Induction of CD73 prevents death after emergency open aortic surgery for a ruptured abdominal aortic aneurysm: a randomized, double-blind, placebo-controlled study.

Mortality remains high after emergency open surgery for a ruptured abdominal aortic aneurysm (RAAA). The aim of the present study was to assess, if intravenous (IV) Interferon (IFN) beta-1a improve survival after surgery by up-regulating Cluster of differentiation (CD73). This is a multi-center phase II double-blind, 2:1 randomized, parallel group comparison of the efficacy and safety of IV IFN beta-1a vs. placebo for the prevention of death after open surgery for an infra-renal RAAA. All study patients presented a confirmed infra-renal RAAA, survived the primary emergency surgery and were treated with IFN beta-1a (10 µg) or matching placebo for 6 days after surgery. Major exclusion criteria included fatal hemorrhagic shock, chronic renal replacement therapy, diagnosed liver cirrhosis, severe congestive heart failure, advanced malignant disease, primary attempt of endovascular aortic repair (EVAR), and per-operative suprarenal clamping over 30 min. Main outcome measure was all-cause mortality at day 30 (D30) from initial emergency aortic reconstruction. The study was pre-maturely stopped due to a reported drug-drug interaction and was left under-powered. Out of 40 randomized patients 38 were included in the outcome analyses (27 IFN beta-1a and 11 placebo). There was no statistically significant difference between treatment groups at baseline except more open-abdomen and intestinal ischemia was present in the IFN beta-1a arm. D30 all-cause mortality was 22.2% (6/27) in the IFN beta-1a arm and 18.2% (2/11) in the placebo arm (OR 1.30; 95% CI 0.21-8.19). The most common adverse event relating to the IFN beta-1a was pyrexia (20.7% in the IFN beta-1a arm vs. 9.1% in the placebo arm). Patients with high level of serum CD73 associated with survival (P = 0.001) whereas the use of glucocorticoids and the presence of IFN beta-1a neutralizing antibodies associated with a poor CD73 response and survival. The initial aim of the trial, if postoperative INF beta-1a treatment results on better RAAA survival, could not be demonstrated. Nonetheless the anticipated target mechanism up-regulation of CD73 was associated with 100% survival. According to present results the INF beta-1a induced up-regulation of serum CD73 was blocked with both use of glucocorticoids and serum IFN beta-1a neutralizing antibodies. The study was pre-maturely stopped due to interim analysis after a study concerning the use if IV IFN beta-1a in ARDS suggested that the concomitant use of glucocorticoids and IFN beta-1a block the CD73 induction. Trial registration: ClinicalTrials.gov NCT03119701. Registered 19/04/2017 (retrospectively registered).

Cognitive Dysfunction and Mortality After Carotid Endarterectomy.

Background: Carotid endarterectomy (CEA) has been associated with both postoperative cognitive dysfunction (POCD) and improvement (POCI). However, the prognostic significance of postoperative cognitive changes related to CEA is largely unknown. The aim of this study was to examine the associations between postoperative cognitive changes after CEA and long-term survival. Methods: We studied 43 patients 1 day before CEA as well as 4 days and 3 months after surgery with an extensive neuropsychological test array, and followed them for up to 14 years. POCD and POCI relative to baseline were determined with the reliable change index derived from 17 healthy controls. Associations between POCD/POCI and mortality within the patient group were studied with Cox regression analyses adjusted for confounders. Results: POCD in any functional domain was evident in 28% of patients 4 days after surgery and in 33% of patients 3 months after surgery. POCI was shown in 23% of patients at 4 days and in 44% of patients at 3 months. POCD at 3 months was associated with higher long-term mortality (hazard ratio 5.0, 95% CI 1.8-13.9, p = 0.002) compared with patients with no cognitive decline. Conclusions: Our findings suggest that POCD in a stable phase, 3 months after CEA predicts premature death. Evaluation of postoperative cognitive changes is essential, and POCD in a stable phase after CEA should prompt scrutiny of underlying factors and better adherence to therapies to prevent recurrences and to promote early intervention in imminent deterioration.

