ABSTRACT
Orthotopic aortic transplantation using the sleeve technique reduces injury to the aorta with failure rate of only 10-20%. The time to anastomose the aorta in mice using the sleeve method was short and easy averaging 20 min, permitting studies of iso/allo grafts. The following article describes the aortic transplantation procedure used in our laboratory. The mice were anesthetized with a mixture of 1.5% volume isoflurane and 100% oxygen through a face mask. At this point, the segment of the aorta between the renal arteries and its bifurcation was separated from the vena cava, freely prepared and clampedat the proximal and distal segments with a single silk suture. Prior to the removal of the aorta, a saline solution containing heparin was injected into the inferior vena cava. Then the aorta was cut between the clamps and a saline heparin solution was used to flush the lumen. The sleeve technique with monofilament sutures was used in order to transplant the abdominal aorta in the orthotopic position.
Subject(s)
Aorta, Abdominal/transplantation , Vena Cava, Inferior/surgery , Animals , Aorta, Abdominal/surgery , Disease Models, Animal , MiceABSTRACT
BACKGROUND: The CX3C chemokine receptor CX3CR1 is expressed on monocytes as well as tissue resident cells, such as smooth muscle cells (SMCs). Its role in atherosclerotic tissue remodeling of the aorta after transplantation has not been investigated. METHODS: We here have orthotopically transplanted infrarenal Cx3cr1-/-Apoe-/- and Cx3cr1+/+Apoe-/- aortic segments into Apoe-/-mice, as well as Apoe-/- aortic segments into Cx3cr1-/-Apoe-/- mice. The intimal plaque size and cellular plaque composition of the transplanted aortic segment were analyzed after four weeks of atherogenic diet. RESULTS: Transplantation of Cx3cr-/-Apoe-/- aortic segments into Apoe-/- mice resulted in reduced atherosclerotic plaque formation compared to plaque size in Apoe-/- or Cx3cr1-/-Apoe-/- mice after transplantation of Apoe-/- aortas. This reduction in lesion formation was associated with reduced numbers of lesional SMCs but not macrophages within the transplanted Cx3cr-/- Apoe-/- aortic segment. No differences in frequencies of proliferating and apoptotic cells could be observed. CONCLUSION: These results indicate that CX3CR1 on resident vessel wall cells plays a key role in atherosclerotic plaque formation in transplanted aortic grafts. Targeting of vascular CX3CL1/CX3CR1 may therefore be explored as a therapeutic option in vascular transplantation procedures.
Subject(s)
Aorta/transplantation , Apolipoproteins E/genetics , Atherosclerosis/therapy , Receptors, Chemokine/genetics , Animals , Aorta/physiopathology , Atherosclerosis/genetics , Atherosclerosis/physiopathology , CX3C Chemokine Receptor 1 , Chemokines, CX3C , Disease Models, Animal , Humans , Macrophages , Mice , Mice, Knockout , Monocytes , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/physiopathology , Plaque, Atherosclerotic/therapy , Tunica Intima/metabolism , Tunica Intima/physiopathologyABSTRACT
Platelets play an important role in the pathogenesis of vascular remodelling after injury. Junctional adhesion molecule A (JAM-A) was recently described to regulate platelet activation. Specific deletion of JAM-A from platelets resulted in increased reactivity and in accelerated progression of atherosclerosis. The aim of this study was to investigate the specific contribution of platelet-derived JAM-A to neointima formation after vascular injury. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e (apoe-/- ) background underwent wire-induced injury of the common carotid artery. Ex vivo imaging by two-photon microscopy revealed increased platelet coverage at the site of injury in trJAM-A-deficient mice. Cell recruitment assays showed increased adhesion of monocytic cells to activated JAM-A-deficient platelets than to control platelets. Inhibition of αM ß2 or GPIbα, but not of CD62P, suppressed those differences. Up to 4 weeks after wire injury, intimal neoplasia and neointimal cellular content were analysed. Neointimal lesion area was increased in trJAM-A-/- apoe-/- mice and the lesions showed an increased macrophage accumulation and proliferating smooth muscle cells compared with trJAM-A+/+ apoe-/- littermates 2 weeks, but not 4 weeks after injury. Re-endothelialization was decreased in trJAM-A-/- apoe-/- mice compared with controls 2 weeks after injury, yet it was complete in both groups after 4 weeks. A platelet gain of function by deletion of JAM-A accelerates neointima formation only during earlier phases after vascular injury, through an increased recruitment of mononuclear cells. Thus, the contribution of platelets might become less important when neointima formation progresses to later stages.
