Critical limb-threatening ischaemia and microvascular transformation: clinical implications.

BACKGROUND AND AIMS: Clinical management of critical limb-threatening ischaemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology. METHODS: Clinical high-resolution imaging of CLTI patients (n = 50) and muscle samples from amputated CLTI limbs (n = 40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischaemia model in rabbits (n = 24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome. RESULTS: Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P < .01) in CLTI muscles. Critical limb-threatening ischaemia muscle microvasculature also exhibited capillary enlargement (P < .001) and further arterialization along worsening of myofibre atrophy and detaching of capillaries from myofibres. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P < .05) and tissue outcome (P < .01) under chronic ischaemia in rabbits and in healthy, normal rabbit muscle. CONCLUSIONS: These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.

Antithrombotic Therapy and Freedom From Bridging Stent Occlusion After Elective Branched Endovascular Repair: A Multicenter International Cohort Study.

CLINICAL IMPACT: Based on our study, no antithrombotic therapy is significantly associated with bridging stent occlusion, and no evidence of the superiority of other antithrombotic therapy exists. Nevertehless, due to the low number of bridging stent occlusions, this study can neither support nor reject the PRINCE2SS recommendations. Further studies with larger cohorts are needed to determine clear guideliness of the best antithrombotic treatment regimen after complex enfovascular aortic repair.

Ultrasound Surveillance is Feasible After Endovascular Aneurysm Repair.

BACKGROUND: Surveillance after endovascular aneurysm repair (EVAR) is traditionally done with computed tomography angiography (CTA) scans that exposes patient to radiation, nephrotoxic contrast media, and potentially increased risk for cancer. Ultrasound (US) is less labor intensive and expensive and might thus provide a good alternative for CTA surveillance. The aim of this study was to evaluate in real-life patient cohorts whether US is able to detect post-EVAR aneurysm-related complications similarly to CTA. METHODS: This retrospective study compared the outcome of consecutive patients who underwent EVAR for intact abdominal aortic aneurysm and were surveilled solely by CTA (CTA-only cohort, n = 168) in 2000-2010 or by combined CTA and US (CTA/US cohort, n = 300) in 2011-2016, as a standard surveillance protocol in the department of vascular surgery, Helsinki University Hospital. The CTA-only patients were imaged at 1, 3, and 12 months and annually thereafter. The CTA/US patients were imaged with CTA at 3 and 12 months, US at 6 months and annually thereafter. If there were suspicion of >5 mm aneurysm growth, CTA scan was performed. The patients were reviewed for imaging data, reinterventions, aneurysm ruptures, and death until December 2018. The 2 groups were compared for secondary rupture, aneurysm-related and cancer-related death, reintervention related to abdominal aortic aneurysm, and maximum aneurysm diameter increase ≥5 mm. The mean follow-up in the CTA-only cohort was 67 months and in CTA/US cohort 43 months. RESULTS: The 2 cohorts were alike for basic characteristics and for the mean aneurysm diameter. The total number of CT scans for detecting aneurysm was 84.1/100 patient years in the CTA-only cohort compared to 74.5/100 patient years for US/CTA cohort. Forty percent of patients under combined CTA/US surveillance received 1 or more additional CTA scans. The 2 cohorts did not differ for 1-year, 5-year and 8-year freedom from aneurysm related death, secondary sac rupture, nor the incidence of rupture preventing interventions. CONCLUSIONS: Based on the follow-up data of this real-life cohort of 468 patients, combined surveillance with US and additional CTA either per protocol or due to suspicion of aneurysm-related complications had comparable outcome with sole CTA-surveillance. Thus, US can be considered a reasonable alternative for the CTA. However, our study showed also that the need of additional CTAs due to suspicion of endoleak or aneurysm nonrelated reasons is substantial.

Perivascular Macrophages Regulate Blood Flow Following Tissue Damage.

[Figure: see text].

External Validation of a Prognostic Model for Survival of Patients With Abdominal Aortic Aneurysms Treated by Endovascular Aneurysm Repair.