Effect of triclosan-coated sutures on the incidence of surgical wound infection after lower limb revascularization surgery: a randomized controlled trial.

BACKGROUND: Surgical wound infection (SWI) is a common complication after peripheral vascular surgery. In a prospective study, triclosan-coated sutures were reported to decrease the incidence of surgical site infection after various surgical procedures. The aim of our study was to test the hypothesis that use of triclosan-coated sutures decreases the incidence of SWI after lower limb vascular surgery. METHODS: This prospective, randomized, multicenter, double-blinded trial was conducted between July 2010 and January 2011 in five hospitals in Finland. We randomly allocated 276 patients undergoing lower limb revascularization surgery to a study (n = 139) or a control (n = 137) group. Surgical wounds in the study group were closed with triclosan-coated suture material, and wounds in the control group were closed with noncoated sutures. The main outcome measure was SWI. A surgical wound complication was considered to be an infection if there were bacteria isolated from the wound or if there were areas of localized redness, heat, swelling, and pain around the wound appearing within 30 days after the operative procedure. Logistic regression analysis was used to assess the independent effect of triclosan-coated sutures on the incidence of SWI. RESULTS: Altogether, 61 (22.1 %) patients developed SWI. SWI occurred in 31 (22.3 %) patients in the study group and in 30 (21.9 %) patients in the control group (odds ratio 1.10, 95% confidence interval 0.61-2.01, p = 0.75.) CONCLUSIONS: The use of triclosan-coated sutures does not reduce the incidence of SWI after lower limb vascular surgery.

Gene expression differences between stroke-associated and asymptomatic carotid plaques.

Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2-fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization.

Supplemental postoperative oxygen in the prevention of surgical wound infection after lower limb vascular surgery: a randomized controlled trial.

BACKGROUND: Surgical wound infection (SWI) is a common complication after peripheral vascular surgery. Infections increase morbidity and costs of treatment. The aim of the present study was to test the hypothesis that supplemental postoperative oxygen decreases the incidence of SWI after lower limb revascularization. METHODS: This prospective, randomized, multicenter, single-blinded trial was conducted between May 2009 and February 2010 in six secondary referral hospitals in Finland. We randomly allocated 274 patients undergoing surgery for lower limb revascularization to the study group (n=137) or a control group (n=137). The study group received supplemental inspired oxygen for the first 2 days after surgery. The main outcome was SWI. Patients were followed up for 30 days or until the SWI was healed. Logistic regression analysis was used to assess the independent effect of supplemental oxygen on the incidence of SWI. RESULTS: Altogether 63 (23%) patients developed SWI; 47 (75%) of the infections were superficial. There were two vascular graft infections. SWI occurred in 25 patients (18.2%) in the study group and in 38 patients (27.7%) in the control group [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.30-1.04; P=0.07]. In isolated groin incisions, 3 patients of 52 (5.8%) in the study group and 12 patients of 51 (23.5%) in the control group developed SWI; OR=0.20, 95% CI 0.04-0.95; P=0.04. CONCLUSIONS: There was an indication that supplemental inspired oxygen tended to decrease the incidence of SWI after lower limb vascular surgery. In isolated groin incisions, the decrease of SWI incidence in the supplemental oxygen group was significant.

Efficacy of thoracic epidural analgesia with or without intercostal nerve cryoanalgesia for postthoracotomy pain.

