PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial.

BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization. METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events. RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048). CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).

Outcome After Conservative and Endovascular Treatment of Stanford Type B Aortic Intramural Hematomas - A Single-Center Retrospective Study.

OBJECTIVES: Aortic intramural hematoma (IMH) is a rare disease. Thus far, only limited data is available and the indications for conservative and endovascular treatment are not well defined. The aim of this study was to investigate clinical presentation, course, CT imaging features and outcome of patients with type B aortic IMHs. METHODS: We included all patients with type B IMHs between 2012 and 2021 in this retrospective monocentric study. Clinical data, localization, thickness of IMHs and the presence of ulcer-like projections (ULPs) was evaluated before and after treatment. RESULTS: Thirty five patients (20 females; 70.3 y ± 11 y) were identified. Almost all IMHs (n = 34) were spontaneous and symptomatic with back pain (n = 34). At the time of diagnosis, TEVAR was deemed indicated in 9 patients, 26 patients were treated primarily conservatively. During the follow-up, in another 16 patients TEVAR was deemed indicated. Endovascularly and conservatively treated patients both showed decrease in thickness after treatment. Patients without ULPs showed more often complete resolution of the IMH than patients with ULPs (endovascularly treated 90.9% (10/11) vs 71.4% (5/7); conservatively treated 71.4% (10/14) vs 33.3% (1/3); P = .207). Complications after TEVAR occurred in 32% and more frequently in patients treated primarily conservatively (37.5% vs 22.2%). No in-hospital mortality was observed during follow-up. CONCLUSIONS: Prognosis of IMH seems favourable in both surgically as well as conservatively treated patients. However, it is essential to identify patients at high risk for complications under conservative treatment, who therefore should be treated by TEVAR. In our study, ULPs seem to be an adverse factor for remodeling.

MRI detects increased aortic stiffening and myocardial dysfunction after TEVAR of blunt injury in young patients.

Background: Thoracic endovascular aortic repair (TEVAR) is a well-established technique for the management of blunt thoracic aortic injury (BTAI). Despite improvements in vascular imaging, graft material properties, and implant techniques, stent-graft deployment artificially induces aortic stiffening. This study aimed to evaluate the midterm effect of thoracic endovascular aortic repair after blunt thoracic aortic injury on aortic stiffness and cardiac function in young patients using cardiovascular magnetic resonance (CMR) imaging. Patients and methods: From all patients who underwent TEVAR for BTAI between 2009 and 2019 in a single institution, 10 patients with no other comorbidities affecting arterial stiffness were sex-, age-, height-, and body surface area-matched to 10 healthy controls. Comprehensive CMR examination was performed in all controls and patients. The mean follow-up period was 5.4±1.8 years; the mean age at the time of TEVAR was 30.3±8.7 years. Results: Four patients who underwent TEVAR developed arterial hypertension. 4D flow CMR-based analysis demonstrated higher global pulse wave velocity (PWV) in TEVAR patients than in controls (p=0.012). Segmental analysis showed a higher PWV in the descending and abdominal aorta. The indexed diameter of the ascending aorta was larger in TEVAR patients than in controls (p=0.007). The CINE acquisitions demonstrated increased left ventricular myocardial thickness (p<0.001). The 3D global diastolic strain rate and diastolic longitudinal velocity (e') decreased, and the A-wave velocity increased. Native myocardial T1 values were significantly higher in TEVAR patients (p=0.037). Conclusions: Young patients with TEVAR after BTAI are at an increased risk of developing vascular and myocardial dysfunction due to increased aortic stiffness. CMR follow-up allows for a comprehensive and radiation-free evaluation of vascular stiffness and associated myocardial changes, especially at the early and subclinical stages.

Selective inhibition of neuronal Cav3.3 T-type calcium channels by TAT-based channel peptide.

