Peri-operative Mortality and Morbidity of Complex Abdominal Aortic Aneurysm Repair in Switzerland: A Swissvasc Report.

OBJECTIVE: Complex abdominal aortic aneurysms (cAAA) pose a clinical challenge. The aim of this study was to assess the 30 day mortality and morbidity rates for open aneurysm repair (OAR) and fenestrated or branched endovascular aortic repair (F/B-EVAR), and the effect of hospital volume in patients with asymptomatic cAAA in Switzerland. METHODS: Retrospective, cohort study using data from Switzerland's national registry for vascular surgery, Swissvasc, including patients treated from 1 January 2019 to 31 December 2022. All patients with asymptomatic, true, non-infected cAAA were identified. The primary outcome was 30 day mortality and morbidity rates reported using the Clavien-Dindo classification. Outcomes were compared between OAR and F/B-EVAR after propensity score weighting. RESULTS: Of the 461 patients identified, 333 underwent OAR and 128 underwent F/B-EVAR for cAAA. At 30 days, the overall mortality rate was 3.3% after OAR and 3.1% after F/B-EVAR (p = .76). Propensity score weighted analysis indicated similar morbidity rates for both approaches: F/B-EVAR (OR 0.69, 95% CI 0.45 - 1.05, p = .055); intestinal ischaemia (1.8% after OAR, 3.1% after F/B-EVAR, p = .47) and renal failure requiring dialysis (1.5% after OAR, 5.5% after F/B-EVAR, p = .024) were associated with highest morbidity and mortality rates. Treatment specific complications with high morbidity were abdominal compartment syndrome and lower limb compartment syndrome following F/B-EVAR. Overall treatment volume was low for most of the hospitals treating cAAA in Switzerland; outliers with increased mortality rates were identified among low volume hospitals. CONCLUSION: Comparable 30 day mortality and morbidity rates were found between OAR and F/B-EVAR for cAAA in Switzerland; lack of centralisation was also highlighted. Organ specific complications driving death were renal failure, intestinal ischaemia, and limb ischaemia, specifically after F/B-EVAR. Treatment in specialised high volume centres, alongside efforts to reduce peri-procedural kidney injury and mesenteric ischaemia, offers potential to lower morbidity and mortality rates in elective cAAA treatment.

Outcomes Following Intact and Ruptured Aneurysm Repair across Nations: Analysis of International Registry Data from the VASCUNET Collaboration 2014 - 2019.

OBJECTIVE: To determine the peri-operative mortality rate for intact and ruptured abdominal aortic aneurysm (AAA) repair in 10 countries and to compare practice and outcomes over a six year period by age, sex, and geographic location. METHODS: This VASCUNET study used prospectively collected data from vascular registries in 10 countries on primary repair of intact and ruptured AAAs undertaken between January 2014 and December 2019. The primary outcome was peri-operative death (30 day or in hospital). Logistic regression models were used to estimate the association between peri-operative death, patient characteristics, and type of procedure. Factors associated with the use of endovascular aortic aneurysm repair (EVAR) were also evaluated. RESULTS: The analysis included 50 642 intact and 9 453 ruptured AAA repairs. The proportion of EVARs for intact repairs increased from 63.4% in 2014 to 67.3% in 2016 before falling to 62.3% in 2019 (p < .001), but practice varied between countries. EVAR procedures were more common among older patients (p < .001) and men (p < .001). Overall peri-operative mortality after intact AAA repair was 1.4% (95% confidence interval [CI] 1.3 - 1.5%) and did not change over time. Mortality rates were stable within countries. Among ruptured AAA repairs, the proportion of EVARs increased from 23.7% in 2014 to 35.2% in 2019 (p < .001). The average aortic diameter was 7.8 cm for men and 7.0 cm for women (p < .001). The overall peri-operative mortality rate was 31.3% (95% CI 30.4 - 32.2%); the rates were 36.0% (95% CI 34.9 - 37.2%) for open repair and 19.7% (95% CI 18.2 - 21.3%) for EVAR. This difference and shift to EVAR reduced peri-operative mortality from 32.6% (in 2014) to 28.7% (in 2019). CONCLUSION: The international practice of intact AAA repair was associated with low mortality rates in registry reported data. There remains variation in the use of EVAR for intact AAAs across countries. Overall peri-operative mortality remains high after ruptured AAA, but an increased use of EVAR has reduced rates over time.

