial disease or amputation were excluded. Statistics: Cox regression model adjusted for all variables related to 1) critical limb ischemia and/or minor/major amputation and 2) renal transplantation. Results: The study group included 336 patients (mean age = 63 years, 221 (66 %) male). The mean follow up was 6, 7 years, with an average time on HD of 4,2 years, and 92 patients (27,4 %) underwent transplantation. Critical limb ischemia and/or amputation free survival rates were 88,6 % and 79,6 % at 5 and 10 years, respectively. The mean follow-up was 6.5 years, and 22 revascularization procedures for critical limb ischemia, 26 minor amputations and 18 major amputations were performed. Kidney transplantation was associated with a protective effect over the development of critical limb ischemia and/or amputation (HR: 0,065; p: < 0,001), after adjustment for diabetes mellitus (HR: 7,316; p< 0,001), a total cholesterol < 125mg/ml (HR: 2,538; p=0,003), time on HD (HR: 1,000; p: 0,003) and male gender (HR: 2,109; p: 0,040). Long-term survival rates of the cohort were 56,8 % and 32,7 % at 5 and 10 years respectively, but decreased to 47 % at 1 year and 18.2 % at 5 years once critical limb ischemia and/or amputation occurred. Conclusion: Patients on HD program show a notorious risk of critical limb ischemia and/or amputation over time. Once this complication occurs patient's survival is markedly reduced. Transplantation confers an independent protective effect over the development of critical limb ischemia and/or amputation. Disclosure: Nothing to disclose

P4710Impact of therapeutic angiogenesis using autologous bone marrow-derived mononuclear cells implantation in critical limb ischemia with collagen disease

Abstract Background Many patients with collagen disease (CD), particularly systemic sclerosis (SSc) and collagen disease-associated vasculitis (CDV), develop critical limb ischemia (CLI) which leads to limb amputation. In SSc vasculopathy, intimal hyperplasia, abnormal vascular contraction, and intravascular micro thrombus due to autoimmune abnormalities are main causes of inadequate blood supply that lead to the development of CLI. Moreover, in CDV, presence of inflammation cells infiltrates and destruction of the vascular wall also lead to vascular stenosis or obstruction. However, conventional therapies including revascularization via surgical bypass showed poor outcomes in CLI patients with CD. Therefore, establishment of new methods to improve peripheral circulation for limb salvage are required. Purpose After discovering that circulating endothelial progenitor cells (EPCs) mobilized from the bone marrow participate in postnatal neovascularization, autologous bone marrow-derived mononuclear cells (BM-MNCs) has been performed as a new treatment for many no-option CLI patients caused by arteriosclerosis obliterans, thromboangiitis obliterans or CD. In this study, we would like to assess the long-term clinical outcomes after autologous BM-MNCs implantation in CLI patients with SSc and CDV. Methods This study was a retrospective, multicenter, observational, and non-controlled study. We assessed no-option CLI patients with CD who were performed the autologous BM-MNCs implantation in 10 institutes. Overall survival (OS), major-amputation-free (MAF) and amputation-free survival (AFS) rates were primary endpoints of this study. In addition, we assessed improvements of ischemic pain as visual analogue scale (VAS) scores. Safety endpoints were defined as cardiovascular events and all-cause adverse events within 6 months after implantation. Results A total of 69 patients (39 with SSc–related diseases (SSc group) and 30 with CDV (CDV group)), were included in this study. The median follow-up duration was 36.5 months. The 10-year OS rate was 59.1% in the SSc group and 82.4% in the CDV group, respectively. The 10-year MAF rates were 97.4% and 82.6%, respectively. The 10-year AFS rates were 57.6% and 67.8%, respectively (Figure 1). The number of major or minor amputations in the SSc group trended to be less than that in the CDV group. In addition, significant improvement in VAS scores were observed in both groups (Figure 2). No patients died, no cardiovascular events, and no severe adverse events associated with BM-MNCs implantation were noted within 6 months after this therapy in both groups. Figure 1 Conclusions The BM-MNCs implantation may be feasible in no-option CLI patients with CD. Improvement of ischemic symptoms by BM-MNCs implantation was significant in both groups and, in the SSc group, limb salvage rate tended to be higher than the CDV group.

Comparative study between lymphocyte-monocyte ratio and platelet-lymphocyte ratio: novel markers for critical limb ischemia in peripheral arterial disease

Background: Peripheral arterial occlusive disease (PAOD) is frequent and often not diagnosed in time. If treatment is not initiated early, disease progression and development of Critical limb ischemia (CLI) is one possible complication. CLI is an entity with high mortality and high risk of limb amputation. As monocytes play a leading role in progression of atherosclerosis and platelets play a key role in atherosclerosis and atherothrombosis, we investigated Lymphocyte-monocyte ratio (LMR), Platelet lymphocyte ratio (PLR) and its association with CLI in peripheral arterial disease.Methods: Retrospective observational study conducted between January 2015-December 2017 including 50 patients admitted in Rajarajeswari Medical College and Hospital, Bangalore. As an optimal cut-off value, a PLR of 150 and LMR of 5 were identified. Their association with CLI noted.Results: 50 patients with critical limb ischemia, stage 3 and 4 of Fontaine classification were included in this study. 72% patients had LMR less than 5.40% patients had PLR more than 150 and 36% patients had both LMR less than 5 and PLR more than 150. 96% patients with LMR&lt;5 and 72% patients with PLR&gt;150 underwent amputation.Conclusions: An increased PLR and reduced LMR are significantly associated with patients at high risk for CLI. They are broadly available and cost effective. When done in early stage of the disease serves as a marker for CLI and aggressive treatment in such patients will reduce the risk of amputation.