OBJECTIVE: Current guidelines recommend diameter monitoring of small and asymptomatic abdominal aortic aneurysms (AAAs) due to the low risk of rupture. Elective AAA repair is recommended for diameters ≥ 5.5 cm in men and ≥ 5.0 cm in women. However, data supporting the efficacy of elective treatment for all patients above these thresholds are diverging. For a subgroup of patients, life expectancy might be very short, and elective AAA repair at the current threshold may not be justified. This study aimed to externally validate a predictive model for survival of patients with an asymptomatic AAA treated by endovascular aneurysm repair (EVAR). METHODS: This was a multicentre international retrospective observational cohort study. Data were collected from four European aortic centres treating patients between 2001 and 2021. The initial model included age, estimated glomerular filtration rate (eGFR), and chronic obstructive pulmonary disease (COPD) as independent predictors for survival. Model performance was measured by discrimination and calibration. RESULTS: The validation cohort included 1 500 patients with a median follow up of 65 months, during which 54.6% of the patients died. The external validation showed slightly decreased discrimination ability and signs of overfitting in model calibration. However, a high risk subgroup of patients with impaired survival rates was identified: octogenarians with eGFR < 60 OR COPD, septuagenarians with eGFR < 30, and septuagenarians with eGFR < 60 and COPD having survival rates of only 55.2% and 15.5% at five and 10 years, respectively. CONCLUSION: EVAR is a valuable treatment option for AAA, especially for patients unsuitable for open repair. Nonetheless, not all these patients will benefit from EVAR, and an individualised treatment recommendation should include considerations on life expectancy. This study provides a risk stratification to identify patients who may not benefit from EVAR using the present diameter thresholds.

Statin use improves survival of patients with known or suspected lower extremity artery disease on all ankle brachial index levels.

Background: Statin medication improves the prognosis of patients with lower extremity artery disease (LEAD). Research has previously focused on patients with a lowered ankle brachial index (ABI) excluding patients with a normal or elevated ankle brachial index. The aim of this study was to analyze the impact of statin use on survival and cardiovascular mortality in patients with LEAD of different severity depicted by the ABI level. Patients and methods: 4128 ABI measurements by trained and experienced nurses between 2000 and 2009 were combined with medication data from the Social Insurance Institution and causes of death data from the national causes of death registry. End of follow-up was set at the end of 2014. The data of statin use included all statin medication with the Anatomical Therapeutic Chemical (ATC) classification codes between C10AA01 and C10AA08. Results: 1956 (47.4%) patients had statin medication. Statin use was associated with improved overall survival and amputation free survival (AFS) on all ABI levels. When adjusted for age, sex and diabetes the greatest overall survival benefit from statin use was for the patients with ABI>1.3 (hazard ratio, HR: 0.67, 95% CI: 0.48-0.94, p=0.020, reference group statin non-users) and ABI 0.9-1.3 (HR: 0.78, 95% CI: 0.65-0.94, p=0.008). In propensity score matched pairs statin treatment was associated with significantly lower all-cause mortality (p<0.0001), cardiovascular mortality (p=0.034), cerebrovascular mortality (p=0.003) and embolic stroke related mortality (p=0.001) in patients with ABI >1.3 or <0.9. Overall survival benefit was significant in females with ABI<0.5 and in males across several ABI levels. Conclusions: According to our study, statins seem to improve overall and amputation free survival regardless of ABI level. Statin use was associated with lower mortality from cerebrovascular disease, overall mortality and in the propensity score matched patients with ABI<0.9 or >1.3 with cardiovascular mortality.

Aortic calcification index predicts mortality and cardiovascular events in operatively treated patients with peripheral artery disease: A prospective PURE ASO cohort follow-up study.

OBJECTIVE: The present study evaluates the association of aortic calcification with mortality and major adverse cardiovascular and leg events (MACEs and MALEs) in patients with peripheral artery disease (PAD). The risk for mortality and MACEs and MALEs is considered in clinical decision-making. METHODS: This cohort found in 2012-2013 consists of 226 patients with symptomatic PAD referred to Turku University Hospital for invasive treatment. Follow-up data about mortality and survival without MACEs and MALEs were collected up to 5 years from the inclusion date, and aortic calcification index (ACI) was measured from patients with available imaging studies (164 of 226). ACIs' association with events and mortality was evaluated in Cox regression, Kaplan-Meier, and classification and regression tree analysis. RESULTS: All-cause mortality at 1, 3, and 5 years was 13.7% (31), 26.1% (59), and 46.9% (106), respectively. In multivariable Cox regression analysis, ACI and ACI > 43 were independent risk factors for all-cause mortality (hazard ratio [HR]: 1.13 per 10 units, 95% confidence interval [CI]: 1.00-1.22 and HR: 1.83, 95% CI: 1.01-3.32, respectively) and for MACEs (HR: 1.10 per 10 units, 95% CI: 1.00-1.22 and HR: 3.14, 95% CI: 1.67-5.91, respectively), but not for MALEs. Classification and regression tree analysis showed that ACI = 43 best divides cohort in relation to mortality. Kaplan-Meier analyses showed that ACI > 43 is associated with greater mortality and occurrence of MACEs compared with those who have ACI ≤ 43 (log-rank P value .005 and .0012, respectively). CONCLUSIONS: Risk for mortality and MACEs is associated with high ACI. ACI can expose the risk in patients with PAD for further cardiovascular events and mortality.