Low-voltage-activated Cav3 calcium channels (T-type) play an essential role in the functioning of the nervous system where they support oscillatory activities that relie on several channel molecular determinants that shape their unique gating properties. In a previous study, we documented the important role of the carboxy proximal region in the functioning of Cav3.3 channels. Here, we explore the ability of a TAT-based cell penetrating peptide containing this carboxy proximal region (TAT-C3P) to modulate the activity of Cav3 channels. We show that chronic application of TAT-C3P on tsA-201 cells expressing Cav3 channels selectively inhibits Cav3.3 channels without affecting Cav3.1 and Cav3.2 channels. Therefore, the TAT-C3P peptide described in this study represents a new tool to address the specific physiological role of Cav3.3 channels, and to potentially enhance our understanding of Cav3.3 in disease.

Transcriptomic analysis of glycan-processing genes in the dorsal root ganglia of diabetic mice and functional characterization on Cav3.2 channels.

Cav3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Cav3.2 expression is associated with the development of peripheral painful diabetic neuropathy (PDN). Several studies have previously documented the role of glycosylation in the expression and functioning of Cav3.2 and suggested that altered glycosylation of the channel may contribute to the aberrant expression of the channel in diabetic conditions. In this study, we aimed to analyze the expression of glycan-processing genes in DRG neurons from a leptin-deficient genetic mouse model of diabetes (db/db). Transcriptomic analysis revealed that several glycan-processing genes encoding for glycosyltransferases and sialic acid-modifying enzymes were upregulated in diabetic conditions. Functional analysis of these enzymes on recombinant Cav3.2 revealed an unexpected loss-of-function of the channel. Collectively, our data indicate that diabetes is associated with an alteration of the glycosylation machinery in DRG neurons. However, individual action of these enzymes when tested on recombinant Cav3.2 cannot explain the observed upregulation of T-type channels under diabetic conditions.Abbreviations: Galnt16: Polypeptide N-acetylgalactosaminyltransferase 16; B3gnt8: UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 8; B4galt1: Beta-1,4-galactosyltransferase 1; St6gal1: Beta-galactoside alpha-2,6-sialyltransferase 1; Neu3: Sialidase-3.

Kidney and liver are the main organs of expression of a key metabolic enzyme alanine:glyoxylate aminotransferase 2 in humans.

BACKGROUND: The metabolic syndrome is a cluster of cardiovascular risk factors and is highly predictive for development of cardiovascular diseases. An association between elevated plasma levels of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) and risk of cardiovascular diseases has been demonstrated in numerous epidemiological studies. ADMA can be catabolized by dimethylarginine dimethylaminohydrolase (DDAH) or metabolized through a much less understood alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2) with the formation of α-keto-δ-(N,N-dimethylguanidino)valeric acid (ADGV). Previous RT-PCR and Western Blot studies suggested that Agxt2 is expressed in the mouse kidney and liver at comparable levels, while Northern Blot and in-situ RNA-hybridisation experiments demonstrated that the kidney is the main organ of Agxt2 expression in rats. Given this discrepancy, the goal of the current study was to analyse the expression of AGXT2 in human tissues. MATERIAL AND METHODS: We analyzed AGXT2 expression in human tissues from a normal tissue bank by RT-PCR and further validated the results by Western Blot. We also performed immunohistochemical staining for AGXT2 and double fluorescent staining with an anti-AGXT2 antibody and a monoclonal anti-mitochondrial antibody. RESULTS: We saw the strongest expression of AGXT2 in the kidney and liver and confirmed this results on protein level. By IHC staining we were able to show that AGXT2 is present in the convoluted tubule in the kidney and in the liver hepatocytes. The double fluorescent staining revealed mitochondrial localization of AGXT2. CONCLUSIONS: Our current data suggest that both hepatocytes and kidney tubular epithelial cells are the major sources of AGXT2 in humans. We also demonstrated the mitochondrial localization of human AGXT2 enzyme.

PLX-PAD Cell Treatment of Critical Limb Ischaemia: Rationale and Design of the PACE Trial.