Editor's Choice - Sex Related Differences in Indication and Procedural Outcomes of Carotid interventions in VASCUNET.

OBJECTIVE: It has been suggested that peri-operative complications after carotid surgery may be higher in women than in men. This assumption may affect the treatment patterns, and it is thus possible that carotid endarterectomy (CEA) is provided to women less often. The aim of the current VASCUNET study was to determine sex related differences in operative risk in routine clinical practice among non-selected patients undergoing carotid revascularisation. METHODS: Data on CEA and carotid artery stenting (CAS) from 14 vascular registries were collected and amalgamated. Comprehensive data were available for 223 626 carotid artery procedures; these were analysed overall and by country. The primary outcome was any stroke and or death within 30 days of carotid revascularisation. Secondary outcomes were stroke, death, or any major cardiac event or haemorrhage leading to re-operation. RESULTS: Of the procedures, 34.8% were done in women. The proportion of CEA for asymptomatic stenosis compared with symptomatic stenosis was significantly higher among women than men (38.4% vs. 36.9%, p < .001). The proportion of octogenarians was higher among women than men who underwent CEA in both asymptomatic (21.2% vs. 19.9%) and symptomatic patients (24.3% vs. 21.4%). In the unadjusted analysis of symptomatic and asymptomatic patients, there were no significant differences between men and women in the rate of post-operative combined stroke and or death, any major cardiac event, or combined death, stroke, and any major cardiac event after CEA. Also, after stenting for asymptomatic or symptomatic carotid stenosis, there were no significant differences between men and women in the rate of post-operative complications. In adjusted analyses, sex was not significantly associated with any of the end points. Higher age and CAS vs. CEA were independently associated with all four end points. CONCLUSION: This study confirmed that, in a large registry among non-selected patients, no significant sex related differences were found in peri-operative complication rates after interventions for carotid stenosis.

Contemporary Treatment of Popliteal Artery Aneurysms in 14 Countries: A Vascunet Report.

OBJECTIVE: Popliteal artery aneurysm (PAA) is the second most common arterial aneurysm. Vascunet is an international collaboration of vascular registries. The aim was to study treatment and outcomes. METHODS: This was a retrospective analysis of prospectively registered population based data. Fourteen countries contributed data (Australia, Denmark, Finland, France, Hungary, Iceland, Italy, Malta, New Zealand, Norway, Portugal, Serbia, Sweden, and Switzerland). RESULTS: During 2012-2018, data from 10 764 PAA repairs were included. Mean values with between countries ranges in parenthesis are given. The incidence was 10.4 cases/million inhabitants/year (2.4-19.3). The mean age was 71.3 years (66.8-75.3). Most patients, 93.3%, were men and 40.0% were active smokers. The operations were elective in 73.2% (60.0%-85.7%). The mean pre-operative PAA diameter was 32.1 mm (27.3-38.3 mm). Open surgery dominated in both elective (79.5%) and acute (83.2%) cases. A medial surgical approach was used in 77.7%, and posterior in 22.3%. Vein grafts were used in 63.8%. Of the emergency procedures, 91% (n = 2 169, 20.2% of all) were for acute thrombosis and 9% for rupture (n = 236, 2.2% of all). Thrombosis patients had larger aneurysms, mean diameter 35.5 mm, and 46.3% were active smokers. Early amputation and death were higher after acute presentation than after elective surgery (5.0% vs. 0.7%; 1.9% vs. 0.5%). This pattern remained one year after surgery (8.5% vs. 1.0%; 6.1% vs. 1.4%). Elective open compared with endovascular surgery had similar one year amputation rates (1.2% vs. 0.2%; p = .095) but superior patency (84.0% vs. 78.4%; p = .005). Veins had higher patency and lower amputation rates, at one year compared with synthetic grafts (86.8% vs. 72.3%; 1.8% vs. 5.2%; both p < .001). The posterior open approach had a lower amputation rate (0.0% vs. 1.6%, p = .009) than the medial approach. CONCLUSION: Patients presenting with acute ischaemia had high risk of amputation. The frequent use of endovascular repair and prosthetic grafts should be reconsidered based on these results.