BACKGROUND: We evaluated effects of thoracic epidural analgesia combined with intercostal nerve cryoanalgesia or epidural analgesia alone on acute and long-term pain after posterolateral thoracotomy. METHODS: Forty-two elective thoracotomy patients were randomly assigned to two groups, epidural combined with cryoanalgesia or epidural alone. A thoracic epidural catheter was inserted before induction of anesthesia. At the end of the operation, cryoanalgesia was performed to 3 intercostals nerves: 1 at the level of the incision, 1 caudal, and 1 cranial. Cryoanalgesia was blinded to the investigating anesthetists and patients. To avoid impingement of intercostal nerves, chest closure in all patients was performed using intracostal sutures through drilled holes in adjacent ribs. In the postanesthesia care unit, epidural infusion of ropivacaine (1 mg/mL) with fentanyl (5 µg/mL) was started and continued 3 days. Thereafter, pain was treated with oral strong or weak opioids combined with nonsteroidal antiinflammatory drugs or acetaminophen. Pain was assessed with the verbal pain scale or visual analog scale. Patients visited a local pain clinic at 8 weeks and at 6 months postoperatively. RESULTS: The cryoanalgesia group had more neuropathic-type pain compared with the epidural-alone group 8 weeks after operation (p < 0.05). The cryoanalgesia group had also more pain on normal daily activities 8 weeks after the operation (p < 0.05). After 6 months, there were no statistically significant differences between groups. CONCLUSIONS: Intercostal cryoanalgesia seems to increase the incidence of long-term pain after thoracotomy.

The effect of severe carotid occlusive disease and its surgical treatment on cognitive functions of the brain.

Surgery of a high-grade carotid stenosis is evidence-based stroke prevention. Also cognitive effects are reported after carotid endarterectomy (CEA): both deterioration and improvement, the former attributed to perioperative complications and the latter often to learning effect. By imaging, brain perfusion and diffusion changes were shown in subjects with a high-grade stenosis undergoing CEA. We wanted to find out if the cognition of patients undergoing CEA display postoperative worsening or true improvement in association with findings in serial MR imaging. The patients had a poorer overall cognition than healthy matched controls. The cerebral hemisphere ipsilateral to the stenosis had higher diffusion and more sluggish perfusion leading to perfusion deficits. These asymmetries were abolished by CEA. Postoperatively, the patients showed a trend for cognitive worsening, most often attentional, but over months, the group performance improved similarly to the controls. Still, lower baseline perfusion was associated with a greater cognitive improvement, most clearly in executive functions. Consequently, despite the risk for transient decline, true cognitive benefit by CEA seems possible.

Adipophilin expression is increased in symptomatic carotid atherosclerosis: correlation with red blood cells and cholesterol crystals.

BACKGROUND AND PURPOSE: Adipophilin is an adipose differentiation-related protein expressed in lipid-containing cells. Using DNA microarray analysis, we previously found the adipophilin gene (ADFP) to be overexpressed in symptomatic carotid plaques (CP). This led us to further examine the role of adipophilin in carotid atherosclerosis relative to symptom status. METHODS: Ninety-eight high-grade (>70%) CPs were obtained in carotid endarterectomy. The relative expression of ADFP mRNA was measured by quantitative real-time RT-PCR, and the relative amount of adipophilin protein was quantified with Western blotting. Detailed topographical correlations with extravasated red blood cells and extracellular cholesterol crystals were obtained by means of immunohistochemistry. RESULTS: The relative expression of ADFP mRNA was increased in symptomatic compared with asymptomatic CPs at both the mRNA level (1.82+/-0.19[SE] versus 1.25+/-0.15, P=0.012) and the protein level (1.04+/-0.23 versus 0.46+/-0.14, P=0.043). Adipophilin colocalized with macrophage foam cells, extravasated red blood cells (P<0.0001), and cholesterol crystals (P<0.0001), and its expression associated with macroscopic ulceration of CP (P<0.0001). CONCLUSIONS: Intraplaque hemorrhages may contribute to intracellular lipid accumulation and consequent adipophilin expression. Because adipophilin blocks cholesterol efflux from lipid-laden cells, they may die and develop a necrotic lipid core, thereby destabilizing the plaque.

Microarray analysis reveals overexpression of CD163 and HO-1 in symptomatic carotid plaques.

