Abdominal Aortic Aneurysm Dissection Research Articles

Lysyl hydroxylase 1 (LH1) deficiency promotes angiotensin II (Ang II)-induced dissecting abdominal aortic aneurysm.

Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention.Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels.Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.

Iatrogenic pulmonary fat embolism after surgery in a patient with fatty liver

Introduction. Fat embolism refers to the presence of fat globules in the lung parenchyma and its peripheral circulation. Obstruction of the lung vessels by fat emboli can lead to acute cor pulmonale when the compensatory capabilities of the pulmonary vasculature are exceeded. Case report. We presented a case of a 78-year old man who suffered a dissection of abdominal aortic aneurysm. Urgent surgical procedure was performed and aneurysm replaced with aortobifemoral bypass grafting using a Dacron graft. Despite the procedure the patient died the following day. The autopsy revealed that the cause of death was hypovolemic shock. There were no bone fractures (also no fractures of ribs and sternum from cardiopulmonary resuscitation) or injuries of the subcutaneous fat tissue or other organs (besides those from the surgery). However, additional autopsy findings included fatty liver change, small liver hemorrhages (confirmed microscopically), as well as a presence of fat droplets in the hepatic veins, as well as in the pulmonary vessels, i.e. pulmonary fat embolism [confirmed with hematoxylin/ eosin (H/E), and Sudan III staining], which could be the contributing cause of death. Conclusion. The presented case indicates that pulmonary (or even systemic) fat embolism should be considered as the possible iatrogenic cause of unexpected and unexplained death in the cases where elective surgical procedures were performed in patients with fatty liver change. Pathologists must be aware of this possibility, since it is not easily recognized on routine H/E staining, and some of the special staining technique should be applied.

Early pathological characterization of murine dissecting abdominal aortic aneurysms.

We report here on the early pathology of a well-established murine model of dissecting abdominal aortic aneurysms (AAAs). Continuous infusion of angiotensin II (AngII) into apolipoprotein E-deficient mice induces the formation of aortic dissection and expansion at some point after implantation of miniosmotic pumps containing AngII. While this model has been studied extensively at a chronic stage, we investigated the early pathology of dissecting AAA formation at multiple scales. Using high-frequency ultrasound, we screened 12-week-old male mice daily for initial formation of these aneurysmal lesions between days 3 and 10 post-implantation. We euthanized animals on the day of diagnosis of a dissecting AAA or at day 10 if no aneurysmal lesion developed. Aortic expansion and reduced vessel wall strain occurred in animals regardless of whether a dissecting AAA developed by day 10. The aortas of mice that did not develop dissecting AAAs showed intermediate changes in morphology and biomechanical properties. RNA sequencing and gene expression analysis revealed multiple proinflammatory and matrix remodeling genes to be upregulated in the suprarenal aorta of AngII-infused mice as compared to saline-infused controls. Histology and immunohistochemistry confirmed that extracellular matrix remodeling and inflammatory cell infiltration, notably neutrophils and macrophages, occurred in AngII-infused mice with and without dissecting AAAs but not saline-infused controls. Understanding early disease processes is a critical step forward in translating experimental results in cardiovascular disease research. This work advances our understanding of this well-established murine model with applications for improving early diagnosis and therapy of acute aortic syndrome in humans.

Systemic Upregulation of IL-10 (Interleukin-10) Using a Nonimmunogenic Vector Reduces Growth and Rate of Dissecting Abdominal Aortic Aneurysm

Objective- Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results- Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE-/- infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.1±10.8% (control) to 131.0±5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4+/CD25+/Foxp3 (forkhead box P3)+ regulatory T cells, with fewer CD8+/GZMB+ (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF-α (tumor necrosis factor-α), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions- Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.

Development and growth trends in angiotensin II-induced murine dissecting abdominal aortic aneurysms.

Abdominal aortic aneurysms are pathological dilations that can suddenly rupture, causing more than 15,000 deaths in the U.S. annually. Current treatment focuses on observation until an aneurysm's size warrants surgical intervention. Thus, there is a need for therapeutic intervention to inhibit growth of smaller aneurysms. An experimental aneurysm model that infuses angiotensin II into apolipoprotein E‐deficient mice is widely used to investigate underlying pathological mechanisms and potential therapeutics, but this model has two caveats: (1) aneurysms do not always form, and (2) aneurysm severity and growth is inconsistent among animals. Here we use high‐frequency ultrasound to collect data from angiotensin II‐induced aneurysms to develop prediction models of both aneurysm formation and growth. Baseline measurements of aortic diameter, volume/length, and strain were used with animal mass and age in a quadratic discriminant analysis and logistic regression to build two statistical models to predict disease status. Longitudinal ultrasound data were also acquired from mice with aneurysms to quantify aneurysm diameter, circumferential strain, blood flow velocity, aneurysm volume/length, and thrombus and open‐false lumen volumes over 28 days. Measurements taken at aneurysm diagnosis were used with branching artery information to produce a multiple linear regression model to predict final aneurysm volume/length. All three statistical models could be useful in future aneurysm therapeutic studies to better delineate the effects of preventative and suppressive treatments from normal variations in the angiotensin II aneurysm model.