Arthroscopic Repair of Massive Cuff Tears With Large Subscapularis Tendon Ruptures (Lafosse III/IV): A Prospective Magnetic Resonance Imaging-Controlled Case Series of 26 Cases With a Minimum Follow-up of 1 Year.

PURPOSE: To prospectively assess arthroscopic repair of massive cuff tears (MCT) in a highly selective patient group with large subscapularis (SSC) tendon tears by means of clinical results and magnetic resonance imaging (MRI) studies. METHODS: Between April 2009 and December 2010, 26 patients with MCT were treated with arthroscopic rotator cuff repair. Only lesions involving a large tear of the SSC tendon (Lafosse III or IV) in combination with a complete tear of the supraspinatus (SSP) tendon and a tear of at least the anterior third of the infraspinatus (ISP) tendon were included. Minimum follow-up was 1 year. Pre- and postoperative assessment included a standardized clinical examination, subjective patient outcome, and MRI (structural integrity, fatty muscle infiltration, and muscular mass). RESULTS: Mean follow-up was 17 months (range, 12 to 34 months). MRI was performed in 25 patients. In 21 (84%) the cuff repair was intact. A partial retear of the SSC was found in 2 patients (8%). In 2 patients (8%) a full-thickness retear of the posterosuperior cuff was observed (1 SSP, 1 SSP/ISP). A significant increase of the muscle mass and decrease of fatty infiltration was observed for the SSC and SSP but not for the ISP. The mean Constant-Murley score improved from 36 to 86 points (P < .001) with all its subscores as well (P < .001). Muscular strength improved for the SSC (4.9 v 3.0, P < .001), SSP (4.6 v 2.9, P < .001), and ISP (4.8 v 3.4, P < .001). Overall patient satisfaction was high (3.6 ± 0.8). CONCLUSIONS: Arthroscopic repair of MCT involving the ISP, SSP, and large tears of the SSC provides a reliable tendon healing, in particular for the SSC tendon, combined with good functional results. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Arthroscopic repair of traumatic isolated subscapularis tendon lesions (Lafosse Type III or IV): a prospective magnetic resonance imaging-controlled case series with 1 year of follow-up.

PURPOSE: The purpose of this study was to prospectively assess the efficacy of arthroscopic repair of isolated high-grade subscapularis (SSC) tendon lesions by means of clinical follow-up combined with magnetic resonance imaging investigations. METHODS: Between January 2008 and September 2010, 11 patients (9 men and 2 women; mean age, 45 ± 10 years) with Lafosse type III or IV traumatic isolated SSC tendon lesions underwent arthroscopic repair including tenodesis of the long head of the biceps tendon. All patients were preoperatively assessed by clinical examination (Constant-Murley score [CMS]) and contrast-enhanced magnetic resonance arthrography. At 1 year of follow-up, specific clinical SSC tests, the CMS, and the loss of external rotation were evaluated. A native magnetic resonance investigation was performed to assess the structural integrity of the repair. The SSC muscle was compared with its preoperative condition regarding fatty infiltration and size (cross-sectional area). Patient satisfaction was graded from 1 (poor) to 4 (excellent). RESULTS: The mean time interval from trauma to surgery was 3.7 months. A concomitant lesion of the biceps tendon was observed in 10 patients (91%). The mean CMS improved from 44 to 89 points (P < .001). The functional tests showed a significant increase in strength (P < .05) (belly-press test, 4.8 v 2.9; lift-off test, 4.8 v 2.9). The mean loss of external rotation at 0° of abduction was 10° compared with the contralateral side (P < .05). Patient satisfaction was high. Magnetic resonance imaging evaluation showed complete structural integrity of the tendon repair in all studies. The SSC showed a significant decrease in fatty infiltration and increase in the cross-sectional area. CONCLUSIONS: Arthroscopic repair of higher-grade isolated SSC lesions provides reliable tendon healing accompanied by excellent functional results 1 year after surgery. LEVEL OF EVIDENCE: Level IV, prospective therapeutic case series.

Surgical treatment of Neer Group VI proximal humeral fractures: retrospective comparison of PHILOS® and hemiarthroplasty.