Incompressible ankle arteries predict increased morbidity and mortality in patients with an elevated ankle brachial index.

OBJECTIVES: Patients with an elevated ankle brachial index (ABI) > 1.3 have a high burden of disease and poorer outcome compared to patients with a lower ABI. Previously differences between patients with ABI > 1.3 have not been studied in detail. The aim of this study was to analyze the morbidity and mortality of patients with ABI > 1.3. METHODS: ABI measurements were performed in the vascular laboratory of Turku university hospital 2011-2013. Patients with ABI>1.3 in at least one lower limb were included in the study and divided into 3 groups: At least one lower limb ABI 1.3-2.5 but both limbs <2.5 (group 1), one limb ABI ≥2.5 (group 2), both limbs ABI ≥ 2.5 (group 3). RESULTS: 534 patients were included in the study. The patients in groups 2 and 3 were more often female (p < .001), older (p < .001), had more diabetes (p = .013), coronary artery disease (p = .001) and chronic heart (p = .010) and kidney failure (p = .013) compared to patients in group 1. The survival of patients in group 2 and 3 was significantly poorer compared to the patients in group 1 (HR1.6, 95% CI 1.2-2.2, p = .002 and 1.7, 95% CI 1.2-2.3, p < .001, respectively). Overall and cardiovascular mortality was higher in groups 2 and 3 than group 1.39.5% of patients with incompressible ankle arteries (ABI ≥ 2.5) in both lower limbs had toe pressure (TP) <50 mmHg and a poorer survival compared to patients with a higher TP. CONCLUSIONS: Patients with incompressible ankle arteries have significantly higher overall and cardiovascular mortality and a greater burden of disease compared to the patients with a measurable yet abnormally high ABI. TP is a useful diagnostic tool when ABI is immeasurably high. All patients with ABI > 1.3 should be considered as high cardiovascular risk patients.

Toe pressure should be part of a vascular surgeon's first-line investigation in the assessment of lower extremity artery disease and cardiovascular risk of a patient.

OBJECTIVE: Toe pressure (TP) is an accurate indicator of the peripheral vascular status of a patient and thus cardiovascular risk, with less susceptibility to errors than ankle-brachial index (ABI). This study aimed to analyze how ABI and TP measurements associate with overall survival and cardiovascular death and to analyze the TP of patients with ABI of 0.9 to 1.3. METHODS: The first ABI and TP measurements of a consecutive 6784 patients treated at the Helsinki University Hospital vascular surgery clinic between 1990 and 2009 were analyzed. Helsinki University Vascular Registry and the national Cause of Death Registry provided the data. RESULTS: The poorest survival was in patients with ABI >1.3 (10-year survival, 15.3%; hazard ratio, 2.2; 95% confidence interval, 1.9-2.6; P < .0001; reference group, ABI 0.9-1.3), followed by the patients with TP <30 mm Hg (10-year survival, 19.6%; hazard ratio, 2.0; 95% confidence interval, 1.7-2.2; P < .0001; reference group, TP ≥80 mm Hg). The best 10-year survival was in patients with TP ≥80 mm Hg (43.9%). Of the 642 patients with normal ABI (0.9-1.3), 18.7% had a TP <50 mm Hg. The highest cardiovascular death rate (64.6%) was in the patients with TP <30 mm Hg, and it was significantly lower than for the patients with TP >50 mm Hg. CONCLUSIONS: Low TP is associated significantly with survival and cardiovascular mortality. Patients with a normal ABI may have lower extremity artery disease (LEAD) and a considerable risk for a cardiovascular event. If only the ABI is measured in addition to clinical examination, a substantial proportion of patients may be left without LEAD diagnosis or adequate treatment of cardiovascular risk factors. Thus, especially if ABI is normal, LEAD is excluded only if TPs are also measured and are normal.

Prognostic risk factors for recurrent acute lower limb ischemia in patients treated with intra-arterial thrombolysis.

