Adrenomedullin Is Associated With Surgical Trauma and Impaired Renal Function in Vascular Surgery Patients.

BACKGROUND:: Patients undergoing vascular surgery are prone to perioperative organ injury because of both higher prevalence of cardiovascular risk factors and the extent of surgery. Early detection of organ failure is essential to facilitate appropriate medical care. Midregional pro-adrenomedullin (MR-proADM) has been investigated in acute medical care settings to guide clinical decision-making regarding patient pathways and to identify patients prone to imminent cardiovascular or inflammatory complications. In this study, we evaluated the impact of perioperative MR-proADM levels as an early marker of perioperative cardiovascular and inflammatory stress reactions and kidney injury. METHODS:: The study was conducted as a monocentric, prospective, noninterventional trial at Hannover Medical School, Germany. A total of 454 consecutive patients who underwent open vascular surgery were followed from the day prior to until 30 days after surgery. The composite primary end point was defined as the occurrence of major adverse cardiac events (MACEs), acute kidney injury (AKI), or systemic inflammatory response syndrome (SIRS). Measurements were correlated with both medical history and postoperative MACE, AKI, or SIRS using univariate and multivariate regression analysis. RESULTS:: One hundred thirty-nine (31%) of the patients reached the primary end point within the study interval. Midregional pro-adrenomedullin change was associated with the combined primary end point and with the intensity of surgical trauma. Midregional pro-adrenomedullin change was increased in patients reaching the secondary end points, SIRS (optimal cutoff: 0.2 nmol/L) and AKI (optimal cutoff: 0.7 nmol/L), but not in patients with MACEs. CONCLUSION:: Increased levels of MR-proADM within the perioperative setting (1) were linked to the invasiveness of surgery and (2) identified patients with ongoing loss of renal function. Increased MR-proADM levels may therefore identify a subgroup of patients prone to excessive cardiovascular stress but did not directly correlate with adverse cardiac events. Consistently low levels of MR-proADM may identify a subgroup of patients with acceptable low risk to guide discharge from high-density care units.

Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo.

Background and Purpose- This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging. Methods- In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers 18F-GE180 and 68Ga-Pentixafor and evaluated by histopathology. In addition, 68Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS. Results- Distinct patterns of upregulation of TSPO (18F-GE180 uptake) and CXCR4 (68Ga-Pentixafor uptake) were identified in carotid plaque by autoradiography. The spatial distribution was associated with specific histological hallmarks that are established features of high-risk plaque: TSPO upregulation correlated with activated macrophages infiltration, whereas CXCR4 upregulation also corresponded to areas of intraplaque hemorrhage. 68Ga-Pentixafor uptake was significantly higher in plaques of symptomatic compared with asymptomatic CS. Clinical positron emission tomography revealed marked 68Ga-Pentixafor uptake in carotid plaque of a patient with high-grade CS. Conclusions- Clinical imaging of molecular signatures of high-risk atherosclerotic plaque is feasible and may become a promising diagnostic tool for comprehensive characterization of carotid disease. This methodology provides a platform for future studies targeting carotid plaque.

Monocyte Subsets and Related Chemokines in Carotid Artery Stenosis and Ischemic Stroke.

Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this study we, therefore, aimed to investigate the potential role of monocyte subsets and associated chemokines as clinical biomarkers for vulnerability of CS. Patients with symptomatic and asymptomatic CS (n = 21), patients with cardioembolic ischemic strokes (n = 11), and controls without any cardiovascular disorder (n = 11) were examined. Cardiovascular risk was quantified using the Essen Stroke Risk Score (ESRS). Monocyte subsets in peripheral blood were measured by quantitative flow cytometry. Plaque specimens were histologically analyzed. Furthermore, plasma levels of monocyte chemotactic protein 1 (MCP-1) and fractalkine were measured. Intermediate monocytes (Mon2) were significantly elevated in symptomatic and asymptomatic CS-patients compared to controls. Mon2 counts positively correlated with the ESRS. Moreover, stroke patients showed an elevation of Mon2 compared to controls, independent of the ESRS. MCP-1 levels were significantly higher in patients with symptomatic than in those with asymptomatic CS. Several histological criteria significantly differed between symptomatic and asymptomatic plaques. However, there was no association of monocyte subsets or chemokines with histological features of plaque vulnerability. Due to the multifactorial influence on monocyte subsets, the usability as clinical markers for plaque vulnerability seems to be limited. However, monocyte subsets may be critically involved in the pathology of CS.