BACKGROUND: Neer Group VI proximal humeral fractures often are related to persistent disability despite surgical treatment. We retrospectively compared the outcome after open reduction and internal fixation with the PHILOS(®) plate or primary hemiarthroplasty in patients with Neer Group VI fractures focusing on complications, shoulder function, health-related quality of life (SF-36), and potential risk factors for complications. QUESTIONS/PURPOSES: The aim of this study was to compare the PHILOS(®) plate with primary hemiarthroplasty for treatment of specific Neer Group VI fractures. We asked whether (1) both procedures have comparable clinical and radiologic complication rates; (2) one procedure is superior in terms of revision rate; (3) objective and subjective shoulder function (Constant-Murley score) and health-related quality of life (SF-36) were comparable in both groups at final followup; and (4) there are clinical or radiologic predictors for complications in any group? METHODS: Between 2002 and 2007, 44 consecutive patients (mean, 75.2 years) with a Neer Group VI proximal humeral fracture were included. Twenty-two patients treated with a PHILOS(®) plate were compared with 22 patients treated by primary hemiarthroplasty. Both groups were similar in all criteria. At minimum followup of 12 months (mean, 30 months; range, 12-83 months), radiographic control, Constant-Murley score, and SF-36 were performed. RESULTS: Fourteen patients with complications (63.6%) were counted in the PHILOS(®) plate group, of which 10 (45.4%) needed revision surgery, mostly as a result of avascular necrosis and screw cut-outs. In the primary hemiarthroplasty group, only one patient needed revision surgery (4.5%). Smoking and steroid therapy were substantially associated with complications in the PHILOS(®) plate group. There were no differences between the two groups regarding Constant-Murley or SF-36 scores. CONCLUSIONS: Angular stable open reduction and internal fixation was associated with high complication and revision rates, especially in patients who smoked and those receiving steroid therapy. Primary hemiarthroplasty provides limited function, which had little influence on the quality of life in this elderly collective. There are predictive factors for complications after the treatment of Neer Group VI proximal humeral fractures with the PHILOS(®) plate. Primary hemiarthroplasty remains a good option, especially when treating elderly patients.

Results of volar locking plate osteosynthesis for distal radial fractures.

BACKGROUND: To evaluate functional, radiologic, and subjective outcome after volar locking plate osteosynthesis (VLPO) for unstable distal radius fractures (DRF). METHODS: In this study, patients treated with VLPO for isolated DRF between March 2005 and December 2007 were prospectively evaluated. Patients with multiple injuries or those unavailable for follow-up were excluded from further evaluation. Range of motion, grip strength, and the subjective Patient-Rated Wrist Evaluation score were monitored for 6 weeks, 3 months, 6 months, and finally 1 year after surgery. The uninjured contralateral wrist served as control. The radiologic outcome after 1 year was scored using the Lidstrom score. RESULTS: In total, 245 patients were included in the study with a mean age of 62 years ± 18 years. At the final follow-up, 1 year after surgery, 228 patients (93%) could be controlled. Range of motion significantly increased during follow-up. One year after surgery, mean flexion was 64° ± 15°, and mean extension reached 64 ° ± 15 ° corresponding with >90% of the uninjured contralateral wrist function. Grip strength increased from 14 kg ± 8 kg (54%) 6 weeks after surgery to 25 kg ± 11 kg (91%) at the final follow-up. Patient-Rated Wrist Evaluation score resulted in mean 8 points ± 16 points after 1 year. Lidstrom score reached a mean of 1.3 points ± 0.6 points, demonstrating a good initial fracture reduction and stable fixation. A complication rate of 15% could be seen in our series, among secondary fracture displacement in two patients (1%). CONCLUSIONS: VLPO for the treatment of unstable DRF is a reliable technique with excellent subjective, objective, and radiologic outcome.

Posterolateral approach to the displaced posterior malleolus: functional outcome and local morbidity.