Subject(s)
Apolipoproteins E/genetics , Atherosclerosis/genetics , Carotid Artery Injuries/genetics , Cell Adhesion Molecules/genetics , Hyperlipidemias/genetics , Neointima/genetics , Receptors, Cell Surface/genetics , Animals , Apolipoproteins E/deficiency , Atherosclerosis/complications , Atherosclerosis/metabolism , Atherosclerosis/pathology , Blood Platelets/metabolism , Blood Platelets/pathology , Carotid Arteries/metabolism , Carotid Arteries/pathology , Carotid Artery Injuries/complications , Carotid Artery Injuries/metabolism , Carotid Artery Injuries/pathology , Cell Adhesion , Cell Adhesion Molecules/deficiency , Female , Gene Expression Regulation , Hyperlipidemias/complications , Hyperlipidemias/metabolism , Hyperlipidemias/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Monocytes/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Neointima/complications , Neointima/metabolism , Neointima/pathology , Receptors, Cell Surface/deficiency , Signal Transduction , Vascular Remodeling/geneticsABSTRACT
PURPOSE: To evaluate changes in aortoiliac volume after endovascular repair (EVAR) for abdominal aortic aneurysm (AAA) in patients with and without endoleaks. MATERIALS AND METHODS: We retrospectively analyzed 137 patients who underwent EVAR for AAA. We manually measured the aortoiliac volume on pre-procedural baseline CT angiograms (CTAs) and post-procedural follow-up CTAs. All post-procedural CTAs were evaluated for the presence of endoleaks. Follow-up examinations were grouped into five time points relative to the date of the EVAR procedure and mean aortoiliac volume changes from the baseline were calculated. RESULTS: In 51 patients (37.2%), endoleaks were detected during follow-up. In patients without any endoleaks, mean aortoiliac volume decreased by 21.1% from the pre-interventional baseline examination to the last follow-up examination. In patients with any endoleak during follow-up aortoiliac volume increased by 12.2% and in patients with only transient, post-procedural endoleaks (nâ=â18), aortoiliac volume decreased by 13.4% over the same time period. CONCLUSION: After EVAR for AAA, aortoiliac volume on CT angiography decreases by approximately 20% over time in the absence of endoleaks and increases in the presence of endoleaks. Transient post-procedural endoleaks, however, do not influence long-term volume regression.
Subject(s)
Aortic Aneurysm, Abdominal/complications , Endoleak/immunology , Endovascular Procedures/methods , Aged , Female , Humans , Male , Retrospective Studies , Treatment OutcomeABSTRACT
OBJECTIVE: Extracorporeal circulation is routinely used in thoracoabdominal aortic aneurysm repair to preserve blood perfusion. Despite this protective measure, acute and chronic kidney disorders can develop. Therefore, the aim of this study was to establish a new large-animal model to assess the efficacy of selective renal perfusion (SRP) with extracorporeal circulation in a setting of thoracoabdominal aortic aneurysm repair. METHODS: Eighteen pigs underwent a thoracolaparotomy, during with the aorta and renal arteries were exposed. The animals were divided into three cohorts of six pigs each: cohort I--control; cohort II--thoracic aortic clamping with distal aortic perfusion (DAP) using a roller pump; and cohort III--thoracic aortic clamping with DAP plus SRP. Kidney metabolism, kidney injury, and red blood cell damage were measured by oxygen extraction ratio (O2ER), neutrophil gelatinase-associated lipocalin, a marker for acute kidney damage, and serum free hemoglobin. RESULTS: With normal mean arterial blood pressures, flow rates in the renal arteries during perfusion decreased to 75% (group II) with DAP and to 50% (group III) with SRP compared with the control animals (group I; P = .0279 for I vs II; P = .0002 for I vs III). Microcirculation, measured by microspheres, did not differ significantly among the groups. In contrast, O2ER (P = .0021 for I vs III) and neutrophil gelatinase-associated lipocalin (P = .0083 for I vs III) levels were significantly increased in group III, whereas free hemoglobin was increased in groups II and III (P = .0406 for I vs II; P = .0018 for I vs III). CONCLUSIONS: SRP with a roller pump induces kidney tubule injury. Thus, distal aortic and SRP in our model does not provide adequate kidney protection. Furthermore, the perfusion system provokes red blood cell damage with increased free hemoglobin. Hence, the SRP perfusion technique should be revised and tested.
