Thomas A. Koeppel

Hemolysis is associated with acute kidney injury during major aortic surgery

Hemolysis is an inevitable side effect of cardiopulmonary bypass resulting in increased plasma free hemoglobin that may impair tissue perfusion by scavenging nitric oxide. Acute kidney injury after on-pump cardiovascular surgery arises from a number of causes and severely affects patient morbidity and mortality. Here, we studied the effect of acute hemolysis on renal injury in 35 patients undergoing on-pump surgical repair of thoracic and thoracoabdominal aortic aneurysms of whom 19 experienced acute kidney injury. During surgery, plasma free hemoglobin increased, as did urinary excretion of the tubular injury marker N-acetyl-beta-D-glucosaminidase, in patients with and without acute kidney injury, reaching peak levels at 2 h and 15 min, respectively, after reperfusion. Furthermore, plasma free hemoglobin was independently and significantly correlated with the urine biomarker, which, in turn, was independently and significantly associated with the later postoperative increase in serum creatinine. Importantly, peak plasma free hemoglobin and urine N-acetyl-beta-D-glucosaminidase concentrations had significant predictive value for postoperative acute kidney injury. Thus, we found an association between increased plasma free hemoglobin and renal injury casting new light on the pathophysiology of acute kidney injury. Therefore, free hemoglobin is a new therapeutic target to improve clinical outcome after on-pump cardiovascular surgery.

microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans

Small non-coding microRNAs (miRNAs) have emerged to play critical roles in cardiovascular biology. Monocytes critically drive atherosclerotic lesion formation, and can be subdivided into a classical and non-classical subset. Here we scrutinised the miRNA signature of human classical and non-classical monocytes, and compared miRNA expression profiles of atherosclerotic plaques from human carotid arteries and healthy arteries. We identified miRNAs to be differentially regulated with a two-fold or higher difference between classical and non-classical monocyte subsets. Moreover, comparing miRNA expression in atherosclerotic plaques compared to healthy arteries, we observed several miRNAs to be aberrantly expressed, with the majority of miRNAs displaying a two-fold or higher increase in plaques and only few miRNAs being decreased. To elucidate similarities in miRNA signatures between monocyte subsets and atherosclerotic plaque, expression of miRNAs highly abundant in monocytes and plaque tissues were compared. Several miRNAs were found in atherosclerotic plaques but not in healthy vessels or either monocyte subset. However, we could identify miRNAs co-expressed in plaque tissue and classical monocytes (miR-99b, miR-152), or non-classical monocytes (miR-422a), or in both monocytes subsets. We thus unravelled candidate miRNAs, which may facilitate our understanding of monocyte recruitment and fate during atherosclerosis, and may serve as therapeutic targets for treating inflammatory vascular diseases.

Visceral Injury and Systemic Inflammation in Patients Undergoing Extracorporeal Circulation During Aortic Surgery

Objectives:Visceral injury and inflammation are evaluated in patients undergoing extracorporeal circulation (ECC) either with distal aortic perfusion (DAP) during thoracic aortic aneurysm (TAA) repair or DAP and selective organ perfusion (DAP and SP) during thoracoabdominal aortic aneurysm (TAAA) repair. Summary Background Data:Visceral hypoperfusion and subsequent visceral injury, mainly to the gut, have been implicated as central events in the development of systemic inflammatory response syndrome (SIRS) and organ dysfunction after major surgery. Patients undergoing DAP or DAP and SP are exposed to artificial visceral perfusion, potentially leading to the development of intestinal injury and systemic inflammation. Methods:To assess visceral injury arteriovenous differences of fatty acid binding proteins were measured for the gut (I-FABP and L-FABP) and left kidney (L-FABP) along with systemic plasma concentrations. Systemic ALT was used as liver injury marker. Plasma IL-6 and IL-8 denoted systemic inflammation. Results:During ECC systemic I-FABP and L-FABP levels increased in both groups, representing intestinal injury. Significantly elevated levels of I-FABP (P < 0.001) and L-FABP (P < 0.001) were found in the DAP and SP group, after ECC was stopped and normal circulation restored. Liver and renal tubular cell injury was not detected. Significant increases in systemic IL-6 and IL-8 values were measured only in patients undergoing DAP and SP. Additionally, the extent of intestinal injury correlated positively with systemic inflammation. Conclusions:This study shows the development of intestinal mucosal injury during ECC with DAP or DAP and SP, indicative of insufficient intestinal perfusion. Intestinal injury was associated with a systemic pro-inflammatory response.