OBJECTIVE: We studied by microarray analysis whether symptomatic and asymptomatic carotid plaques from the same patient differ in gene expression and whether the same changes are present in an independent sample set. METHODS AND RESULTS: Carotid plaques from four patients with bilateral high-grade stenosis, one being symptomatic and the other asymptomatic, were analyzed on Affymetrix U95Av2 arrays. 33 genes showed >1.5-fold change between symptomatic and asymptomatic plaques in an intraindividual comparison with FDR ranging from 0.28 to 0.40. Three genes involved in iron-heme homeostasis, CD163, HO-1, and transferrin receptor, were further analyzed in 40 independent plaques. HO-1 (fold-change 1.93, 95%CI 1.04 to 3.94, P=0.040) and CD163 (1.58, 1.11 to 2.40, P=0.013) mRNAs were again induced, and also HO-1 protein was overexpressed in symptomatic plaques (4.38, 1.54 to 12.20, P=0.024). The expression of HO-1 and CD163 correlated with tissue iron content but iron itself was not associated with the symptom status. CONCLUSIONS: Symptomatic plaques show overexpression of CD163 and HO-1 both in intraindividual and interindividual comparison. Their expression correlates with iron deposits but asymptomatic and symptomatic plaques from isolated patients do not differ in macroscopic hemorrhages or iron deposits. We suggest that symptomatic plaques show a more pronounced induction of CD163 and HO-1 in response to plaque hemorrhages.

Endothelial apoptosis does not determine symptom status in carotid artery disease.

BACKGROUND: We examined the hypothesis that endothelial denudation in advanced carotid plaques (CPs) occurs by increased apoptosis of endothelial cells (ECs) using scanning electron microscopy (SEM) as well as markers of cellular proliferation and apoptosis in advanced symptomatic CPs (SCPs) and asymptomatic CPs (ACPs). METHODS: 93 consecutive patients underwent carotid endarterectomy. Five additional specimens were studied by SEM. We performed TUNEL assays, and immunostaining against Fas receptor (FasR), Fas ligand (FasL), activated caspase 3 (ACA3) and Ki-67. RESULTS: SEM revealed morphological changes consistent with EC detachment. Surprisingly, ACA3 positivity was more pronounced on the endothelium of ACPs (4.6 +/- 0.7% of total EC count) than on SCPs (3.3 +/- 0.7%, p = 0.049), and was found to correlate positively with nuclear Ki-67 expression (r(s) = 0.275, p = 0.040). FasL expression was significantly increased on the endothelium of SCPs compared with ACPs (66.4 +/- 4.4 vs. 53.9 +/- 4.5%, p = 0.047). CONCLUSIONS: Absence of increased positivity of apoptotic markers dismisses apoptosis as a dominant mechanism underlying endothelial detachment of SCPs. Rather, increased ACA3 with co-expression of Ki-67 in ACPs might suggest that renewal of endothelium by active cell turnover may contribute to clinically silent evolution of plaques with preserved EC integrity. These observations may assist in designing novel therapies to prevent endothelial decay and symptom generation in advanced carotid artery disease.

Association of the fibrinolytic system and hemorheology with symptoms in patients with carotid occlusive disease.

BACKGROUND AND OBJECTIVES: The risk of stroke caused by a symptomatic high-grade carotid stenosis (CS) is high. Disturbed balance between the procoagulant and fibrinolytic activity in blood associated with unfavorable hemorheology could render CS symptomatic. We wanted to assess whether hemostatic and fibrinolytic plasma markers as well as basic indicators of hemorheology differentiate asymptomatic and symptomatic patients with a high-grade CS and whether they are associated with the macroscopic appearance of the plaque and the rate of microembolization. METHODS: We recruited 92 consecutive consenting patients referred to the neurological or the surgical department of our university teaching hospital for treatment of their high-grade CS. Blood samples were collected before surgery for determination of prothrombin fragments F1 and 2, thrombin-antithrombin complex, tissue-type plasminogen activator (tPA) activity and antigen, plasminogen activator inhibitor-1 (PAI-1) activity and antigen, D-dimer, homocysteine, fibrinogen, in plasma, and hematocrit in blood, and the patients underwent transcranial Doppler ultrasonology for evaluation of microembolic signals (MES). RESULTS: Patients with symptomatic plaques had higher hematocrit levels (p = 0.04), as well as trends for higher tPA antigen and MES rate (p = 0.07). Hematocrit, tPA antigen, and PAI-1 antigen and activity were positively correlated with the degree of stenosis. Ulceration was more common in symptomatic plaques but did not reflect variables of hemostasis or fibrinolysis. In multivariate analysis, tPA antigen and hematocrit were risk factors for a symptomatic high-grade stenosis. CONCLUSION: Mediators of fibrinolysis and unfavorable hemorheology may contribute to the development of a symptomatic disease in patients with a high-grade CS.