Subject(s)
Acute Kidney Injury/etiology , Aorta, Thoracic/surgery , Extracorporeal Circulation/adverse effects , Kidney Tubules/injuries , Perfusion/adverse effects , Renal Artery/physiopathology , Renal Circulation , Vascular Surgical Procedures/adverse effects , Acute Kidney Injury/blood , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , Animals , Aorta, Thoracic/physiopathology , Arterial Pressure , Biomarkers/blood , Blood Flow Velocity , Constriction , Disease Models, Animal , Extracorporeal Circulation/methods , Female , Hemoglobins/metabolism , Hemolysis , Kidney Tubules/blood supply , Kidney Tubules/metabolism , Kidney Tubules/pathology , Lipocalins/blood , Microcirculation , Oxygen/blood , Perfusion/methods , Swine , Time Factors , Vascular Surgical Procedures/methodsABSTRACT
Arteriovenous fistula (AVF) is the common vascular access type for a hemodialysis patient. Its failure is due to neointimal hyperplasia. Vitamin K antagonists are given to lower thrombosis tendency, but have side effects that enhance arterial calcifications. Here, we investigated the effects of vitamin K antagonists and vitamin K2 (K2) treatment on neointimal hyperplasia development and calcification in rats and in arterialized human veins. AVF was generated in female rats while chronic kidney disease (CKD) was induced using an adenine-enriched diet. Arterialization, CKD, and vitamin K antagonists all significantly enhanced venous neointimal hyperplasia. K2 treatment, additional to vitamin K antagonists, significantly reduced neointimal hyperplasia in arterialized veins in healthy rats but not in rats with CKD. Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD. K2 significantly enhanced matrix Gla protein carboxylation in control rats and rats with CKD. Arterialized human vein samples contained inactive matrix Gla protein at calcification and neointimal hyperplasia sites, indicating local vitamin K deficiency. Thus, vitamin K antagonists have detrimental effects on AVF remodeling, whereas K2 reduced neointimal hyperplasia and calcification indicating vasoprotective effects. Hence, K2 administration may be useful to prevent neointimal hyperplasia and calcification in arterialized veins
Subject(s)
Anticoagulants/pharmacology , Arteriovenous Shunt, Surgical/adverse effects , Femoral Vein/drug effects , Neointima , Renal Insufficiency, Chronic/drug therapy , Vascular Calcification/prevention & control , Vascular Remodeling/drug effects , Vitamin K 2/pharmacology , Vitamin K/antagonists & inhibitors , Aged , Aged, 80 and over , Animals , Disease Models, Animal , Female , Femoral Vein/metabolism , Femoral Vein/pathology , Femoral Vein/surgery , Humans , Hyperplasia , Male , Middle Aged , Rats, Sprague-Dawley , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology , Vascular Calcification/etiology , Vascular Calcification/metabolism , Vascular Calcification/pathology , Vitamin K/metabolismABSTRACT
OBJECTIVE: Extracorporeal circulation (ECC) is regularly applied to maintain organ perfusion during major aortic and cardiovascular surgery. During thoracoabdominal aortic repair, ECC-driven selective visceral arterial perfusion (SVP) results in changed microcirculatory perfusion (shift from the muscularis toward the mucosal small intestinal layer) in conjunction with macrohemodynamic hypoperfusion. The underlying mechanism, however, is unclear. Therefore, the aim of this study was to assess in a porcine model whether ECC itself or the hypoperfusion induced by SVP is responsible for the mucosal/muscular shift in the small intestinal wall. METHODS: A thoracoabdominal aortic approach was performed in 15 healthy pigs divided equally into three groups: group I, control; group II, thoracic aortic cross-clamping with distal aortic perfusion; and group III, thoracic aortic cross-clamping with distal aortic perfusion and SVP. Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurement and fluorescent microspheres. In addition, markers for metabolism and intestinal ischemia-reperfusion injury were determined. RESULTS: ECC with a roller pump induced a significant switch from the muscularis and mucosal layer of the small intestine, even with adequate macrocirculation (mucosal/muscular perfusion ratio: group I vs II, P = .005; group I vs III, P = .0018). Furthermore, the oxygen extraction ratio increased significantly in groups II (>30%) and III (>40%) in the beginning of the ECC compared with the control (group I vs II, P = .0037; group I vs III, P = .0062). Lactate concentrations and pH values did not differ between groups I and II; but group III demonstrated a significant shifting toward a lactate-associated acidosis (lactate: group I vs III, P = .0031; pH: group I vs III, P = .0001). CONCLUSIONS: We demonstrated a significant shifting between the small intestinal gut wall layers induced by roller pump-driven ECC. The shift occurs independently of macrohemodynamics, with a significant effect on aerobic metabolism in the gut wall. Consequently, an optimal intestinal perfusion cannot be guaranteed by a roller pump; therefore, perfusion techniques need to be optimized.
Subject(s)
Extracorporeal Circulation , Intestinal Mucosa/blood supply , Intestine, Small/blood supply , Microcirculation , Muscle, Smooth/blood supply , Splanchnic Circulation , Acidosis, Lactic/blood , Acidosis, Lactic/etiology , Acidosis, Lactic/physiopathology , Animals , Aorta, Thoracic/physiopathology , Aorta, Thoracic/surgery , Blood Flow Velocity , Constriction , Extracorporeal Circulation/adverse effects , Female , Hydrogen-Ion Concentration , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Lactic Acid/blood , Mesenteric Ischemia/blood , Mesenteric Ischemia/etiology , Mesenteric Ischemia/physiopathology , Models, Animal , Muscle, Smooth/metabolism , Regional Blood Flow , Reperfusion Injury/blood , Reperfusion Injury/etiology , Reperfusion Injury/physiopathology , Swine , Time FactorsABSTRACT
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 αIIbß3-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 αIIbß3 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 αIIbß3 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.
Subject(s)
Aorta/metabolism , Aortic Diseases/etiology , Atherosclerosis/etiology , Blood Platelets/metabolism , Carotid Artery Diseases/etiology , Cell Adhesion Molecules/deficiency , Hyperlipidemias/complications , Platelet Aggregation , Receptors, Cell Surface/deficiency , Animals , Aorta/pathology , Aortic Diseases/blood , Aortic Diseases/genetics , Aortic Diseases/pathology , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Atherosclerosis/blood , Atherosclerosis/genetics , Atherosclerosis/pathology , Carotid Artery Diseases/blood , Carotid Artery Diseases/genetics , Carotid Artery Diseases/pathology , Cell Adhesion , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/genetics , Cells, Cultured , Chemotaxis, Leukocyte , Diet, High-Fat , Disease Models, Animal , Disease Progression , Female , Genotype , Humans , Hyperlipidemias/blood , Hyperlipidemias/genetics , Inflammation Mediators/metabolism , Leukocytes/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Plaque, Atherosclerotic , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Receptors, Cell Surface/blood , Receptors, Cell Surface/genetics , Thrombosis/blood , Thrombosis/etiology , Time Factors , src-Family Kinases/metabolismABSTRACT
INTRODUCTION: The aim of our study was to develop a reproducible murine model of elastase-induced aneurysm formation combined with aortic transplantation. METHODS: Adult male mice (n = 6-9 per group) underwent infrarenal, orthotopic transplantation of the aorta treated with elastase or left untreated. Subsequently, both groups of mice were monitored by ultrasound until 7 weeks after grafting. RESULTS: Mice receiving an elastase-pretreated aorta developed aneurysms and exhibited a significantly increased diastolic vessel diameter compared to control grafted mice at 7 week after surgery (1.11 ± 0.10 mm vs. 0.75 ± 0.03 mm; p ≤ 0,001). Histopathological examination revealed disruption of medial elastin, an increase in collagen content and smooth muscle cells, and neointima formation in aneurysm grafts. CONCLUSIONS: We developed a reproducible murine model of elastase-induced aneurysm combined with aortic transplantation. This model may be suitable to investigate aneurysm-specific inflammatory processes and for use in gene-targeted animals.