OBJECTIVE: The objective of this study was to assess factors predisposing patients to recurrent acute lower limb ischemia (RALLI). METHODS: Acute lower limb ischemia patients treated with catheter-directed thrombolysis (CDT) at Tampere University Hospital and Turku University Hospital between March 2002 and December 2015 were included. The patients' baseline demographics, comorbidities, and other characteristics were assessed retrospectively. Significant factors revealed by univariable analysis were tested in a multivariable model for associations with RALLI. A patency analysis was performed, and the risks of reocclusion were identified. The limb salvage rates after reocclusion were evaluated. RESULTS: Altogether, 303 consecutive patients with a mean age of 71 years (standard deviation, 11.8 years) were included. Of them, 159 (52.5%) were men. A total of 164 (54.1%) native arterial and 139 (45.9%) bypass graft occlusions were initially treated with CDT. On completion of CDT, 204 additional endovascular or conventional surgical procedures on 203 patients were performed to obtain adequate distal perfusion. During a median follow-up of 40 months (interquartile range, 69 months), 40 (24.4%) cases of RALLI occurred in native arteries and 90 (64.7%) in bypass graft patients (P < .001). In native arteries, the absence of appropriate anticoagulant and antiplatelet medication was independently associated with the development of acute reocclusions (hazard ratio, 6.51) in the Cox multivariable regression analysis. The patency rates were 86.6%, 72.2%, and 68.0% at 1 year, 5 years, and 9 years, respectively. In bypass grafts, worsened tibial runoff (crural index III: hazard ratio, 2.40) was independently associated with RALLI. The respective patency rates were 60.5%, 34.0%, and 29.2% for synthetic conduits and 30.8%, 20.5%, and 13.7% for autologous vein grafts at 1 year, 5 years, and 9 years. Altogether, 38 (29.2%) major amputations were performed on patients with reocclusions. Patients with synthetic conduits demonstrated superior limb salvage rates after reocclusion in comparison to native arteries or vein grafts (P = .025). CONCLUSIONS: Appropriate post-thrombolytic antiplatelet or anticoagulant treatment after native arterial events is of great importance, but additional data are needed to improve treatment algorithms. Adequate outflow in bypass graft patients is crucial. Patients with prosthetic bypass grafts have superior limb salvage rates after reocclusion.

Vein Harvest Wound Healing after Bypass Surgery for Critical Limb Ischemia.

BACKGROUND: Lower-limb revascularization surgery, especially when performed using the great saphenous vein, predisposes patients to major surgical trauma on initially ischemic tissue. Vein harvest wounds (VHWs) after infrainguinal revascularization heal slowly. This study's aim was to assess the factors associated with VHW healing after infrainquinal bypass surgery for critical limb ischemia (CLI). METHODS: A retrospective patient record study was conducted. All patients with CLI who underwent infrainguinal bypass surgery with autologous vein graft between January 1, 2015, and December 31, 2017, in the Turku University Hospital, were included. Follow-up data were collected until February 28, 2018. The following data was collected from the patient files; risk factors, ankle-brachial indices (ABIs), systolic toe pressures (STPs), the presence of an ischemic ulcer, VHW dehiscence, and the time when the VHW was completely healed. Procedures with outflow vessels at either popliteal or tibial artery were analyzed separately. Descriptive and univariate statistical analyses were performed. RESULTS: Altogether, 195 patients were operated on for CLI, of whom 133 (68.2%) patients had ischemic ulcers. The mean follow-up time was 535.0 days (range 3.0-1143.0 days). The mean ABI improvement was 0.49 (P = 0.00), and STP improvement, 39.9 mm Hg (P = 0.00). The median time taken when VHW was healed was 48.0 days (95% confidence interval [CI], 39.4-56.6) in patients without ischemic ulcers and 82.0 days (95% CI, 59.7-104.3) in patients with ischemic ulcers, P = 0.03. VHW in patients who underwent popliteal artery bypass (62 days, 95% CI, 12.9-93.0) healed faster than VHW in those who underwent tibial artery bypass (132 days, 95% CI, 48.0-93.0), P = 0.02. Risk factors and the preoperative or postoperative ABIs or STPs had no effect on VHW healing time. CONCLUSIONS: VHW healing was remarkably slower after revascularization surgery in patients with an ischemic foot ulcer than in those without ischemic ulcers.

Association between anatomical distribution of symptomatic peripheral artery disease and cerebrovascular disease.