Loss of vascular smooth muscle cell autophagy exacerbates angiotensin II-associated aortic remodeling

ObjectiveThe pathophysiologic processes of abdominal aortic aneurysms (AAAs) and atherosclerosis often intersect. Given that anomalies in vascular smooth muscle cell (SMC) autophagy have been noted in models of atherosclerosis, we sought to evaluate the potential role that SMC autophagy may play in the initiation and progression of AAAs. MethodsStudies were conducted in ATG7flx/flxSM22α-Cretg/+ (SMC ATG7 knockout [SMC-ATG7-KO]) and ATG7WT/WT; SM22α-Cretg/+ (SMC ATG7 wild-type [SMC-ATG7-WT]) littermates that were continuously infused with angiotensin II (Ang II; 1.5 mg/kg/d) for up to 12 weeks. Mortality, morbidity, hemodynamics, and aortic remodeling were documented. ResultsDuring the 12-week observation window, all of the Ang II-treated SMC-ATG-WT mice (n = 6) survived, whereas 10 of the 19 Ang II-treated SMC-ATG-KO mice had died by week 7 (log-rank test, P < .001). Mean arterial pressure (128.07 ± 3.4 mm Hg for Ang II-treated SMC-ATG-KO vs 138.5 ± 5.87 mm Hg for Ang II-treated SMC-ATG-WT mice) and diastolic arterial pressure (109.7 ± 2.55 mm Hg for Ang II-treated SMC-ATG7-KO vs 119.4 ± 2.12 mm Hg for Ang II-treated SMC-ATG7-WT mice) were significantly different between the two groups (P < .01). Cardiac rupture, myocardial infarct, end-organ damage, pleural effusion, and venous distention were noted in Ang II-treated SMC-ATG7-KO but not in Ang II-treated SMC-ATG7-WT mice. Although the suprarenal aortic diameters of the Ang II-treated SMC-ATG7-KO group demonstrated a trending increase (at week 4, 1.26 ± 0.06 mm [n = 14] for Ang II-treated SMC-ATG-KO mice vs 1.09 ± 0.02 mm [n = 5] for Ang II-treated SMC-ATG-WT mice; P < .05), only 2 of the 19 developed abdominal aortic dissections. ConclusionsMice with SMC ATG7 deficiency that are chronically infused with Ang II do not tend to develop dissecting AAA but do exhibit adverse aortic remodeling and appreciable cardiac failure-associated mortality.

Vitamin D Receptor Activation Reduces Angiotensin-II-Induced Dissecting Abdominal Aortic Aneurysm in Apolipoprotein E-Knockout Mice.

Abdominal aortic aneurysm (AAA) is a vascular disorder characterized by chronic inflammation of the aortic wall. Low concentrations of vitamin D3 are associated with AAA development; however, the potential direct effect of vitamin D3 on AAA remains unknown. This study evaluates the effect of oral treatment with the vitamin D3 receptor (VDR) ligand, calcitriol, on dissecting AAA induced by angiotensin-II (Ang-II) infusion in apoE(-/-) mice. Oral treatment with calcitriol reduced Ang-II-induced dissecting AAA formation in apoE(-/-) mice, which was unrelated to systolic blood pressure or plasma cholesterol concentrations. Immunohistochemistry and reverse-transcription polymerase chain reaction analysis demonstrated a significant increase in macrophage infiltration, neovessel formation, matrix metalloproteinase-2 and matrix metalloproteinase-9, chemokine (CCL2 [(C-C motif) ligand 2], CCL5 [(C-C motif) ligand 5], and CXCL1 [(C-X-C motif) ligand 1]) and vascular endothelial growth factor expression in suprarenal aortic walls of apoE(-/-) mice infused with Ang-II, and all were significantly reduced by cotreatment with calcitriol. Phosphorylation of extracellular signal-regulated kinases 1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB was also decreased in the suprarenal aortas of apoE(-/-) mice cotreated with calcitriol. These effects were accompanied by a marked increase in VDR-retinoid X receptor (RXR) interaction in the aortas of calcitriol-treated mice. In vitro, VDR activation by calcitriol in human endothelial cells inhibited Ang-II-induced leukocyte-endothelial cell interactions, morphogenesis, and production of endothelial proinflammatory and angiogenic chemokines through VDR-RXR interactions, and knockdown of VDR or RXR abolished the inhibitory effects of calcitriol. VDR activation reduces dissecting AAA formation induced by Ang-II in apoE(-/-) mice and may constitute a novel therapeutic strategy to prevent AAA progression.