Subject(s)
Aneurysm/surgery , Aorta/transplantation , Pancreatic Elastase/therapeutic use , Aneurysm/drug therapy , Animals , Male , Mice , Mice, Inbred C57BLABSTRACT
Neointimal hyperplasia is one the primary causes of stenosis in arterialized veins that are of great importance in arterial coronary bypass surgery, in peripheral arterial bypass surgery as well as in arteriovenous fistulas.(1-5) The experimental procedure of vein graft interposition in the common carotid artery by using the cuff-technique has been applied in several research projects to examine the aetiology of neointimal hyperplasia and therapeutic options to address it. (6-8) The cuff prevents vessel anastomotic remodeling and induces turbulence within the graft and thereby the development of neointimal hyperplasia. Using the superior caval vein graft is an established small-animal model for venous arterialization experiment.(9-11) This current protocol refers to an established jugular vein graft interposition technique first described by Zou et al., (9) as well as others.(12-14) Nevertheless, these cited small animal protocols are complicated. To simplify the procedure and to minimize the number of experimental animals needed, a detailed operation protocol by video training is presented. This video should help the novice surgeon to learn both the cuff-technique and the vein graft interposition. Hereby, the right external jugular vein was grafted in cuff-technique in the common carotid artery of 21 female Sprague Dawley rats categorized in three equal groups that were sacrificed on day 21, 42 and 84, respectively. Notably, no donor animals were needed, because auto-transplantations were performed. The survival rate was 100 % at the time point of sacrifice. In addition, the graft patency rate was 60 % for the first 10 operated animals and 82 % for the remaining 11 animals. The blood flow at the time of sacrifice was 8±3 ml/min. In conclusion, this surgical protocol considerably simplifies, optimizes and standardizes this complicated procedure. It gives novice surgeons easy, step-by-step instruction, explaining possible pitfalls, thereby helping them to gain expertise fast and avoid useless sacrifice of experimental animals.
Subject(s)
Carotid Artery, Common/surgery , Jugular Veins/transplantation , Microsurgery/methods , Animals , Female , Rats , Rats, Sprague-DawleyABSTRACT
INTRODUCTION: Despite its presumed effectiveness and clinical use, the physiology of selective visceral perfusion combined with distal aortic perfusion during open thoracoabdominal aortic surgery has not been characterized. Thus, the aim of this study was to establish a translatable model of thoracic aortic-clamping to assess the effect of selective visceral perfusion with added distal aortic perfusion on local intestinal macrohemodynamics and microhemodynamics, intestinal histopathology, and markers of inflammation and intestinal damage. METHODS: A thoracolaparotomy was performed in 15 pigs, and the aorta was exposed, including the origins of celiac trunk and superior mesenteric artery. The animals were divided into three cohorts: control (I), thoracic aortic cross-clamping (II), and thoracic aortic cross-clamping with selective visceral perfusion plus distal aortic perfusion using extracorporeal circulation (III). Macrocirculatory and microcirculatory blood flow was assessed by transit time ultrasound volume flow measurements and fluorescent microspheres. Intestinal ischemia-reperfusion injury was determined by the analysis of perioperative intestinal fatty acid-binding protein (IFABP) and interleukin-8 (IL-8) levels and correlated with histopathologic changes. RESULTS: Severe intestinal tissue injury and an inflammatory response were observed in cohort II compared with cohort III for IL-8 (38.2 vs 3.56 pg/mL; P = .04). The procedure in cohort III resulted in a flow and pressure-associated intestinal hypoperfusion compared with cohort I in the superior mesenteric artery (mean blood pressure, 24.1 ± 10.4 vs 67.2 ± 7.4 mm Hg; P < .0001; mean flow rates: 353.3 ± 133.8 vs 961.7 ± 310.8 mL/min; P < .0001). This was paralleled in cohort III vs cohort I by a significant mucosal injury (IFABP, 713 ± 307.1 vs 170 ± 115.4 pg/mL; P = .014) despite a profound recruitment of intestinal microcirculation (338% ± 206.7% vs 135% ± 123.7%; P = .05). CONCLUSIONS: This study reports a novel large-animal model of thoracic aortic cross-clamping that allows the study of visceral perfusion strategies. However, we demonstrated with IL-8 and IFABP measurements that thoracoabdominal aortic aneurysm surgery with selective visceral perfusion and distal aortic perfusion is superior to the clamp-and-sew technique, even though small intestinal tissue damage cannot be completely avoided by selective visceral perfusion and distal aortic perfusion. In any case, this model seems to be a platform to evaluate and optimize measures for gut wall protection.