BACKGROUND: Critical limb ischaemia (CLI) is a life threatening condition with a considerable risk of major amputation and death. Besides revascularisation, no treatment has been proven to reduce the risks. Therapeutic angiogenesis by gene or cell therapy has not demonstrated definitive evidence in randomised controlled trials. PLX-PAD is an "off the shelf" allogeneic placental derived, mesenchymal like cell therapy, which, in preclinical studies, has shown pro-angiogenic, anti-inflammatory, and regenerative properties. Favourable one year amputation free survival (AFS), and trends in reduction of pain scores and increase of tissue perfusion have been shown in two small, open label, phase I trials. METHODS: The PACE study is a phase III randomised, double blind, multicentre, multinational placebo controlled, parallel group study to evaluate the efficacy, tolerability, and safety of intramuscular injections of PLX-PAD cells to treat patients with atherosclerotic CLI with minor tissue loss (Rutherford Category 5) up to the ankle level, who are unsuitable for revascularisation or carry an unfavourable risk benefit for that treatment. The study will enroll 246 patients, who after screening are randomised in a ratio of 2:1 to treatment with intramuscular injections of PLX-PAD 300 × 106 cells or placebo on two occasions, eight weeks apart. The primary efficacy endpoint is time to major amputation or death (amputation free survival), which will be assessed in follow up of at least 12 months and up to 36 months. CONCLUSIONS: Based on favourable pre-clinical and initial clinical study results, the PACE phase III randomised controlled trial will evaluate placenta derived PLX-PAD cell treatment in patients with critical limb ischaemia, with an unfavourable risk benefit for revascularisation. Clinicaltrials.gov: NCT03006770.

Management of the left subclavian artery during TEVAR - complications and mid-term follow-up.

BACKGROUND: Numerous conditions that affect the boundary between the aortic arch and descending aorta are treated with thoracic endovascular aortic repair (TEVAR). In 40 % of cases, coverage of the left subclavian artery (LSA) cannot be prevented. Subsequently, neurological complications such as stroke or ischemia of the left upper extremity may develop. However, the actual risk of these complications is subject to considerable controversy. The optimal treatment approach, specifically the question whether primary revascularization of the LSA should be performed in all cases, is unclear. PATIENTS AND METHODS: The present retrospective study analyzed the short- and mid-term results of patients treated with TEVAR with complete coverage of the LSA. The postoperative protocol consisted of clinical and noninvasive examinations as well as morphological imaging. Survival, complication, and reintervention rates were recorded. RESULTS: A total of 40 patients, undergoing TEVAR with complete coverage of the LSA between January 2010 and December 2014 were analyzed retrospectively. The 30-day survival rate was 95 %, the survival one year after performed TEVAR was 67.5 %. The average follow-up was 1.5 years. After TEVAR procedure with complete coverage of the LSA, only one patient (2.5 %) developed critical ischemia of the left arm immediately after aortic stent implantation, requiring revascularization by transposition of the LSA. Anterior spinal artery syndrome occurred in another patient (2.5 %) immediately following TEVAR. During follow-up examinations, all patients showed a compensated arterial arm status. None of the patients developed new neurological deficits during the follow-up period. CONCLUSIONS: The study shows that performing TEVAR without primary revascularization of the LSA was justifiable in our cohort. An important risk factor of developing cerebral ischemia seems to be insufficient collateralization through the circle of Willis.

Microarray analysis for delineating the gene expression in biopsies of gastrocnemius muscle of patients with chronic critical limb ischaemia compared with non-ischaemic controls.