Evaluation of Risk Factors for Limb-Specific Peripheral Vascular Events in Patients With Peripheral Artery Disease: A Post Hoc Analysis of the SEASON Prospective Observational Study

Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) is a 2-year, prospective, real-world, registry study conducted in Japan from 2009 to 2013. This post hoc analysis evaluated risk factors for limb ischemia in patients with peripheral arterial disease (PAD) and ankle-brachial index (ABI) <0.90. Vascular events were adjudicated by an Efficacy Endpoint Review Committee. Cox regression identified predictors of limb-specific peripheral vascular events (amputation, development of critical limb ischemia, and acute limb ischemia). Patients (n = 6565) were stratified according to ABI: normal (≥1.0; n = 1300), borderline (0.90 ≤ ABI ≤ 1.0; n = 776), and abnormal (<0.90; n = 4489). Compared to normal ABI, patients with ABI <0.90 had a significantly higher risk of any vascular event, all-cause death, and any limb-specific peripheral vascular event. Risk factors for limb-specific vascular events included history of lower extremity revascularization/amputation (adjusted hazard ratio: 2.18; 95% confidence interval [CI]: 1.49-3.20), chronic kidney disease (2.00; 1.33-3.00), diabetes (1.71; 1.16-2.52), and ABI <0.4 (4.45; 2.62-7.55) or <0.7 (1.78; 1.15-2.76). These findings from a Japanese real-world population confirm the increased vascular risk of patients with PAD and ABI <0.90 and identified risk factors for limb-specific peripheral vascular events.

Abstract P243: Retinal Microvascular Findings and Future Risk of Peripheral Artery Disease: the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Lower-extremity peripheral artery disease (PAD) is often considered as a subtype of macrovascular disease. For the development of critical limb ischemia (CLI), a severe form of PAD, microvascular disease is indicated to play a crucial role by impairing collateral formation and wound healing. However, the contribution of microvascular disease to the development of PAD has not been systematically evaluated in a large cohort study. Hypothesis: Microvascular disease, as represented by retinal findings, will be associated with future PAD risk, and its association will be stronger for CLI. Methods: Retinal photographs were taken at the 3 rd examination (1993-1995) of the ARIC Study. We investigated 9390 participants free of clinical history of PAD and quantified the associations of each retinal finding with PAD risk using Cox models. PAD was defined as hospitalizations with PAD diagnosis (ICD-9: 440.2x, 440.3, 440.4) or leg revascularization (38.18, 39.25, 39.29, 39.50). Of PAD cases, those with ulcer (707.1), gangrene (785.4) or leg amputation (84.1x) were considered CLI. Results: During a median follow-up of 19 years, 304 participants developed PAD, of which 92 were considered CLI. Retinal hemorrhages, exudates, microaneurysms and any retinopathy demonstrated independent associations with PAD (Table) beyond potential confounders including diabetes, while generalized arteriolar narrowing did not. These significant retinal findings were more strongly associated with CLI than with PAD (HR range 3.1-6.5 vs. 2.2-3.3, with all p-values for difference in HR from seemingly unrelated regression &lt;0.05 except soft exudates). Also, these retinal findings tended to have stronger associations with PAD outcomes among persons with diabetes than those without. Conclusions: Retinal hemorrhages, exudates, microaneurysms and any retinopathy were independently associated with PAD, especially its severe form, CLI. Our results suggest the importance of microvascular wall fragility/permeability in the development of PAD.

Prediction of Development of Critical Limb Ischemia in Hemodialysis Patients.

Hemodialysis (HD) patients with critical limb ischemia (CLI) suffer chronic inflammation and repeated infection, require intervention, and may have a protracted hospital stay. Therefore, early prediction is particularly important for management of CLI in patients with suspected peripheral artery disease. The purpose of this study is to develop a simple score for predicting the incidence of CLI in HD patients with suspected peripheral artery disease. The subjects were 139 asymptomatic patients receiving maintenance HD and with ABI <1.0. Multivariate logistic regression analysis was used to identify factors associated with development of CLI. These factors were subsequently weighted and integrated into a scoring system for the prediction of onset of CLI. Twenty-five patients had onset of CLI. Five factors selected from the multivariate model were weighted proportionally using their respective odds ratio (OR) for incidence of CLI (history of cerebral vascular disease, OR 6.42 [3 points]; diabetes, OR 3.92 [2 points]; hypoesthesia, OR 4.21 [2 points]; left ventricular ejection fraction <50%, OR 3.89 [2 points]; serum albumin <3.5 g/dL, OR 4.39 [2 points]). Three strata of risk were defined (low risk, 0 to 3 points; intermediate risk, 4 to 6 points; and high risk 7 to 11 points) with excellent prognostic accuracy for progression to CLI using the Kaplan-Meier method. Five factors were identified that increased the risk of progression to CLI in HD patients with suspected peripheral artery disease. A combination of those factors permitted establishment of three risk strata for accurate prediction of onset of CLI.