Good History and High Suspicion of Gastric Volvulus in Patient With Known Hiatal Hernia Are Key to Better Outcomes

Introduction: Gastric volvulus is relatively uncommon, potentially life-threatening entity that occurs when the stomach twists upon itself. We present a case with history of hiatal hernia that presented with Mesenteroaxial gastric volvulus. Mesenteroaxial gastric volvulus accounts for about one-third of the cases where stomach folds along its short axis from the lesser to greater curvature. Presentation of Case: A 79-year-old female with history of hiatal hernia, COPD, coronary artery disease and infrarenal abdominal aortic aneurysm (AAA) presented with epigastric pain, nausea and non-bilious/non-bloody vomiting. Reports having regular bowel movements. On exam: Temperature 98.3F, Blood Pressure 94/61, Heart Rate 82, Respiratory rate 22 and Oxygen saturation 93% on room air. Abdominal exam was significant for mild distention but otherwise soft and non-tender. Laboratory findings were notable for WBC 7.6 and Lactate 1.3. On bedside ultrasound was found to have severely dilated stomach and CT angiography of abdomen/pelvis was done to rule out dissection of AAA and further investigate ultrasound findings. It showed large hiatal hernia with gastroesophageal junction, pylorus and antrum above diaphragm and distended body of the stomach below suggestive of gastric volvulus (see image 1). She was managed with decompression with nasogastric tube and patient was kept NPO on IV fluids and IV protonix (PPI). Upper endoscopy (EGD) was performed and showed abnormal anatomical configuration of fundus and body of stomach (see image 2) were body was noted to loop up towards the diaphragm adjacent to the gastroesophageal junction and with great difficulty of intubating the pylorus. No evidence of torsion was seen. EGD finding were consistent with paraesophageal hernia type IV and mesenteroaxial gastric volvulus without signs of strangulation. Patient underwent laparoscopic paraesopphageal hernia and gastric volvulus repair and was doing well on postop clinic follow up. Conclusion: Gastric volvulus can range from a transient event, with mild symptoms of abdominal pain and vomiting to complete obstruction with ischemia and necrosis of the stomach. A good history and physical examination can provide the clues needed to make the presumptive diagnosis, which can then be confirmed with radiographic studies and EGD, ultimately leading to early surgical treatment which is essential to reduce the morbidity and mortality of gastric volvulus.Figure 1Figure 2Figure 3

The genetic architecture of non-syndromic thoracic aortic aneurysm

### Learning objectives Curriculum topic : Disease of the aorta and trauma to the aorta and heart Aortic aneurysm/dissection is a common cause of cardiovascular morbidity and mortality in the...

Incidence, severity, mortality, and confounding factors for dissecting AAA detection in angiotensin II-infused mice: a meta-analysis.

While angiotensin II-infused mice are the most popular model for preclinical aneurysm research, representative data on incidence, severity, and mortality of dissecting abdominal aortic aneurysms (AAAs) have never been established, and the influence of confounding factors is unknown. We performed a meta-analysis including 194 manuscripts representing 1679 saline-infused, 4729 non-treated angiotensin II-infused, and 4057 treated angiotensin II-infused mice. Incidence (60%) and mortality (20%) rates are reported overall as well as for grade I (22%), grade II (26%), grade III (29%), and grade IV (24%) aneurysms. Dissecting AAA incidence was significantly (P < 0.05) influenced by sex, age, genetic background, infusion time, and dose of angiotensin II. Mortality was influenced by sex, genetic background, and dose, but not by age or infusion time. Surprisingly, both incidence and mortality were significantly different (P < 0.05) when comparing angiotensin II-infused mice in descriptive studies (56% incidence and 19% mortality) with angiotensin II-infused mice that served as control animals in treatment studies designed to either enhance (35% incidence and 13% mortality) or reduce (73% incidence and 25% mortality) dissecting AAA formation. After stratification to account for confounding factors (selection bias), the observed effect was still present for incidence, but not for mortality. Possible underlying causes are detection bias (non-uniform definition for detection and quantification of dissecting AAA in mice) or publication bias (studies with negative results, related to incidence in the control group, not being published). Our data provide a new meta-analysis-based reference for incidence and mortality of dissecting AAA in angiotensin II-infused mice, and indicate that treatment studies using this mouse model should be interpreted with caution.