BACKGROUND: Microarray analysis has been carried out in this pilot study to compare delineated gene expression profiles in the biopsies of skeletal muscle taken from patients with chronic critical limb ischaemia (CLI) and non-ischaemic control subjects. PATIENTS AND METHODS: Biopsy of gastrocnemius muscle was obtained from six patients with unreconstructed CLI referred for surgical major amputation. As control, biopsies of six patients undergoing elective knee arthroplasty without evidence of peripheral arterial occlusive disease were taken. The differences in gene expression associated with angiogenic processes in specimens obtained from ischaemic and non-ischaemic skeletal muscle were confirmed by quantitative real-time polymerase chain reaction (PCR) analysis. RESULTS: Compared with non-ischaemic skeletal muscle biopsy of chronic-ischaemic skeletal muscle contained 55 significantly up-regulated and 45 down-regulated genes, out of which 64 genes had a known genetic product. Tissue samples of ischaemic muscle were characterized by increased expression of cell survival factors (e. g. tissue factor pathway inhibitor 2) in combination with reduced expression of cell proliferation effectors (e. g. microfibrillar-associated protein 5 and transferrin receptor). The expression of growth factors (e. g. early growth response 3 and chemokine receptor chemokine C-X-C motif ligand 4) which play a central role in arterial and angiogenic processes and anti-angiogenetic factors (e. g. pentraxin 3) were increased in chronic ischaemic skeletal muscle. An increased expression of extracellular matrix proteins (e. g. cysteine-rich angiogenic inducer 61) was also observed. CONCLUSIONS: Gene expression profiles in biopsies of gastrocnemius muscle in patients with chronic critical limb ischaemia showed an increase in pro-survival factors, extracellular matrix protein deposition, and impaired proliferation, compared with non-ischaemic controls. Further studies are required to analyse the endogenous repair mechanism.

Legitimacy of Entry-Oriented Strategy in DeBakey I Dissection in the Era of Endovascular Therapy.

BACKGROUND: Legitimacy of entry-oriented therapy for DeBakey I aortic dissection is of eminent importance in the era of emerging ascending aorta endovascular therapy. This study aims to evaluate early, midterm, and reintervention results of entry-oriented operative strategy compared to more aggressive strategies for treatment of DeBakey type I aortic dissection with an isolated intimal tear in the ascending aorta. METHODS: This study prospectively followed 98 consecutive patients who received an operation for DeBakey type I aortic dissection with the intimal tear in the ascending aorta between 2007 and 2013 for up to 6 years. Follow-up included survival, medical therapy, CT-imaging results, and reinterventions. Patients were grouped into entry-oriented (group I) receiving an isolated replacement of the ascending aorta and/or hemiarch (65 patients); and aggressive therapy (group II) receiving a replacement of the ascending aorta and complete aortic arch (33 patients). Results: The in-hospital mortality was 19% and 23% respectively. The 3-year survival was 52% and 47% respectively (P = .193). Group II showed no advantage regarding persistence or progression of the dissection, thrombosis of false lumen, increase in aortic diameter, peripheral organ malperfusion (as assessed by follow-up computed tomography imaging) or freedom from reintervention. Conclusion: In treating DeBakey I aortic dissection with an entry tear in the ascending aorta, it might be legitimate to adopt an entry-oriented operative strategy. Further research is also needed to clearly describe the indication of extending the operative strategy in such cases.

Rationale and design of MultiSELECt: A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by lipoprotein apheresis on Cardiovascular outcomes.

BACKGROUND: Dyslipidemia is a well-known risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). While low density lipoprotein cholesterol (LDL-C) is well-established and taken into consideration for risk management and therapy, lipoprotein(a) is another established CVD risk factor frequently not undergoing screening due to a lack of medical treatment options. For patients suffering from CVD due to massive elevation of Lp(a) in presence of normal LDL-C levels, lipoprotein apheresis is the only available treatment option. While this constellation is an accepted indication for lipoprotein apheresis (LA) in Germany, prospective studies including a control group are still lacking. OBJECTIVE: Primary objective of this trial is to evaluate the clinical benefit of lipoprotein apheresis on myocardial infarction, PCI, CABG and death from cardiovascular disease in subjects with elevated Lp(a). This study evaluates the clinical benefit of weekly LA in subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee (treatment group). Comparator will be well-matched subjects under maximum tolerated lipid lowering therapy without access to LA treatment (control group). METHODS: MultiSELECt, is a prospective, multicenter, multinational, two-arm matched-pair cohort study designed to directly compare subjects with significantly elevated Lp(a) approved for LA subsequently undergoing weekly apheresis treatment versus a continuation of maximal medical therapy. The follow-up period will be 2 years after the baseline visit and until at least 60 events of the primary end-point occurred in the control group. A central trial expert committee will review all subjects with respect to their potential indication for LA according to established German guidelines in a blinded fashion. All control subjects will be contacted monthly via telephone visits to compensate for the more frequent visits during apheresis. Approximately 150 matched pairs will be necessary to detect an event reduction of at least 10% in subjects under LA treatment. CONCLUSION: The MultiSELECt trial provides the unique opportunity to demonstrate the efficiency of LA on CVD in patients with elevated Lp(a) under strongly controlled conditions.