Subject(s)
Aorta, Thoracic/surgery , Intestines/blood supply , Reperfusion Injury/prevention & control , Vascular Surgical Procedures/methods , Viscera/blood supply , Animals , Aortic Aneurysm, Thoracic/surgery , Blood Flow Velocity , Constriction , Extracorporeal Circulation , Fatty Acid-Binding Proteins/analysis , Female , Hemodynamics , Interleukin-8/analysis , Models, Animal , Regional Blood Flow , SwineABSTRACT
INTRODUCTION: As yet, murine aortic grafts have merely been monitored histopathologically. The aim of our study was to examine how these grafts can be monitored in vivo and non-invasively by using high-resolution ultrasound microimaging to evaluate function and morphology. A further aim was to prove if this in vivo monitoring can be correlated to immunohistological data that indicates graft integrity. METHODS: Murine infrarenal aortic isografts were orthotopically transplanted into 14 female mice (C57BL/6-Background) whereas a group of sham-operated animals (n = 10) served as controls. To assess the graft morphology and hemodynamics, we examined the mice over a post-operative period of 8 weeks with a sophisticated ultrasound system (Vevo 770, Visual Sonics). RESULTS: The non-invasive graft monitoring was feasible in all transplanted mice. We could demonstrate a regular post-transplant graft function and morphology, such as anterior/posterior wall displacement and wall thickness. Mild alterations of anterior wall motion dynamics could only be observed at the site of distal graft anastomosis (8 weeks after grafting (transplant vs. sham mice: 0.02 mm ± 0.01 vs. 0.03 mm ± 0.01, p<0.05). However, the integrity of the entire graft wall could be confirmed by histopathological evaluation of the grafts. CONCLUSIONS: With regard to graft patency, function and morphology, high resolution ultrasound microimaging has proven to be a valuable tool for longitudinal, non-invasive, in vivo graft monitoring in this murine aortic transplantation model. Consequently, this experimental animal model provides an excellent basis for molecular and pharmacological studies using genetically engineered mice.
Subject(s)
Aorta/diagnostic imaging , Aorta/transplantation , Echocardiography/methods , Image Enhancement/methods , Information Storage and Retrieval/methods , Surgery, Computer-Assisted/methods , Animals , Female , Mice , Mice, Inbred C57BL , Monitoring, Intraoperative/methods , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
PURPOSE: To evaluate a cardiovascular magnetic resonance imaging (MRI) technique which allows the longitudinal analysis of cardiovascular remodeling in a rodent femoral arteriovenous fistula (AVF) model by means of a clinical scanner. MATERIALS AND METHODS: Eight rats underwent femoral AVF surgery and four rats served as controls. Vascular and cardiac morphology as well as cardiac function was assessed from Week 3 to 12 using contrast-enhanced, time-resolved magnetic resonance angiography (MRA) and cardiac MRI (cine gradient-echo sequence) at 3 T in one imaging session. RESULTS: Arteriovenous surgery resulted in progressive venous dilation and a subsequent cardiac adaptation. This procedure led to downstream vasodilation of the iliac vein and inferior vena cava of 179% and 188%, respectively (3 weeks). To accommodate the increased returning blood volume, cardiac output (CO) increased significantly (P=.014; 6 weeks). This was caused by increased end-diastolic volume (EDV), stroke volume (SV) and heart rate (HR) consistent with an increased volume load. A continuous increase in heart weight peaked at 12 weeks. This increase combined with a distinct end-diastolic left ventricular dilation implied eccentric hypertrophy. CONCLUSION: Small rodent MRI is feasible and clearly depicts fistula maturation and cardiac alterations. This technique proved to be a valuable tool for longitudinal in vivo monitoring in this model, which strongly resembles clinical findings in hemodialysis patients.