Perioperative levels and changes of high-sensitivity troponin T are associated with cardiovascular events in vascular surgery patients.

OBJECTIVES: Myocardial infarction after major surgery is frequent, drives outcome, and consumes health resources. Specific prediction and detection of perioperative myocardial infarction is an unmet clinical need. With the widespread use of high-sensitive cardiac troponin T assays, positive tests become frequent, but their diagnostic or prognostic impact is arguable. We, therefore, studied the association of routinely determined pre- and postoperative high-sensitive cardiac troponin T with the occurrence of major adverse cardiac events. DESIGN: This study was a prospective non-interventional trial. SETTING: This study was conducted at Hannover Medical School in Germany. PATIENTS: A total of 455 patients undergoing open vascular surgery were followed for 30 days for the occurrence of major adverse cardiac events. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Preoperative and 24-hour postoperative high-sensitive cardiac troponin T measurements and the respective changes were correlated to medical history and the occurrence of major adverse cardiac events (cardiovascular death, myocardial infarction, and ischemia). Pre- and postoperative high-sensitive cardiac troponin T measurements demonstrated a majority of patients with detectable troponin levels preoperatively and an increase over the 24 hours after surgery. The level of high-sensitive cardiac troponin T was significantly associated with preexisting diseases that constitute the Lee's Revised Cardiac Risk Index. A preoperative high-sensitive cardiac troponin T greater than or equal to 17.8 ng/L and a perioperative high-sensitive cardiac troponin T change greater than or equal to 6.3 ng/L are independently associated with the occurrence of major adverse cardiac events. Adding high-sensitive cardiac troponin T absolute change to the Revised Cardiac Risk Index improves the risk predictive accuracy of the score as evidenced by increased area under receiver operating characteristic and significant reclassification effects. CONCLUSIONS: The risk predictive power of high-sensitive cardiac troponin T change in addition to the Revised Cardiac Risk Index could facilitate 1) detection of patients at highest risk for perioperative myocardial ischemia, 2) evaluation and development of cardioprotective therapeutic strategies, and 3) decisions for admission to and discharge from high-density care units.

The role of pericyte detachment in vascular rarefaction.

BACKGROUND: Pericytes surround endothelial cells at the perivascular interface. Signaling between endothelial cells and pericytes is crucial for capillary homeostasis, as pericytes stabilize vessels and regulate many microvascular functions. Recently it has been shown that pericytes are able to detach from the vascular wall and contribute to fibrosis by becoming scar-forming myofibroblasts in many organs including the kidney. At the same time, the loss of pericytes within the perivascular compartment results in vulnerable capillaries which are prone to instability, pathological angiogenesis, and, ultimately, rarefaction. AIMS: This review will give an overview of pericyte-endothelial cell interactions, summarize the signaling pathways that have been identified to be involved in pericyte detachment from the vascular wall, and present pathological endothelial responses in the context of disease of the kidney.

Neoadjuvant targeted therapy in a primary metastasized renal cell cancer patient leads to down-staging of inferior vena cava thrombus (IVC) enabling a cardiopulmonary bypass-free tumor nephrectomy: a case report.