Carotid plaque mast cells associate with atherogenic serum lipids, high grade carotid stenosis and symptomatic carotid artery disease. Results from the helsinki carotid endarterectomy study.

OBJECTIVE: Increased numbers of mast cells (MCs) are present in ruptured coronary plaques, suggesting to play a role in acute coronary syndromes. We evaluated the distribution densities of MCs, macrophages and T cells in carotid plaques and correlated these findings to stroke risk factors as well as history of stroke or TIA. METHODS AND RESULTS: Seventy-eight carotid samples from 75 patients (16 plaques from asymptomatic patients and 62 from patients with recent ischemic symptoms) undergoing carotid endarterectomy with an internal carotid stenosis >70% that were immunostained and quantified for MCs, macrophages and T cells. The MC distribution density showed positive correlation with the degree of carotid stenosis (p = 0.012), serum levels of total cholesterol (p = 0.021), LDL cholesterol (p = 0.013) and triglycerides (p = 0.005), and an inverse correlation with serum HDL cholesterol levels (p = 0.001). The average MC density (p = 0.023), but not the macrophage (p = 0.58) or T cell (p = 0.74) density, was higher in the symptomatic than in the asymptomatic patients. In a comparison of plaques ipsilateral and contralateral to the thromboembolic event, the densities of the three types of inflammatory cells were similar. CONCLUSIONS: Increased MC distribution density is associated with an atherogenic serum lipid profile, high-grade carotid artery stenosis and symptomatic carotid artery disease. These findings suggest a potential involvement of MCs in the pathophysiology of carotid artery stenosis.

Cerebral hemodynamics in asymptomatic and symptomatic patients with high-grade carotid stenosis undergoing carotid endarterectomy.

BACKGROUND AND PURPOSE: Asymptomatic patients with carotid stenosis benefit less from carotid endarterectomy (CEA) than symptomatic patients because the risk of embolic events is lower, but it is not known whether the hemodynamic effect of CEA is different between the groups. We evaluated hemodynamics of symptomatic and asymptomatic patient groups before and after CEA. METHODS: Forty-six independent patients with a unilateral high-grade carotid stenosis, 23 asymptomatic and 23 symptomatic, underwent dynamic susceptibility contrast MRI (DSC-MRI) and transcranial Doppler ultrasound (TCD) evaluation before CEA and 3 and 100 days afterward. Quantitative perfusion parameters were calculated separately in selected regions of white and gray matter and watershed regions in each hemisphere, and mean transit time (MTT) maps were assessed visually by 2 independent observers. Vasomotor reactivity was determined with breath-holding index and flow impedance with pulsatility index ipsilaterally. RESULTS: In contrast to the asymptomatic carotid stenosis group, symptomatic carotid stenosis patients had preoperatively increased MTT and lower cerebral blood flow values in the ipsilateral hemisphere, more in white matter and watershed regions than in gray matter. Visually detected perfusion deficits were associated with symptomatic status. The interhemispheric asymmetries were abolished by CEA. The improving trend over time was greater in the symptomatic carotid stenosis group and was best seen in MTT. On TCD, pulsatility index was lower in symptomatic carotid stenosis patients preoperatively, with no postoperative difference, whereas the breath-holding index improved only in the symptomatic carotid stenosis group after CEA. CONCLUSIONS: Patients with asymptomatic and symptomatic carotid stenosis differ significantly by means of DSC-MRI and TCD before and in response to CEA.