Simvastatin Reduces Endotoxin-Induced Acute Lung Injury by Decreasing Neutrophil Recruitment and Radical Formation

Introduction Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. Methods C57Bl/6 mice were exposed to aerosolized LPS (500 µg/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. Results Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. Conclusion Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI.

Surgical correction of failed thoracic endovascular aortic repair

OBJECTIVE The number of thoracic aortic endovascular procedures is increasing rapidly, and the clinical outcome largely depends on the underlying aortic pathology. When primary stent grafting is unsuccessful, secondary endovascular solutions are most often feasible. However, in recurrent endovascular failure without further minimally invasive options, conservative treatments or conversion to open surgery are the only remaining therapeutic strategies. METHODS In our experience, 106 patients received thoracic aortic endovascular treatment. Five of these patients and three from other centers underwent conversion to open repair because of 4 type Ia endoleaks (3 thoracic aortic aneurysms, 1 traumatic rupture), 2 retrograde type A dissections, 1 type Ib endoleak with contained rupture, and 1 secondary false aneurysm rupture due to stent graft migration. The latter four were surgical emergencies; the other four were urgent or elective procedures. Three patients underwent supracoronary arch replacement through sternotomy. One patient had arch and proximal descending aortic replacement, three had hemiarch and descending aortic replacement, and one had descending aortic replacement through left thoracotomy. Five stent grafts were totally removed, and three endografts were left in situ. All conversions were performed according to a protocol including total extracorporeal circulation (n = 7) or left heart bypass (n = 1), cerebrospinal fluid drainage and monitoring motor-evoked potentials, transcranial Doppler, and electroencephalography. RESULTS All patients survived the surgical procedure. Six patients had an uneventful postoperative course, whereas necrotic cholecystitis developed in one patient who required cholecystectomy and prolonged intensive care stay. One polytrauma patient died from secondary rupture due to prosthesis infection 24 days after stent graft explantation. No stroke, paraplegia, renal failure, or other major complication occurred. With a mean follow-up of 14 months (range, 4-71 months), seven patients are alive without any sign of recurrent aortic problems. CONCLUSION Failure of thoracic endovascular aortic repair comprises a new aortic pathology. Secondary endovascular treatment is feasible in most patients; however, some patients will require open surgery to repair failures of thoracic endovascular aortic treatment. These procedures constitute a large surgical trauma and require an extensive protocol, including extracorporeal circulation, neuromonitoring, and adjunctive modalities to provide organ protection. We recommend that these procedures be performed in centers with experience and the infrastructure to offer these protective measures.

Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

Rationale: Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin &agr;IIb&bgr;3-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity. Objective: This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. Methods and Results: JAM-A–deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On &agr;IIb&bgr;3 ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e (apoe–/–) background were fed a high-fat diet. After ⩽12 weeks of diet, trJAM-A–/–apoe–/– mice showed increased aortic plaque formation when compared with trJAM-A+/+ apoe–/– controls, and these differences were most evident at early time points. At 2 weeks, the plaques of the trJAM-A–/– apoe–/– animals revealed increased macrophage, T cell, and smooth muscle cell content. Interestingly, plasma levels of chemokines CC chemokine ligand 5 and CXC-chemokine ligand 4 were increased in the trJAM-A–/– apoe–/–mice, and JAM-A–deficient platelets showed increased binding to monocytes and neutrophils. Whole-blood perfusion experiments and intravital microscopy revealed increased recruitment of platelets and monocytes to the inflamed endothelium in blood of trJAM-A–/– apoe–/–mice. Notably, these proinflammatory effects of JAM-A–deficient platelets could be abolished by the inhibition of &agr;IIb&bgr;3 signaling in vitro. Conclusions: Deletion of JAM-A causes a gain-of-function in platelets, with lower activation thresholds and increased inflammatory activities. This leads to an increase of plaque formation, particularly in early stages of the disease.