BACKGROUND: Stable anatomical reconstruction of the joint surface in ankle fractures is essential to successful recovery. However, the functional outcome of fractures involving the posterior tibial plafond is often poor. We describe the morbidity and functional outcome for plate fixation of the displaced posterior malleolus using a posterolateral approach. MATERIALS AND METHODS: The posterolateral approach was used for osteosynthesis of the posterior malleolus in 45 consecutive patients (median age 54 years) with AO/Muller-classification type 44-A3 (n = 1), 44-B3 (n = 35), 44-C1 (n = 7), and 44-C2 (n = 2) ankle fractures. Thirty-three of the patients suffered complete fracture dislocation. Functional outcome at followup was measured using the modified Weber protocol and the standardized AAOS foot and ankle questionnaire. Radiological evaluation employed standardized anterior-posterior and lateral views. RESULTS: The fragment comprised a median of 24% (range, 10% to 48%) of the articular surface. Postoperative soft tissue problems were encountered in five patients (11%), one of whom required revision surgery. Two patients (4%) developed Stage I complex regional pain syndrome. Clinical and radiological followup at 25 months disclosed no secondary displacement of the fixed fragment. The median foot and ankle score was 93 (range, 58 to 100), shoe comfort score was 77 (range, 0 to 100). A median score of 7 (range, 5 to 16) was documented using the modified Weber protocol. CONCLUSION: The posterolateral approach allowed good exposure and stable fixation of a displaced posterior malleolar fragment with few local complications. The anatomical repositioning and stable fixation led to good functional and subjective outcome.

Comparison of 2 surgical approaches for volar locking plate osteosynthesis of the distal radius.

PURPOSE: To determine whether a volar radial (Henry) exposure to the distal radius is associated with less median nerve dysfunction than a direct volar exposure of the distal radius through the carpal tunnel that has been abandoned due to median nerve problems. METHODS: Over an 18-month period, all patients with distal radius fractures treated with volar locking plate osteosynthesis were consecutively integrated into this therapeutic study. A direct volar midline approach ulnar to the flexor tendons and median nerve including prophylactic carpal tunnel release (CTR) was routinely performed from July 2003 to December 2004 (CTR group). Due to median nerve problems, this approach was abandoned and a distal part of the classical Henry approach (HRY) through the flexor carpi radialis (FCR) tendon sheath was performed for volar locking plate osteosynthesis in a second period from April 2005 to May 2006 (HRY group). In this group, the carpal tunnel was released only in selected cases. Data were collected prospectively for both groups. Analysis included clinical examination, the Patient-Rated Wrist Evaluation, and radiological follow-up up to 1 year after surgery. RESULTS: Eighty-three patients entered the CTR group during the initial series. Thirty-one patients showed median nerve dysfunction 6 weeks after surgery. In the second period of observation, 91 patients entered the HRY group. The carpal tunnel was therapeutically decompressed in 18 patients, leaving the carpal tunnel untouched in 91 patients. Temporary median nerve paraesthesia was seen in 4 patients without CTR in the HRY group 6 weeks after surgery. After 1 year, persistent median nerve irritation was observed in 4 patients of the CTR group and none of the HRY group. Grip strength, range of motion, and Patient-Rated Wrist Evaluation were similar after 1 year. CONCLUSIONS: The direct volar approach to the distal radius with routine CTR should be abandoned because it was associated with an increased rate of temporary and persistent median nerve irritation compared to the distal part of the classic Henry approach in our series. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Upregulation of endothelin converting enzyme-1 in host liver during chronic cardiac allograft rejection.

Endothelin regulates cytokine expression in vitro and in vivo. This study investigated the effects of chronic allograft rejection on hepatic endothelin-converting enzyme-1 (ECE-1) gene expression and endothelin-1 (ET-1) plasma clearance. Using the Lewis-F344 minor histocompatibility mismatch model of heterotopic cardiac transplantation, hepatic ECE-1 gene expression was measured by real-time polymerase chain reaction and host plasma clearance of ET-1 was measured 8 weeks after transplantation in the absence of immunosuppression. In animals undergoing allograft rejection, hepatic ECE-1 gene expression increased 2-fold (P < 0.05), whereas no effect of rejection on ET-1 clearance from plasma was observed. In summary, upregulation of ECE-1 gene expression occurs in the liver of the host during chronic allograft rejection. Because the liver represents both a key organ for cytokine production and for endothelin metabolism, increased hepatic ECE-1-mediated ET-1 synthesis may contribute to host responses and cytokine production during allograft rejection.

[Well-Tried and New Ones ­ Update Varicose Vein Treatment 2016]. / Altbewährtes und Neues - Update Krampfaderbehandlung 2016.