Management of hepatic artery aneurysms

Hepatic artery aneurysm (HAA) is a rare clinical entity that can lead to potentially life threatening complications. We reported our personal experience of 4 cases, in which we used different procedures. The first case had a pseudo-aneurysm involving the right hepatic artery. The second case had a pseudo-aneurysm, which was localized distal to the accidentally ligated right hepatic artery from the previous cholecystectomy operation. The third case had multiple aneurysms with accompanying dissecting abdominal aortic aneurysm. The fourth case had a pseudo-aneurysm originating from the proper hepatic artery. A covered stent was successfully placed in the case 1. In the second case, the right hepatic artery was ligated distal to the aneurysm. In the third case, vascular structures were not appropriate for vascular reconstruction, and a covered stent placement and embolization were unsuccessful. In the fourth case, ligation of the proper hepatic artery and cholecystectomy was performed. The third case with multiple aneurysms died from multi-organ failure due to sepsis. The remaining cases (case 1, 2, and 4) are disease free and alive. HAAs are more commonly observed clinical entities, and their treatment should be handled for each patient separately. Computerized tomography-Angiography and intraoperative Doppler ultrasound are useful radio-diagnostics for determination of aneurysm and planning the operative procedure (Fig. 5, Ref. 15).

Proton beam therapy for hepatocellular carcinoma with limited treatment options

The authors conducted a retrospective review to define the usefulness of proton beam therapy for patients who had hepatocellular carcinoma (HCC) with limited treatment options. Twenty-one patients with HCC for whom other treatment modalities either were contraindicative or were unfeasible because of coexisting diseases and unfavorable conditions received proton beam therapy. Four patients had renal failure, 2 patients had severe heart disease, 9 patients had severe cirrhosis, 1 patient had aplastic anemia, 1 patient had a dissecting abdominal aortic aneurysm before treatment, and 4 patients had bleeding tendency or unresectable tumors. Moreover, 2 of the latter 4 patients were allergic to iodine, and 2 other patients were unable to be catheterized for transcatheter arterial chemoembolization. Hepatic tumors were solitary in 14 patients and multiple in 7 patients, and the tumors ranged in greatest dimension from 25 mm to 100 mm (median, 40 mm). No patient had regional lymph node or distant metastasis. Total doses of 63 grays (Gy) to 84 Gy (median, 73 Gy) in 13 to 27 fractions (median, 18 fractions) were used for tumor treatments. All but 1 of the irradiated tumors were controlled at a median follow-up of 3.3 years. The objective response rate was 81%, and the primary site-control rate was 93% at 5 years. Eleven patients had intrahepatic recurrences, and 2 patients had distant metastases in the lungs. Four of 11 patients with intrahepatic recurrences received a second course of proton beam therapy, and all recurrent tumors were controlled. The overall and cause-specific survival rates were 62% and 82% at 2 years, respectively, and 33% and 67% at 5 years, respectively. Grade > or =3 therapy-related toxicities were not observed. Proton beam therapy was safe and effective for a variety of patients with HCC. The current results suggested that this method was tolerable and effective, even for patients with HCC who had limited treatment options.

Limited Dissection of Abdominal Aortic Aneurysm in a Patient with Multiple Myeloma

Dissection limited to the abdominal aorta contributes 4% of all aortic dissections, and inflammatory injury of the aortic media is one of factors associated with dissection. In multiple myeloma, leukocytoclastic vasculitis of the skin has been known. We describe limited dissection of an abdominal aortic aneurysm with dense lymphocyte infiltration in a 62-year-old man with multiple myeloma. Although it is unclear whether the lymphocyte infiltration in the aortic wall, which was denser than that of atherosclerotic aneurysm, was associated with multiple myeloma, the excessive aortic wall inflammation may have somewhat influenced aneurysm formation or aortic dissection.

False positive dissection of abdominal aortic aneurysm by color Doppler duplex ultrasonography.

False positive dissection of abdominal aortic aneurysm by color Doppler duplex ultrasonography.

Parenteral chlorpromazine and frusemide: safe and effective treatment for hypertensive emergencies.

Hypertensive emergencies present a difficult problem of management. Although many treatment regimens have been described over the years, their application has presented problems of adverse effects and all have required detailed and intensive supervision of patients. After favourable results obtained in a preliminary study using a combination of parenteral chlorpromazine and frusemide, a 5-year prospective study was conducted using this treatment to produce rapid reduction in blood pressure in patients with acute onset severe hypertension (blood pressure greater than 225/130 mmHg). The patients involved covered a wide range from 22 to 74 years (mean 47 years) and, on subsequent or previous investigation, were all considered to have essential hypertension. Twenty-seven patients were treated successfully with a single administration of the regimen. Two women required a second treatment before adequate control of blood pressure was achieved and 1 man died of extensive dissecting abdominal aortic aneurysm before the effects of the therapy could be fully assessed. The reduction in blood pressure was gradual but progressive over 4 hours and the pattern of response was uniform. No significant adverse effects related to the treatment were found. Only basic measurement of pulse and blood pressure was considered necessary and so this regimen of therapy is suitable for general use even when sophisticated monitoring facilities are not available and staff levels are limited.