Vascular dysfunction of brachial artery after transradial access for coronary catheterization: impact of smoking and catheter changes.

OBJECTIVES The aim of this study was to investigate the effect of diagnostic transradial catheterization on vascular function of upstream brachial artery (BA). BACKGROUND The transradial access has recently become an alternative to transfemoral cardiac catheterization. A potential caveat of this approach lies in possible sustained physical radial artery (RA) damage. METHODS We studied 30 patients (age 61 +/- 11 years) undergoing diagnostic coronary angiography with the transradial access (5-F). Endothelium-dependent, flow-mediated vasodilation (FMD) was measured before and at 6 and 24 h after catheterization of the right-sided RA and BA with high-resolution ultrasound. The left-sided RA served as a control. RESULTS Transradial catheterization significantly decreased FMD in the RA (overall mean 8.5 +/- 1.7% to 4.3 +/- 1.6%) and the upstream BA (overall mean 4.4 +/- 1.6% to 2.9 +/- 1.6%) at 6 h. Subgroup analysis showed that FMD of both arteries at 6 h was significantly lower in active smokers and that it only remained impaired at 24 h in this group, whereas nonsmoker FMD fully recovered. The degree of BA but not RA FMD dysfunction was related to the number of catheters used, with no change after 2 catheters, 1.9 +/- 1.2% decrease (6 h) and recovery (24 h) after 3 catheters, and 3.9 +/- 1.2% decrease (6 h) without recovery (24 h) after 4 to 5 catheters. The RA dysfunction correlated with the baseline diameter. The contralateral control RA exhibited no change ruling out systemic effects. CONCLUSIONS Transradial catheterization not only leads to dysfunction of the RA but also the upstream BA, which is more severe and sustained in smokers and with increasing numbers of catheters.

Chronic kidney disease aggravates arteriovenous fistula damage in rats.

Neointimal hyperplasia (NIH) and impaired dilatation are important contributors to arteriovenous fistula (AVF) failure. It is unclear whether chronic kidney disease (CKD) itself causes adverse remodeling in arterialized veins. Here we determined if CKD specifically triggers adverse effects on vascular remodeling and assessed whether these changes affect the function of AVFs. For this purpose, we used rats on a normal diet or on an adenine-rich diet to induce CKD and created a fistula between the right femoral artery and vein. Fistula maturation was followed noninvasively by high-resolution ultrasound (US), and groups of rats were killed on 42 and 84 days after surgery for histological and immunohistochemical analyses of the AVFs and contralateral femoral vessels. In vivo US and ex vivo morphometric analyses confirmed a significant increase in NIH in the AVFs of both groups with CKD compared to those receiving a normal diet. Furthermore, we found using histological evaluation of the fistula veins in the rats with CKD that the media shrank and their calcification increased significantly. Afferent artery dilatation was significantly impaired in CKD and the downstream fistula vein had delayed dilation after surgery. These changes were accompanied by significantly increased peak systolic velocity at the site of the anastomosis, implying stenosis. Thus, CKD triggers adverse effects on vascular remodeling in AVFs, all of which contribute to anatomical and/or functional stenosis.