BACKGROUND: We report on a 62-year-old gentleman presenting at our urological department with an advanced renal cell cancer of the right kidney (10 cm in diameter), with an extensive caval vein thrombus (level IV) and bilateral pulmonary metastases. Another suspicious lesion at the left hemithorax was radiologically described. METHOD: A presurgical, neoadjuvant systemic therapy with sunitinib, a tyrosine kinase inhibitor, was initiated for 4 cycles in total (50 mg/day; 4 weeks on/2 weeks off). The cytoreductive nephrectomy was performed following the fourth cycle of sunitinib and after a 14-day break. Transesophageal echocardiography was used for intraoperative monitoring of the caval vein thrombus. Systemic treatment with sunitinib was continued 4 weeks after surgery. RESULTS: A significant reduction in tumor size, metastatic sites and down-staging of IVC from level IV to level III according to Novick classification was achieved. CONCLUSION: Significant down-staging of the tumor caval vein thrombus which initially reached the right atrium enabled us to perform surgery limited to the abdominal cavity without extracorporeal circulation nor hypothermia.

Valiant thoracic stent-graft deployed with the new captivia delivery system: procedural and 30-day results of the Valiant Captivia registry.

PURPOSE: To evaluate procedural and 30-day outcomes of thoracic endovascular aortic repair (TEVAR) employing the Valiant Thoracic Stent Graft with the Captivia Delivery System. METHODS: Enrollment in the study ( www.ClinicalTrials.com identifier NCT01181947) included all eligible patients implanted with the Valiant Captivia System retrospectively and prospectively at 15 sites in Europe and Turkey between October 2009 and June 2010. In the 100 treated patients (81 men; mean age 64.6 ± 12.0 years, range 25-87), indications included descending thoracic aortic aneurysm (TAA, 49.0%) and aortic dissection (42.0%). RESULTS: Technical success was 100.0%, with no misaligned deployments or aortic perforations. Mean follow-up was 68.9 ± 34.9 days (range 20-147, median 61). The 30-day rate of all-cause mortality was 4.0% (all 4 cases procedure-related, 3 device-related). Retrograde type A dissection occurred in 2 patients. The only conversion to open surgery was successful in a patient experiencing intraoperative aneurysm rupture. Stroke occurred in 4 (4.0%) patients and paraplegia in 1 (1.0%). Among 66 patients with 30-day imaging studies evaluable for endoleak, 4 (6.1%) had type I and 7 (10.6%) had type II endoleak; there were no types III or IV. Within 30 days, no secondary endovascular procedures were required due to endoleak. One patient with type II endoleak died 3 weeks postimplantation before scheduled embolization. CONCLUSION: In this analysis of procedural and 30-day results, the high technical success and clinical outcome rates showed that the Valiant Thoracic Stent Graft with the new Captivia Delivery System has promising capacity to treat a variety of thoracic aortic conditions in a range of anatomies.

Cryopreserved arterial homografts vs silver-coated Dacron grafts for abdominal aortic infections with intraoperative evidence of microorganisms.

OBJECTIVE: The gold standard for the treatment of abdominal aortic infections remains controversial. Cryopreserved arterial homografts and silver-coated Dacron grafts have both been advocated as reasonable grafts. Direct clinical or experimental comparisons between these two treatment options have not been published before. This study compared cryopreserved arterial homografts and silver-coated Dacron grafts for the treatment of abdominal aortic infections in a contaminated intraoperative field. METHODS: From January 2004 to December 2009, 56 patients underwent in situ arterial reconstruction for an abdominal aortic infection. Patients with negative intraoperative microbiologic specimens were excluded. We compared 22 of 36 patients (61%) receiving cryopreserved arterial homografts (group A) vs 11 of 20 (55%) receiving a silver-coated Dacron graft (group B). Primary outcomes were survival and limb salvage; secondary outcomes were graft patency and reinfection. Direct costs of therapy were also calculated. RESULTS: Thirty-day mortality was 14% in group A and 18% in group B (P >.99), and 2-year survival rates were 82% and 73%, respectively (P = .79). After 2 years, limb salvage was 96% and 100%, respectively (P = .50), whereas graft patency was 100% for both groups. Major complications were an aneurysmal degeneration in group A and graft reinfection in group B (n = 2). Median direct costs of therapy (in US $) were $41,697 (range, $28,347-$53,362) in group A and $15,531 (range, $11,310-$22,209) in group B (P = .02). CONCLUSIONS: Our results show comparable effectiveness between cryopreserved arterial homograft and silver-coated Dacron graft in the contaminated operative field with respect to early mortality and midterm survival. Graft-inherent complications, aneurysmal degeneration for homografts, and reinfection for silver graft, were also observed. The in situ arterial reconstruction with homografts is nearly three times more expensive than with silver graft.