AIM: Peripheral arterial disease is frequently associated with significant atherosclerosis of other vascular beds. The aim of the present study was to investigate a possible association between peripheral arterial disease segment-specific disease burden and cerebrovascular disease. METHODS: Two-hundred and twenty-six patients with clinically symptomatic peripheral arterial disease from the prospective PureASO registry were followed up after revascularization. The breadth of peripheral arterial disease was quantified at the time patients entered the study. The segment-specific peripheral arterial disease burden was correlated to cerebrovascular disease and imaging findings during a five-year follow-up. RESULTS: At five years, cerebrovascular disease-free survival after lower limb revascularization was 31%. Patients with peripheral arterial disease involving the crural arteries had significantly more ischemic degenerative changes at brain imaging (p = 0.031), whereas patients with aorto-iliac and femoropopliteal segment peripheral arterial disease had more significant (>50% uni- or bilaterally) internal carotid artery stenosis compared to patients with crural peripheral arterial disease (p = 0.006). According to Cox regression analyses, crural arteries burden was associated with a significantly increased risk of mortality (adjusted HR 2.07, CI 95% 1.12-3.28, p = 0.021) and cerebrovascular events (adjusted HR 1.97, CI 95% 1.19-3.26, p = 0.008). CONCLUSIONS: Present results suggest that atherosclerosis burden at different lower limb artery segments is associated with defined cerebrovascular disease. This further suggests that risk factors and pathophysiological mechanisms are congruent across particular vascular beds.

Bilateral low systolic toe pressure and toe-brachial index are associated with long-term mortality in patients with peripheral artery disease.

OBJECTIVE: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachial index (TBI) have a strong association with midterm cardiovascular and overall mortality as well as with amputation-free survival in patients with symptomatic lower extremity peripheral artery disease (PAD). The effect of the often overlooked contralateral lower limb on patient outcome remains unknown. This study aimed to resolve the significance of contralateral STP (CL_STP) and contralateral TBI for long-term overall and cardiovascular mortality. METHODS: This is a retrospective cohort study of 727 consecutive patients with symptomatic lower extremity PAD. All patients admitted to the Department of Vascular Surgery at Turku University Hospital for digital subtraction angiography between January 2009 and August 2011 and for whom STP measurements were available were recruited and observed for up to 7 years. Dates and causes of death were collected from the national cause of death registry of Statistics Finland. RESULTS: In the study cohort, STP was <30 mm Hg in 67 contralateral limbs and 227 ipsilateral limbs. CL_STP <30 mm Hg resulted in a 60-month estimated freedom from cardiovascular death and overall survival of 39% (standard deviation [SD], 0.57) and 25% (SD, 0.41), respectively, and contralateral TBI <0.25, of 45% (SD, 0.54) and 36% (SD, 0.54), respectively. Cumulative freedom from cardiovascular death and overall survival at 60 months for patients with ipsilateral STP <30 mm Hg varied by CL_STP as follows: CL_STP <30 mm Hg: 41% (SD, 0.58) and 25% (SD, 0.43); CL_STP of 30 to 49 mm Hg: 56% (SD, 0.49) and 44% (SD, 0.49); STP ≥50 mm Hg: 62% (SD, 0.52) and 47% (SD, 0.52), respectively. In Cox regression analysis, low STP or TBI of either extremity was associated with significant (P < .001) risk of death for cardiovascular or any reason. CONCLUSIONS: Low STP and TBI of both contralateral and ipsilateral lower extremities are associated with high cardiovascular and overall mortality in symptomatic PAD patients. Bilaterally low STP and TBI are associated with a particularly poor prognosis.

Serum cytokine levels differ according to major cardiovascular risk factors in patients with lower limb atherosclerosis.

Different cardiovascular risk factors present a heterogenic manifestation of lower limb atherosclerosis. The molecular mechanisms behind this phenomenon remain unknown. We aimed to clarify this phenomenon by studying the association of major cardiovascular risk factors with the profile of serum cytokines in 226 consecutive patients with lower limb atherosclerosis treated at a department of Vascular Surgery during a one-year enrollment period. Increasing age independently associated with higher levels of IFN-γ inducible factors MIG, CTACK and IP-10 (P < 0.001 for all). Patients with chronic kidney disease had higher serum levels of MIF, IL-16 and SCF (P = 0.001 or less for all). Smoking and hypertension associated with IL-17 (P = 0.037 and 0.015, respectively). In addition, smoking associated with growth factors known to induce myeloid progenitor cell proliferation: GM-CSF (P = 0.035), PDGF (P = 0.024), bFGF (P = 0.026), and HGF (P = 0.030). Dyslipidemia also associated with myeloproliferative factors: MIB-1α (P = 0.005) and PDGF (P = 0.01). Type II diabetes associated with Th2 mediated inflammation: IL-5 (P < 0.001), IL-7 (P = 0.004) and IL-13 (P = 0.015). Major cardiovascular risk factors are associated with different circulating cytokines implicating different immunological pathology.

Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques.

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR-/-ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR-/-ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.

Correlation between increasing tissue ischemia and circulating levels of angiogenic growth factors in peripheral artery disease.

INTRODUCTION: The aim of the present study was to assess the circulating levels of vascular endothelial growth factor (VEGF) and other suggested therapeutic growth factors with the degree of ischemia in patients with different clinical manifestations of peripheral arterial disease (PAD) according to the Rutherford grades. METHODS: The study cohort consists of 226 consecutive patients admitted to a Department of Vascular Surgery for elective invasive procedures. PAD patients were grouped according to the Rutherford grades after a clinical assessment. Ankle-brachial pressure indices (ABI) and absolute toe pressure (TP) values were measured. Serum levels of circulating VEGF, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) were measured from serum and analysed against Rutherford grades and peripheral hemodynamic measurements. RESULTS: The levels of VEGF (P = 0.009) and HGF (P < 0.001) increased significantly as the ischaemic burden became more severe according to the Rutherford grades. PDGF behaved in opposite manner and declined along increasing Rutherford grades (P = 0.004). A significant, inverse correlations between Rutherford grades was detected as follows; VEGF (Pearson's correlation = 0.183, P = 0.004), HGF (Pearson's correlation = 0.253, P < 0.001), bFGF (Pearson's correlation = 0.169, P = 0.008) and PDGF (Pearson's correlation = 0.296, P < 0.001). In addition, VEGF had a clear direct negative correlation with ABI (Pearson's correlation -0.19, P = 0.009) and TP (Pearson's correlation -0.20, P = 0.005) measurements. CONCLUSIONS: Our present observations show that the circulating levels of VEGF and other suggested therapeutic growth factors are significantly increased along with increasing ischemia. These findings present a new perspective to anticipated positive effects of gene therapies utilizing VEGF, HGF, and bFGF, because the levels of these growth factors are endogenously high in end-stage PAD.

Drug-Eluting Stent Shows Similar Patency Results as Prosthetic Bypass in Patients with Femoropopliteal Occlusion in a Randomized Trial.

BACKGROUND: Claudication and critical limb threatening ischemia are significant causes of mortality in the elderly. The gold standard of superficial femoral artery (SFA) revascularization is thus far considered to be the femoropopliteal bypass. The aim of this study was to compare mid-term patency between drug-eluting stents (DESs) and prosthetic bypass grafts (BSX). Studies have reported comparable results for both the methods. METHODS: Forty-six patients with claudication or rest pain due to a 5-25 cm SFA occlusion were randomized between DES and BSX groups. The follow-up period was 24 months, and the primary outcome measure was overall patency. Secondary outcome measures were primary and primary assisted patency, change in ankle-brachial index (ABI), and amputation-free survival. RESULTS: Forty-one patients were eventually analyzed. Six-month secondary patency was 91% (DES) versus 83% (BSX) (P = 0.450). The corresponding numbers at 12 months in the DES and BSX groups were 74% and 80% (P = 0.750), respectively. At 24 months, the respective numbers were 56% and 71% (P = 0.830). There were no statistically significant differences in primary or assisted primary patency at 1, 6, or 12 months. CONCLUSION: There were no demonstrable differences in patency rates or clinical outcomes such as ABI or major amputations between DES and BSX. Although underpowered, the results suggest noninferiority of the DES compared with prosthetic bypass surgery. TRIAL REGISTRATION: The trial was preregistered at ClinicalTrials.org (NCT01450722).

Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis.

RATIONALE: Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans. OBJECTIVE: The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease. METHODS AND RESULTS: Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5'-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease (P<0.0001). Low CD39 activity was associated with disease progression (P=0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia (P=0.001). Statin use was associated with lower ADP (P=0.041) and tended to associate with higher CD73 (P=0.054), while lower ATP was associated with the use of angiotensin receptor blockers (P=0.015). CONCLUSIONS: Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y12 receptor antagonists more than their nonsmoking peers.

Regulation of CD73 in the development of lower limb atherosclerosis.

Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5'-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.

18-kDa translocator protein ligand 18F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice.

BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.