Venous leg symptoms are frequent, but their relevance is frequently underestimated. With the introduction of effective, minimal-invasive endovenous treatment modalities the treatment of varicose veins has recently made major advances. The basis of every treatment decision is a competent anamnesis, clinical investigation and duplex scan. Outpatient varicose vein treatment using endovenous methods has been proofed to be at least as effective as traditional varicose vein surgery but is associated with fewer adverse events. Accordingly, the endovenous methods are exspected to replace surgery as goldstandard treatment and endovenous thermal vein ablation (Laser/Radiofrequency) is accepted by the Swiss Federal Office of Public Health for general reimbursment since 1st january 2016. All currently available methods have their advantages and limitations, the individual selection based on the present symptoms, anatomic findings and patients' preferences is fundamental for an optimal treatment result and maximized patient satisfaction.

The PHILOS plate for proximal humeral fractures--risk factors for complications at one year.

BACKGROUND: Since 2003, we have used the Proximal Humerus Interlocking System plate for treatment of proximal humeral fractures. Although many patients have good and excellent results, the reported rate of complications varies. We have focused on the complication rate and risk factors for complications 1 year after surgery. METHODS: From 2003 until 2008, a total of 294 (223 women; 71 men; median age, 72.9) patients were included. General data were collected at the time of injury (Charlson Index, smoking, and steroid therapy). Fractures were classified (AO/OTA) retrospectively. The follow-up of 1 year included radiographs and Constant-Murley score for functionality. Complications and revision surgeries were analyzed specifically. RESULTS: We found 83 (28.2%) patients with a total of 105 complications, requiring a total of 72 (24.5%) revision surgeries. The most frequent complication was screw cutout (33 of 294, 11.2%), because of secondary fracture displacement or avascular necrosis (AVN). AVN (20 of 294, 6.8%) was the main reason for secondary arthroplasty. Smoking more than 20 pack years had a significant impact on the complication rate. Fractures classified 11-A3 showed more implant failures. Fracture dislocations predisposed to secondary screw cutout and AVN. Patients without complications (211, 71.8%) achieved a median Constant-Murley score of 89 (40-100) points. CONCLUSION: This study points out several predisposing factors for negative outcome after open reduction and internal fixation with the Proximal Humerus Interlocking System plate (fracture type: 11-A3, fracture dislocations, and smoking). Accounting for these, patient's risk for complications can be evaluated more individually and taken into consideration for the concept of treatment. Altering the surgical technique was associated with a significant reduction in the incidence of secondary screw cutout.

Anatomically distinct activation of endothelin-3 and the L-arginine/nitric oxide pathway in the kidney with advanced aging.

Aging is associated with spontaneous degenerative changes of renal function and structure. The aim of this study was to determine changes of the endothelin (ET) system and NO tissue bioactivity during the physiological aging process. Renal protein expression of ET-1 and ET-3, ETA, and ETB receptor mRNA expression, ET receptor binding and distribution, and tissue NO metabolite content were determined in adult, middle-aged, and senescent normotensive female Wistar rats. In senescent animals, medullary ET-3 content increased 3.4-fold (p<0.05 vs. adult), whereas aging did not affect ET-3 levels in the cortex. Local NO bioavailability, determined by NO metabolite tissue measurements, decreased in the cortex only. ET receptor binding capacity--predominantly due to ETB receptor binding--was lower in medulla than in cortex. Aging had no effect on ET-1 binding capacity or ET receptor distribution, whereas with advanced age gene expression of both receptors decreased. In conclusion, aging causes distinctive expressional changes of the renal endothelin system in otherwise healthy rats. The pronounced increase of endothelin-3 in the renal medulla is associated with preservation of local NO metabolite levels, changes not observed in the cortex. These findings could be important for pathologies and possibly therapy associated with renal aging.

Activation of pro-inflammatory and anti-inflammatory cytokines in host organs during chronic allograft rejection: role of endothelin receptor signaling.