Subject(s)
Arteriovenous Shunt, Surgical , Heart Ventricles/anatomy & histology , Magnetic Resonance Imaging/methods , Ventricular Remodeling/physiology , Animals , Female , Prognosis , Rats , Rats, Sprague-Dawley , Treatment OutcomeABSTRACT
PURPOSE: The aim of this study was to evaluate cardiovascular remodeling after arteriovenous fistula (AVF) surgery and to characterize the effect of chronic kidney disease (CKD) in a rodent femoral AVF model. METHODS: Sixteen rats (8 healthy; 8 CKD) underwent femoral AVF surgery; 4 animals served as controls. AVF and cardiac morphology as well as function were assessed during the fistula maturation process (until day 84 after surgery) using magnetic resonance imaging and histopathological analyses. RESULTS: Histopathological analysis revealed that a glomerular and interstitial nephropathy caused CKD. In healthy and CKD animals, AVF surgery resulted in progressive downstream vein dilation and a subsequent cardiac adaptation. This vein dilation during maturation was less in CKD rats during the early postoperative course (day 21: p=0.0475) and similar thereafter until day 84. The dilation was accompanied by an aggravation of neointimal hyperplasia (NIH) and calcification in AVFs of CKD rats. The chronic volume overload resulted in both groups in a significantly increased end-diastolic volume (healthy rats: p=0.0087; CKD rats: p=0.0333). Simultaneously, cardiac output increased 195% in healthy and 244% in uremic rats, which was caused by both a significantly increased stroke volume and heart rate. The left ventricular mass rose in AVF animals and was increased at the end of the study period, indicating a distinct cardiac hypertrophy. CONCLUSION: Our rat model showed typical cardiovascular features of the AVF maturation process, which strongly resemble clinical findings in patients. Uremia caused inferior dilation in the early phase after surgery and an exacerbation of NIH. This model should help to identify the cellular and molecular mechanisms that contribute to AVF failure.
Subject(s)
Arteriovenous Shunt, Surgical/adverse effects , Cardiomegaly/etiology , Femoral Artery/surgery , Femoral Vein/surgery , Hemodynamics , Kidney Diseases/therapy , Uremia/therapy , Vascular Calcification/etiology , Adenine , Animals , Biomarkers/blood , Cardiac Output , Cardiomegaly/blood , Cardiomegaly/pathology , Cardiomegaly/physiopathology , Chronic Disease , Dilatation, Pathologic , Disease Models, Animal , Female , Femoral Artery/pathology , Femoral Vein/pathology , Heart Rate , Hyperplasia , Kidney Diseases/blood , Kidney Diseases/etiology , Kidney Diseases/physiopathology , Magnetic Resonance Imaging , Nephrectomy , Rats , Rats, Sprague-Dawley , Time Factors , Uremia/blood , Uremia/etiology , Uremia/physiopathology , Vascular Calcification/pathology , Vascular Calcification/physiopathologyABSTRACT
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.
Subject(s)
Arteriovenous Shunt, Surgical , Calcinosis/etiology , Calcinosis/physiopathology , Femoral Artery/physiopathology , Femoral Vein/physiopathology , Kidney Diseases/complications , Adenine/adverse effects , Animals , Blood Pressure/physiology , Chronic Disease , Constriction, Pathologic , Disease Models, Animal , Female , Femoral Artery/diagnostic imaging , Femoral Artery/surgery , Femoral Vein/diagnostic imaging , Femoral Vein/surgery , Kidney Diseases/chemically induced , Rats , Rats, Sprague-Dawley , Regional Blood Flow/physiology , UltrasonographyABSTRACT
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.