Brain and spinal cord protection during simultaneous aortic arch and thoracoabdominal aneurysm repair

OBJECTIVE We assessed the surgical and neurological outcome of patients undergoing simultaneous repair of aortic arch and descending thoracic aortic aneurysms (DTAA) or thoracoabdominal aortic aneurysms (TAAA) via left thoracotomy or thoracolaparotomy. METHODS During a 6-year period, we performed 32 procedures in 23 male and 9 female patients with DTAA or TAAA with concomitant aortic arch aneurysms. The mean age of the patients was 50.9 years (range, 18-75 years). Twenty-two patients suffered from DTAA, 4 had type-I TAAA, and 6 had type-II TAAA. The entire aortic arch was involved in 12 patients and the distal hemi-arch in 20 patients. The mean diameter of the aneurysms was 6 cm (range, 4.9-7.6 cm). All patients were operated on according to the protocol with cerebrospinal fluid drainage, distal aortic and selective organ perfusion, as well as antegrade brain perfusion. Neuromonitoring was performed by means of motor evoked potentials (MEPs), transcranial Doppler (TCD), and electroencephalography (EEG). RESULTS All patients survived the surgical procedure and 30-day mortality did not occur. At the end of the procedure, all patients had adequate MEPs, TCD, and EEG. One patient died 47 days after operation due to gastrointestinal bleeding and therapy-resistant coagulopathy. Major postoperative complications like paraplegia or paraparesis, renal failure, and myocardial infarction were not encountered. One patient had a stroke but neurological deficits were irrelevant. Mean preoperative creatinine level was 125 mmol/L, which peaked to a mean maximal level of 130 and returned to 92 mmol/L at discharge. Other complications included bleeding requiring surgical intervention (n = 4), arrhythmia (n = 1), pneumonia (n = 5), and respiratory distress syndrome (n = 2). At a median follow-up of 38 months, all but 1 patient was alive and free of re-intervention. CONCLUSION Single-stage repair of aortic arch and concomitant thoracic and thoracoabdominal aortic aneurysms via left-sided thoracotomy or thoraco-laparotomy yields excellent short- and midterm outcomes. Monitoring of cerebral and spinal cord function contributes to improved neurologic outcome.

Unmasking pedal arteries in patients with critical ischemia using time-resolved contrast-enhanced 3D MRA

OBJECTIVE To test the diagnostic relevance of fast Gadobenate dimeglumine (Gd-BOPTA) enhanced, time-resolved, three-dimensional magnetic resonance angiography (t3D MRA) of distal calf and pedal vasculature in critical limb ischemia in a prospective comparison with conventional selective digital subtraction angiography (DSA) and high-resolution duplex ultrasound (US) scan. METHODS From April 2007 to June 2008, 34 feet of 29 consecutive patients suffering from limb-threatening ischemia underwent diagnostic US scan, DSA, and t3D MRA before treatment. The investigations took place within 3 days. A t3D MRA was performed using a 3 Tesla whole-body magnetic resonance (MR) system with an eight-element phased-array coil. Image quality and diagnostic findings were subjectively analyzed by two radiologists and one vascular surgeon. Each distal calf and foot was divided into six arterial segments for DSA and t3D MRA, and four segments were investigated by US scan. Patency or occlusion was studied with all the techniques, whereby DSA and t3D MRA were additionally evaluated in patients having greater or less than 50% stenosis. Finally, images were visually assessed by the three observers by applying a six-point grading scale. The acquired data was statistically analyzed using McNemars test and Wilcoxons matched-pairs signed-rank sum test. The P values of less than an alpha level of .05 were considered to be statistically significant. RESULTS We achieved MRA images of diagnostic quality in all patients. Significantly more patent pedal arteries were identified by applying t3D MRA than DSA (P < .001) and US scan (P < .02). For estimating the degree of stenosis, no technique proved to be superior (P > .28). Overall image quality was rated best for t3D MRA. Additionally, potential bypass target vessels could be clearly discriminated from pedal veins due to the temporal resolution. CONCLUSION In our prospective study, t3D MRA has been proven to be superior to DSA and US scan in pedal vasculature imaging in critical limb ischemia. This is a valuable, noninvasive method for detecting potential pedal bypass target arteries.