Impact of Critical Limb Ischemia on Long-Term Cardiac Mortality in Diabetic Patients Undergoing Percutaneous Coronary Revascularization

OBJECTIVEDevelopment of critical limb ischemia (CLI) has been reported as an independent predictor of cardiac mortality in diabetic patients. We aimed to determine whether CLI, managed in a structured setting of close collaboration between different vascular specialists and treated with early endovascular intervention, has any impact on long-term cardiac mortality of diabetic patients initially presenting with symptomatic coronary artery disease (CAD).RESEARCH DESIGN AND METHODSWe designed a prospective observational study of 764 consecutive diabetic patients undergoing percutaneous coronary intervention (PCI) in whom development of CLI was assessed by a dedicated diabetic foot clinic. Cardiac mortality at 4-year follow-up was the primary end point of the study.RESULTSAmong the 764 patients, 111 (14%) developed CLI (PCI-CLI group) and underwent revascularization of 145 limbs, with procedural success in 140 (96%). PCI-CLI patients at baseline had lower left ventricular ejection fraction (51 ± 11% vs. 53 ± 10%, P = 0.008), higher prevalence of dialysis (7% vs. 0.3%, P < 0.0001), and longer diabetes duration (13 ± 8 vs. 11 ± 7 years, P = 0.02) compared with PCI-only patients. At 4-year follow-up, cardiac mortality occurred in 10 (9%) PCI-CLI patients vs. 42 (6%) PCI-only patients (P = 0.2). Time-dependent Cox regression model for cardiac death revealed that CLI was not associated with an increased risk of cardiac mortality (hazard ratio 1.08 [95% CI 0.89–3.85]; P = 0.1).CONCLUSIONSThe development of promptly assessed and aggressively treated CLI was not significantly associated with increased risk of long-term cardiac mortality in diabetic patients initially presenting with symptomatic CAD.

Does endothelial dysfunction contribute to the clinical status of patients with peripheral arterial disease?

Peripheral arterial disease leads to lower extremity ischemia and limb loss, and is linked to cardiovascular events. The anatomical extent of lower extremity atherosclerosis fails to fully explain ischemic symptoms or predict the development of critical limb ischemia. Endothelial dysfunction is known to contributed to the pathogenesis and clinical expression of coronary artery disease, but the importance of endothelial dysfunction in peripheral arterial disease remains incompletely understood. Endothelial dysfunction could contribute to lower extremity ischemia by impairing blood flow responses to ischemia, collateral formation and arterial remodelling, and by promoting vasospasm, thrombosis, plaque rupture and lesion progression. There is a need for additional studies examining the contribution of endothelial dysfunction to the pathogenesis of peripheral arterial disease, and the potential role of endothelial dysfunction as a surrogate marker with utility in the management of patients.

Treatment strategies for peripheral artery disease

Peripheral arterial disease is an underecognized manifestation of systemic atherosclerosis associated with high rates of cardiovascular morbidity and mortality. The rationale of therapy is to reduce cardiovascular risk, improve symptoms of intermittent claudication, and prevent the development of critical limb ischemia and amputation. Exercise therapy and several pharmacologic agents have been shown to improve walking distance in patients with intermittent claudication. Patients with lifestyle-interfering symptoms despite exercise, or those who progress to critical limb ischemia, frequently undergo revascularization. Endovascular techniques are commonly used in these patients. Combined pharmacological and endovascular strategies will play an increasing role in management of these patients in the future.

Regulation of VEGF in Diabetic Patients with Critical Limb Ischemia

Diabetic patients are at a 10- to 20-fold increased risk for the development of critical limb ischemia. Vascular endothelial growth factor (VEGF) is critical for the development of collateral blood vessels, which can effectively bypass peripheral arterial occlusions. We therefore set out to determine if the regulation of VEGF in patients with peripheral vascular disease differs in diabetic and nondiabetic patients. Diabetic and nondiabetic patients with peripheral vascular disease were divided into those with or without critical limb ischemia as defined by clinical criteria (rest pain, nonhealing ulcer). Monocytes from peripheral blood were isolated from all patients and the hypoxic induction of VEGF was determined in vitro. In patients without diabetes, we found that there was no significant difference in the hypoxic induction of VEGF between patients with or without critical limb ischemia. However, in diabetic patients we found that patients with critical limb ischemia produced significantly more VEGF than patients without critical limb ischemia (6.3 +/- 1.3 vs. 2.1 +/- 0.3, p < 0.015). We conclude that diabetic patients with critical limb ischemia do not have an impairment in the ability to produce VEGF with hypoxia. Contrary to current dogma, treatment paradigms directed at increasing VEGF production in the diabetic patient with critical limb ischemia might not be beneficial.