Experts' Results in Blunt Thoracic Aortic Injury are Reproducible in Lower Volume Tertiary Institutions. Early and Mid-term Results of an Observational Study.

OBJECTIVES: The aim of this study was to evaluate the early and mid-term clinical results, the device performance, and the mid-term re-intervention rates of patients suffering blunt thoracic aortic injury (BTAI) managed by a multidisciplinary team in a low-volume BTAI centre. METHODS: This was a retrospective observational study in a tertiary hospital setting. From December 2005 to March 2016, all patients over 18 years old admitted with BTAI were included in the study. No exclusion criteria were applied. The study data were collected and analysed retrospectively. Follow-up of survivors included computed tomography imaging 3 and 9 months post-procedure, then annually. RESULTS: Twenty-eight patients were included in the study. Their mean age was 42 ± 16 years and 89% were male. A contained aortic rupture was diagnosed in 20 patients, a Stanford type B dissection in six, and intramural haematoma in two patients. Multidisciplinary evaluations were performed and an intervention was indicated in 25 patients (89%), four of whom died before the intervention. Nineteen patients underwent thoracic endovascular aortic repair of the descending thoracic aorta and two patients underwent a frozen elephant trunk procedure. The procedures were performed 0.7 ± 1.2 days after injury. All procedures were successful. There were no device related complications. The post-operative 30 day mortality was 5%, with one patient dying on the day of operation from other vascular injuries. The 30 day mortality of all patients was 18%. The median mid-term follow-up period was 786 days. All 30 day survivors survived the follow-up period. The mid-term imaging showed stable results in 19 patients. Two patients required frozen elephant trunk procedures after 240 and 681 days and both procedures were successful. CONCLUSIONS: In a low volume centre, a multidisciplinary team using a standardised protocol with the endovascular first approach demonstrated excellent outcomes, similar to those of large centres. If the aortic trauma is adequately managed, the patient's outcome is closely related to the additional trauma.

Endovascular Creation of an Arteriovenous Fistula (endoAVF) for Hemodialysis Access: First Results.

INTRODUCTION: Surgical creation of a radiocephalic fistula is the gold standard of vascular access for hemodialysis. Recently, an endovascular approach for upper arm fistula creation (endoAVF) has been developed, which may be an alternative to open surgery. We describe a case series of eight cases showing feasibility, early complications and outcome of this novel treatment option. MATERIALS AND METHODS: Between July 2015 and February 2016, we created an endoAVF in eight patients. Indications for endoAVF were confirmed by a multidisciplinary vascular board upon the exclusion for Cimino fistula candidates. Patients were suitable for the procedure after a pre-therapeutic ultrasound showed adequate brachial and ulnar vessels and no ipsilateral central venous stenosis. Patient characteristics, technical success, total patient radiation dose, complication rates, time to maturation of endoAVF and clinical effectiveness at six months were assessed retrospectively. RESULTS: Creation of endoAVF using the everlinQ endoAVF system (TVA Medical Inc., Austin, TX, USA) was successful in all eight cases. There were one minor intraprocedural complication and no postoperative complications. Median time to endoAVF maturation was 63 days (range 26-137 days). One patient was lost to follow-up after the first monitoring visit. In the remaining seven patients, hemodialysis was started without problems. Patency after 6 months was 100%. DISCUSSION: The endoAVF demonstrated to be feasible and safe for the creation of arteriovenous fistula suitable for hemodialysis access. Further studies with more patients and longer follow-up periods are needed to assess long-term outcomes and comparability to surgical dialysis access creation.

Quality of Life after Surgery for Stanford Type A Aortic Dissection: Influences of Different Operative Strategies.