Subject(s)
Acute Kidney Injury/etiology , Acute Kidney Injury/urine , Cardiopulmonary Bypass/adverse effects , Acetylglucosaminidase/urine , Aged , Aorta , Biomarkers/urine , Creatinine/blood , Creatinine/urine , Female , Hemolysis , Humans , Kidney , Male , Middle Aged , Postoperative Period , Plastic Surgery Procedures/adverse effects , Vascular Surgical Procedures/adverse effectsABSTRACT
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.
Subject(s)
Aorta, Thoracic/surgery , Aortic Aneurysm, Thoracic/surgery , Aortic Dissection/surgery , Brain Ischemia/prevention & control , Spinal Cord Ischemia/prevention & control , Vascular Surgical Procedures/adverse effects , Adolescent , Adult , Aged , Aortic Dissection/mortality , Aortic Dissection/pathology , Aortic Aneurysm, Thoracic/mortality , Aortic Aneurysm, Thoracic/pathology , Brain Ischemia/diagnosis , Brain Ischemia/etiology , Electroencephalography , Evoked Potentials, Motor , Female , Humans , Laparotomy/adverse effects , Male , Middle Aged , Monitoring, Intraoperative/methods , Perfusion , Prospective Studies , Spinal Cord Ischemia/diagnosis , Spinal Cord Ischemia/etiology , Thoracotomy/adverse effects , Time Factors , Treatment Outcome , Ultrasonography, Doppler, Transcranial , Vascular Surgical Procedures/mortality , Young AdultABSTRACT
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 McNemar's test and Wilcoxon's 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.
Subject(s)
Angiography, Digital Subtraction , Arterial Occlusive Diseases/pathology , Foot/blood supply , Imaging, Three-Dimensional , Ischemia/pathology , Magnetic Resonance Angiography/methods , Ultrasonography, Doppler, Duplex , Aged , Aged, 80 and over , Arterial Occlusive Diseases/complications , Arterial Occlusive Diseases/diagnostic imaging , Arteries/pathology , Constriction, Pathologic , Contrast Media , Critical Illness , Female , Humans , Image Enhancement , Image Interpretation, Computer-Assisted , Ischemia/diagnostic imaging , Ischemia/etiology , Male , Meglumine/analogs & derivatives , Middle Aged , Organometallic Compounds , Predictive Value of Tests , Prospective Studies , Severity of Illness Index , Time Factors , Vascular PatencyABSTRACT
BACKGROUND: Neointimal hyperplasia is considered to be the major cause of arteriovenous fistula (AVF) failure, resulting in vein wall thickening, stenosis and, ultimately, occlusion. Ultrasound (US) has been shown to be effective for detecting these morphological changes in patients. The aim of this study was to develop an experimental AVF model in the rat that shows typical features of fistula maturation and allows longitudinal monitoring of fistula veins by high-resolution ultrasound. METHODS: AVFs were created by a handsewn end-to-side anastomosis between the femoral vein and the femoral artery in 15 rats. A group of sham-operated animals (n = 3) served as controls. Time-related functional and morphological AVF characteristics were assessed up to 12 weeks using ultrasound (15-MHz transducer) and were correlated to histopathological changes. RESULTS: All rats survived surgery, and the patency rate was 93%. US showed a 2-fold increase in the fistula vein diameter and mean flow velocity as well as a 4-fold increase in the intima-media thickness without significant luminal loss. The afferent femoral artery exhibited no change in intima-media thickness and only minimal adaptive increases in diameter and flow velocity. Histological evaluation confirmed these observations. CONCLUSIONS: Our AVF model in the rat demonstrates maturation effects in fistula veins similar to typical clinical findings in haemodialysis patients. Noninvasive ultrasound proved to be a valuable tool for longitudinal in vivo monitoring of the fistulas in this rodent model.
Subject(s)
Arteriovenous Shunt, Surgical , Femoral Vein/diagnostic imaging , Femoral Vein/surgery , Animals , Arteriovenous Shunt, Surgical/methods , Female , Models, Animal , Rats , Rats, Sprague-Dawley , UltrasonographyABSTRACT
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.