Eight-year experience with cryopreserved arterial homografts for the in situ reconstruction of abdominal aortic infections.

OBJECTIVE: This study investigated short-term and long-term outcomes in patients with abdominal aortic infection (mycotic aneurysm, prosthetic graft infection, aortoenteric fistula) managed by total excision of the aneurysm or the infected vascular graft and in situ aortic reconstruction with a cryopreserved arterial homograft (CAH). METHODS: From January 2000 to December 2008, 110 consecutive patients underwent CAH implantation for treatment of vascular infections. In 57 (52%), in situ revascularization of the abdominal aorta with Y-prosthesis constructed from CAHs was performed. Early outcome included 30-day mortality and the levels of daily blood markers (leucocytes, C-reactive protein, and platelets) during the postsurgical 10-day period. We reported long-term survival and freedom from reoperation rates, including all indications for reoperation. RESULTS: Indications for operation were infected vascular graft in 31 patients (55%), aortodigestive fistulae in 11 (19%), nonruptured mycotic aneurysms in 4 (7%), and ruptured mycotic aneurysms of abdominal aorta in 11 (19%). In 39 of 57 patients (68%), the intraoperative specimens were positive for at least one microorganism, and Staphylococcus aureus was present in 14 (25%). In 32 patients (82%) with intraoperative specimens positive for microorganisms, there was no evidence of the intraoperatively detected microorganisms in the postoperative specimens (wound, blood culture, and drainage fluid). The peak value of leucocytes (13.7 +/- 4.4 x 10(3)/L) and C-reactive protein (200 +/- 75 mg/L) occurred on postoperative day 3. Platelets reached the lowest value on postoperative day 2 (178 +/- 67 x 10(9)/L). Median peak body temperature was 37.7 degrees +/- 0.6 degrees C. Thirty-day mortality was 9% (5 of 57 patients). Median follow-up was 36 months (range, 4-118 months); 3-year survival was 81%, and freedom from reoperation was 89%. Five patients (9%) required reoperation, in one patient each for postoperative bleeding, acute cholecystitis, homograft occlusion, homograft-duodenum fistula, and aneurysmal degeneration. No recurrence of infection was reported. CONCLUSION: These results demonstrate an encouraging outcome after cryopreserved allograft implantation for the treatment of vascular infections in the abdominal aorta. The data represent a basis for future comparisons with other treatment modalities for vascular infections, including silver-coated prostheses and autogenous femoral veins.

Midterm results from the TRAVIATA registry: treatment of thoracic aortic disease with the valiant stent graft.

PURPOSE: To assess early and midterm outcomes after thoracic endovascular aortic repair (TEVAR) with the Valiant Thoracic Stent Graft. METHODS: Data were reviewed retrospectively for 92 patients (69 men; mean age 65+/-14.5 years) who underwent TEVAR in 52.2% elective and 47.8% urgent/emergent procedures for treatment of 56 degenerative aneurysms, 32 aortic dissections, and 4 traumatic injuries at 4 German centers between June 2005 and March 2008. RESULTS: The technical success rate was 86.9%. Through 30 days, there were 3 (3.3%) deaths. Periprocedural complications included endoleak (n = 6), systemic complications (n = 6), arterial rupture or dissection (n = 6), device-related complications (n = 5), retrograde aortic dissection (n = 1), aortic rupture (n = 1), spinal cord ischemia (n = 1), and stroke (n = 1). Cumulative survival was 95.5% at 1 year, 87.4% at 2 years, and 76.4% at 3 years. The rate of aneurysm-related mortality was 2.2% (n = 2). For aneurysm and dissection patients, respectively, the rates of major complications were 9.3% and 15.6%, and secondary procedures were required in 7.4% and 12.5%. Type I endoleaks were detected in 4 aneurysm and 2 dissection patients, and graft migration occurred in 1 patient each from the aneurysm and dissection groups. No patients were converted to open surgery during follow-up. Aortic diameter reduction >5 mm was confirmed for 58.4% of patients overall. CONCLUSION: The high technical and clinical success, the low all-cause and aneurysm-related mortality, the negligible rates of neurological complications and spinal cord ischemia, and the low incidence of endoleak support the safety and effectiveness of TEVAR with the Valiant Thoracic Stent Graft. However, some deployment-related complications could be avoided by enhancements of the deployment mechanism.