This study investigated whether allograft rejection is associated with local inflammatory activation in host organs and whether endothelin ET(A) receptor signaling is involved. Expression of IL-1beta, IL-1ra, IL-6, IL-10 and TNF-alpha was investigated in host liver, lung and native heart in a rat model of chronic rejection 8 weeks after heterotopic cardiac transplantation in the absence of immunosuppression. In the presence of rejection, circulating levels of cytokines increased, while tissue level activation was dependent on the organ involved. Similarly, tissue-specific regulatory patterns were observed regarding transcriptional activation. Although chronic ET(A) receptor blockade did not reduce transplant vasculopathy or tissue protein expression, treatment had pronounced effects on plasma levels and transcriptional regulation of chemokines. These data provide evidence for distinct pro-inflammatory local activation in host organs during chronic rejection and suggest a role for ET(A) receptors contributing to regulation of cytokine plasma levels and transcriptional activity.

Acute effects of 17 beta-oestradiol on functional activity of endothelin-converting enzymes in human arteries and veins.

In this study, we investigated the short-term effect of 17 beta-oestradiol on functional enzyme activity (FEA) of endothelin-converting enzymes in vitro using human internal mammary arteries (n=7-8) and human saphenous veins (n=16-17) obtained from patients undergoing coronary artery bypass graft surgery. Vascular rings were preincubated with either solvent control (0.2% ethanol) or 17 beta-oestradiol (1 microM) for 30 min and concentration-response curves to big ET-1 (0.1-100 nM) or ET-1 (0.1-100 nM) were performed. FEA for each concentration was calculated as the percentage activity [(contraction to big ET-1/contraction to ET-1)x100] normalized to KCl (100 mM). In control experiments, at low concentrations FEA was lower in internal mammary arteries than in saphenous veins (P<0.05). While FEA was suppressed in saphenous veins by 10 nM (4+/-1 versus 22+/-5%, P<0.01) and 30 nM (26+/-4 versus 48+/-7%, P<0.05) 17 beta-oestradiol, FEA was markedly enhanced in internal mammary arteries by 10 nM (33+/-12 versus 1+/-1%, P<0.001) and 30 nM (44+/-12 versus 8+/-3%, P<0.01) 17 beta-oestradiol. FEA was not affected by 100 nM 17 beta-oestradiol. These results demonstrate for the first time that short-term exposure to 17 beta-oestradiol affects FEA in vitro. Human internal mammary arteries have lower FEA than the saphenous veins, but FEA is differentially affected by acute exposure to 17 beta-oestradiol in human arteries and veins. Whether changes in FEA play a role in the vascular effects of 17 beta-oestradiol in vivo remains to be determined.

Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition.

The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET(A)) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET(A) receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by >50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21Cip1/WAF1. In vitro experiments blocking ET(A) receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury.

Dysfunctional renal nitric oxide synthase as a determinant of salt-sensitive hypertension: mechanisms of renal artery endothelial dysfunction and role of endothelin for vascular hypertrophy and Glomerulosclerosis.

This study investigated the role of renal nitric oxide synthase (NOS), endothelin, and possible mechanisms of renovascular dysfunction in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were treated for 8 wk with high salt diet (4% NaCl) alone or in combination with the ET(A) receptor antagonist LU135252 (60 mg/kg per d). Salt loading markedly increased NOS activity (pmol citrulline/mg protein per min) in renal cortex and medulla in DR but not in DS rats by 270 and 246%, respectively. Hypertension in DS rats was associated with renal artery hypertrophy, increased vascular and renal endothelin-1 (ET-1) protein content, and glomerulosclerosis. In the renal artery but not in the aorta of hypertensive DS rats, endothelium-dependent relaxation to acetylcholine was unchanged; however, endothelial dysfunction due to enhanced prostanoid-mediated, endothelium-dependent contractions and attenuation of basal nitric oxide release was present. Treatment with LU135252 reduced hypertension in part, but completely prevented activation of tissue ET-1 without affecting ET-3 levels. This was associated with a slight increase of renal NOS activity, normalization of endothelial dysfunction and renal artery hypertrophy, and marked attenuation of glomerulosclerosis. Thus, DS rats fail to increase NOS activity in response to salt loading. This abnormality may predispose to activation of the tissue ET-1 system, abnormal renal vasoconstriction, and renal injury. Chronic ET(A) receptor blockade normalized salt-induced changes in the renal artery and reduced glomerular injury, suggesting therapeutic potential for ET antagonists in salt-sensitive forms of hypertension.