BACKGROUND: Outcome of surgery for acute Stanford type A aortic dissection extends beyond mortality and morbidity. More than one operative strategy is available but little is known regarding their influence on quality of life. This study analyzes the influence of defensive and aggressive operative strategies on the patients' midterm quality of life (QoL). METHODS: From July 2007 to July 2010, 95 patients underwent surgery for acute Stanford type A aortic dissection in our institution. Patients who survived the procedure, gave consent to inclusion in the institution prospective registry, completed at least 2-years of follow-up protocol, and answered two quality of life questionnaires (SF-36 and WHO-QOL-BREF) were included in the study. Patients were divided into two groups according to operative strategy: defensive (DS) with replacement of the ascending aorta only, and aggressive (AS) with replacement of the ascending aorta, aortic arch with/out a frozen elephant trunk procedure. The preoperative, operative, postoperative and the midterm QoL were analyzed and compared. RESULTS: 39 patients were included in the study. The DS group had a shorter operative time (184 ± 54 versus 276 ± 110 minutes respectively, P = .001). The AS group had higher incidence of dialysis (31% versus 4% respectively, P = .038). The midterm QoL analysis showed a collective lower value than the normal population. In the SF-36, DS performed better in all categories but with no statistical significance. In the WHO-QOL-BREF, DS performed significantly better in the global life quality and psychological health categories (P = .038 and .049 respectively). CONCLUSION: In Stanford type A aortic dissection, adopting an aggressive surgical strategy does not improve the quality of life in midterm follow-up compared to a defensive strategy. Unless the clinical setting dictates an aggressive management strategy, a defensive strategy can be safely adopted.

Anastomotic leak after surgical repair of type A aortic dissection - prevalence and consequences in midterm follow-up.

BACKGROUND: This study reports the mid-term prevalence and therapeutic consequences of anastomotic leaks after surgery for Stanford type A aortic dissections. PATIENTS AND METHODS: From July 2007 to July 2013, 93 patients survived surgery for acute type A dissections at our center and underwent a standardized follow-up. The pre-, peri-, and postoperative as well as the midterm results were collected prospectively. Follow-up computed tomography (CT) imaging was performed 7 days, 3, and 12 months after surgery, and yearly thereafter, to assess the presence or progression of anastomotic leaks at the aorto-prosthesis anastomotic sites. RESULTS: The mean follow-up was 4 years (1534 ± 724 days). Follow-up CT revealed anastomotic leaks in 4 patients (4.3 %). All leaks developed during midterm follow-up and half of them did not increase with time. Two patients required redo surgery for an increase in periaortic extravasation and compression of neighboring structures. Further analysis was not able to reveal independent risk factors for development or deterioration of leaks. CONCLUSIONS: Anastomotic leaks after surgery for Stanford Type A aortic dissection can develop in midterm follow-up, even after initially excellent results. Meticulous follow-up is mandatory to detect possible deterioration and a need for redo surgery.

Predictive factors for better bypass patency and limb salvage after prosthetic above-knee bypass reconstruction.