Prospective evaluation of preoperative lung ultrasound for prediction of perioperative outcome and myocardial injury in adult patients undergoing vascular surgery (LUPPO study).

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a frequent perioperative event in vascular surgery, associated both with worse outcome and subsequent cardiovascular events. Current guidelines advocate troponin (hs-cTnT) and NT-proBNP measurements in selected patients before surgery, but accurate preoperative identification of patients at risk for MINS is an unmet clinical need. Focused lung ultrasound (LUS) might help to select patients at increased risk for MINS, because it can visualize B-line artifacts correlating to cardiopulmonary disease. Therefore, we investigated whether quantification of B-line artifacts improves perioperative risk predictive accuracy for MINS. METHODS: In this prospective single-center observational study, 136 consecutive open vascular surgery patients underwent conventional preoperative assessment expanded by lung ultrasound. Lung ultrasound B-lines were counted in each of 28 bilateral scan fields of the anterior and lateral chest. Improvement of risk predictive accuracy was quantified with area under receiver operating characteristic (ROC) curve analysis and net reclassification improvement (NRI). RESULTS: We included 118 patients into the final analysis. Twenty-three (19%) patients fulfilled the criteria for the primary endpoint MINS. Three or more bilateral positive B-line fields were calculated as the best ROC-derived cutoff associated with an increased incidence of MINS (odds ratio: 4.4; 95% confidence interval [CI]: 1.5 to 12.7; P=0.007). Adding LUS to hs-cTnT measurements improved risk predictive accuracy for MINS (NRI: 0.36, P=0.043). CONCLUSIONS: Lung ultrasound in combination with hs-cTnT showed a better test accuracy than hs-cTnT alone and might guide clinicians to identify vascular patients at increased risk for MINS.

Sequential Surgical Procedures in Vascular Surgery Patients Are Associated With Perioperative Adverse Cardiac Events.

Patients at elevated cardiovascular risk are prone to perioperative cardiovascular complications, like myocardial injury after non-cardiac surgery (MINS). We have demonstrated in a mouse model of atherosclerosis that perioperative stress leads to an increase in plaque volume and higher plaque vulnerability. Regulatory T cells (Tregs) play a pivotal role in development and destabilization of atherosclerotic plaques. For this exploratory post-hoc analysis we identified 40 patients recruited into a prospective perioperative biomarker study, who within the inclusion period underwent sequential open vascular surgery. On the basis of protein markers measured in the biomarker study, we evaluated the perioperative inflammatory response in patients' plasma before and after index surgery as well as before and after a second surgical procedure. We also analyzed available immunohistochemistry samples to describe plaque vulnerability in patients who underwent bilateral carotid endarterectomy (CEA) in two subsequent surgical procedures. Finally, we assessed if MINS was associated with sequential surgery. The inflammatory response of both surgeries was characterized by postoperative increases of interleukin-6,-10, Pentraxin 3 and C-reactive protein with no clear-cut difference between the two time points of surgery. Plaques from CEA extracted during the second surgery contained less Tregs, as measured by Foxp3 staining, than plaques from the first intervention. The 2nd surgical procedure was associated with MINS. In conclusion, we provide descriptive evidence that sequential surgical procedures involve repeat inflammation, and we hypothesize that elevated rates of cardiovascular complications after the second procedure could be related to reduced levels of intraplaque Tregs, a finding that deserves confirmatory testing and mechanistic exploration in future populations.

Resistance to infection of long-term cryopreserved human aortic valve allografts.