BACKGROUND: Peripheral arterial disease (PAD) is one of the most underestimated diseases because of its high prevalence and unfavorable prognosis. Many PAD patients without suitable autologous veins or options for endovascular treatment receive prosthetic above-knee femoropopliteal bypass (PAKB). Until now predictors of prosthetic bypass failure and of increased amputation risk remain indistinct. This study aimed to identify predictive factors associated with better bypass patency and limb salvage to achieve a more favorable outcome after PAKB reconstruction. METHODS: Pre-, intra-, and postoperative data of 244 PAKB procedures performed at a German university medical center were collected and analyzed using univariate and multivariate methods. To our knowledge this 12-year experience is the largest retrospective study to identify predictors for patency and limb salvage after PAKB reconstruction. RESULTS: Of the PAD patients 94% (229/244) were followed for an average of 34.9 months. Patient cohorts characteristics were: mean age, 66.1 years, 181 men (74%), claudication (64%), rest pain (16%), ischemic lesions (20%), arterial hypertension (92%), smoking (79%), hyperlipidemia (65%) and type 2 diabetes (43%). Cumulative primary 1- and 3-year graft patency rates were 60.8% and 50.7%, respectively, and cumulative 1- and 3-year limb salvage rates were 89.3% and 86.1%, respectively. One hundred seven bypasses (43.9%) failed, 26 patients (10.7%) required a major and seven patients (2.9%) required a minor amputation. Overall survival rates of PAD patients after 1- and 3-years were 94.4% and 82.9%, respectively. Subjective symptom improvement was found to be the most important prognostic follow-up factor for graft patency and limb salvage. Patients with recurrent symptoms in the follow-up had an increased risk of emerging bypass failure compared with patients with subjective symptom improvement (patency at 1 year: 40.8% vs 100% and at 3 years: 26% vs 100%; P < .001). No patient with subjective improvement in symptoms during follow-up underwent an amputation (limb salvage at 1 year: 100% vs 79% and at 3 years: 100% vs 72.8%; P < .001). Therefore, subjective symptom improvement should be the decisive criterion to determine follow-up intervals of PAD patients. In univariate analysis further significant factors associated with better graft patency and limb salvage rates were: claudication compared with critical ischemia, larger graft diameter (>6 mm), pre- and postoperative antiplatelet therapy, statin therapy independent from lipid values after PAKB revascularization, and an experienced vascular surgeon. CONCLUSIONS: In our study, we determined the subjective improvement in symptoms as the most important prognostic factor for bypass function and limb salvage after PAKB. Furthermore, disease stage of critical ischemia, graft diameter, preoperative aspirin use, and postoperative statin medication were independent predictive factors. Therefore, PAD patients should be treated with aspirin pre- and postoperatively as well as with a statin postoperatively. In case of PAKB reconstruction only prostheses with a large diameter (>6 mm) should be used and the procedure should be performed by an experienced surgeon. Considering these results with regard to the predictive factors for better graft patency and limb salvage rates a significant more favorable outcome during the follow-up and an increased 5-year patency rate for PAKB reconstructions can be expected.

A Novel Pathway for Metabolism of the Cardiovascular Risk Factor Homoarginine by alanine:glyoxylate aminotransferase 2.

Low plasma concentrations of L-homoarginine are associated with an increased risk of cardiovascular events, while homoarginine supplementation is protective in animal models of metabolic syndrome and stroke. Catabolism of homoarginine is still poorly understood. Based on the recent findings from a Genome Wide Association Study we hypothesized that homoarginine can be metabolized by alanine:glyoxylate aminotransferase 2 (AGXT2). We purified human AGXT2 from tissues of AGXT2 transgenic mice and demonstrated its ability to metabolize homoarginine to 6-guanidino-2-oxocaproic acid (GOCA). After incubation of HepG2 cells overexpressing AGXT2 with isotope-labeled homoarginine-d4 we were able to detect labeled GOCA in the medium. We injected wild type mice with labeled homoarginine and detected labeled GOCA in the plasma. We found that AGXT2 knockout (KO) mice have higher homoarginine and lower GOCA plasma levels as compared to wild type mice, while the reverse was true for AGXT2 transgenic (Tg) mice. In summary, we experimentally proved the presence of a new pathway of homoarginine catabolism - its transamination by AGXT2 with formation of GOCA and demonstrated that endogenous AGXT2 is required for maintenance of homoarginine levels in mice. Our findings may lead to development of novel therapeutic approaches for cardiovascular pathologies associated with homoarginine deficiency.

Anesthesia management during aortic surgery: Preoperative patient assessment.

Patients with aortic diseases have a high rate of cardiac, cerebrovascular, or pulmonary comorbidities. Open surgery or endovascular interventions of the aorta are associated with high perioperative cardiac risk. Simple scoring systems for preoperative risk stratification can be used to identify high-risk patients. In these patients, further diagnostic and therapeutic interventions are required to reduce perioperative morbidity and mortality. In contrast, low-risk patients can be identified, who may proceed to intervention without additional cardiopulmonary diagnostic testing. According to evidence-based recommendations in patients at risk, statin therapy should be initiated and beta blockers should be uptitrated preoperatively. Smoking cessation preoperatively reduces perioperative complications and should be encouraged in all patients.