OBJECTIVE: To analyze the in vitro antimicrobial activity of 3 antibiotic regimens (group A, gentamicin-piperacillin-vancomycin-metronidazole-amphotericin B; group B, gentamicin-piperacillin-flucloxacillin-metronidazole-amphotericin B; and group C, meropenem-vancomycin-tobramycin-colistin-amphotericin B) used in the processing of cryopreserved human ascending aortic tissue and aortic valves against Staphylococcus epidermidis and Staphylococcus aureus. The results were additionally compared with the infection resistance of cryopreserved ascending aortic tissue against Escherichia coli and Pseudomonas aeruginosa. MATERIALS: Each of 10 cryopreserved human allografts (CHAs) was divided into 25 pieces (separating aortic wall and valve). Eighteen segments were microbiologically tested, and 7 pieces underwent scanning electron microscopy. A bacterial solution (4 mL; optical density, 0.20 ± 0.02) was used for contamination. After incubation, the optical density of the solution was measured. CHAs underwent sonication to release viable adherent bacteria. The number of attached bacteria was quantified by the colony forming units per square centimeter of CHA surface. RESULTS: Antibiotic regimen groups B and C were more efficient than group A in eradicating gram-positive organisms adherent to the aortic wall (P < .001). Group C showed enhanced resistance against E coli compared with group A or B (P < .001), whereas group B appeared to be more effective against P aeruginosa (P < .001). With reference to each antibiotic regimen, ascending aortic tissue showed significantly less bacterial contamination with staphylococcal bacteria than valve grafts (P ≤ .01). CONCLUSIONS: CHAs possess antibacterial activity despite long-term storage over 5 years. Antibiotic combinations applied during CHA processing have a significant influence on their infection resistance. Ascending aortic tissue shows a significantly enhanced bacterial resistance against staphylococcal bacteria compared with aortic valves.

Thoracic endovascular aortic repair after iatrogenic aortic dissection and false lumen stent grafting.

Iatrogenic aortic dissections are a severe complication after thoracic endovascular aortic repair, and treatment guidelines do not exist. Herein, we report a patient who experienced an iatrogenic type B aortic dissection during elective thoracic endovascular aortic repair and suggest an interventional treatment option.

Renal function interferes with copeptin in prediction of major adverse cardiac events in patients undergoing vascular surgery.

OBJECTIVE: Precise perioperative risk stratification is important in vascular surgery patients who are at high risk for major adverse cardiovascular events (MACE) peri- and postoperatively. In clinical practice, the patient's perioperative risk is predicted by various indicators, e.g. revised cardiac index (RCRI) or modifications thereof. Patients suffering from chronic kidney disease (CKD) are stratified into a higher risk category. We hypothesized that Copeptin as a novel biomarker for hemodynamic stress could help to improve the prediction of perioperative cardiovascular events in patients undergoing vascular surgery including patients with chronic kidney disease. METHODS: 477 consecutive patients undergoing abdominal aortic, peripheral arterial or carotid surgery from June 2007 to October 2012 were prospectively enrolled. Primary endpoint was 30-day postoperative major adverse cardiovascular events (MACE). RESULTS: 41 patients reached the primary endpoint, including 63.4% aortic, 26.8% carotid, and 9.8% peripheral surgeries. Linear regression analysis showed that RCRI (P< .001), pre- (P< .001), postoperative Copeptin (P< .001) and Copeptin level change (P= .001) were associated with perioperative MACE, but CKD remained independently associated with MACE and Copeptin levels. Multivariate regression showed that increased Copeptin levels added risk predictive information to the RCRI (P= .003). Especially in the intermediate RCRI categories was Copeptin significantly associated with the occurrence of MACE. (P< .05 Kruskal Wallis test). Subdivision of the study cohort into CKD stages revealed that preoperative Copeptin was significantly associated with CKD stages (P< .0001) and preoperative Copeptin measurements could not predict MACE in patients with more severe CKD stages. CONCLUSION: Preoperative Copeptin loses its risk predictive potential for perioperative MACE in patients with chronic kidney disease undergoing vascular surgery.