Biomedical subjects

Gilbert R Upchurch

Publications and source records attributed to Gilbert R Upchurch.

At least 19 recordsLinked to original sources

PubMed2007

Challenges and opportunities in abdominal aortic aneurysm research.

Abdominal Aortic Aneurysms (AAAs) are associated with advanced age, male gender, cigarette smoking, atherosclerosis, hypertension, and genetic predisposition. Basic research studies have led to a better understanding of aneurysm disease over the past two decades. There has also been a growing appreciation that fundamental knowledge regarding the process of aneurysmal degeneration is still somewhat limited. Opportunities in research include: 1) the investigation of potential new mechanism-based pharmacologic interventions; 2) identify the genetic basis for an inherited predisposition; 3) develop and refine noninvasive approaches for the early detection; 4) examine potential novel surgical approaches and design new biomaterials; and 5) initiate and promote awareness programs for diagnosis and treatment of aortic aneurysms. The optimal approach to addressing these issues will require integrative, multidisciplinary research programs that involve basic scientists working in concert with vascular and cardiothoracic surgeons, as well as other clinical specialists with expertise in vascular disease.

Animals↗

PubMed2006

Differential regulation of the superoxide dismutase family in experimental aortic aneurysms and rat aortic explants.

OBJECTIVE: Oxidative stress has been implicated in abdominal aortic aneurysm pathogenesis. This study sought to characterize the relevance of superoxide dismutases (SOD), a family of reactive oxygen catalyzing metalloenzymes, including manganese SOD (MnSOD), copper-zinc SOD (CuZnSOD), and extracellular SOD (EcSOD), in a rodent aortic aneurysm model. METHODS: Male rat infrarenal abdominal aortas were perfused with either saline (control) or porcine pancreatic elastase (6 U/mL). Aortic diameter was measured and aortas harvested on post-operation days 1, 2, and 7 (N=5-6 per treatment group per day). MnSOD, CuZnSOD, EcSOD, catalase, MMP-2, MMP-9, and beta-actin expression in aortic tissue was determined by quantitative real-time PCR. MnSOD protein levels were measured using western immunoblotting and immunohistochemistry. In subsequent experiments, aimed at understanding the mechanism by which SOD is involved in AAA pathogenesis, rat aortic explants (RAEs) were incubated in media for 24 h in the presence of interleukin-1beta (IL-1beta, 2 ng/mL) and TEMPOL (SOD mimetic), catalase, or a combined SOD and catalase mimetic. Media MMP-2 and MMP-9 activity was determined by zymography. Data were analyzed by Student's t-tests and ANOVA. RESULTS: Elastase-perfused aortic diameters were significantly increased compared to control aortas by post-perfusion day 7 (P=0.016). MnSOD mRNA levels in elastase perfused aortas were 6.0 (P=0.05) and 7.5 times (P<0.01) greater than control aortas at post-perfusion days 1 and 2, respectively. EcSOD, CuZnSOD, catalase, and MMP-2 mRNA expression did not statistically vary between the two groups. MMP-9 expression was 3.5-fold higher in the elastase group on post-perfusion day 2 (P=0.04). Western immunoblotting confirmed MnSOD protein was up-regulated on day 4 in the elastase-perfused group compared to controls (P=0.02). Immunohistrochemistry demonstrated increased MnSOD staining in the elastase group on day 4. In RAE experiments, TEMPOL increased both MMP-9 and MMP-2 activity 2 (P=0.09) and 3-fold (P=0.05), respectively, whereas catalase and the combined SOD/catalase mimetic failed to increase MMP-2 or MMP-9 activity. CONCLUSION: Experimental abdominal aortic aneurysm formation is associated with early increases in MnSOD expression and an increase in MMP-9 activity. Strategies aimed at inhibiting oxidative stress during AAA formation should focus on MnSOD.

Animals↗

PubMed2006

Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.

PURPOSE: This study was undertaken to characterize the contemporary surgical treatment of pediatric renovascular hypertension. METHODS: A retrospective analysis was conducted of the clinical data of 97 consecutive pediatric patients (39 girls, 58 boys), aged from 3 months to 17 years, who underwent operation at the University of Michigan from 1963 to 2006. All but one patient had refractory hypertension not responsive to contemporary medical therapy. Developmental renal artery stenoses accounted for 80% of the renal artery disease, with inflammatory and other ill-defined stenoses encountered less frequently. Splanchnic arterial occlusive lesions affected 24% and abdominal aortic coarctations, 33%. RESULTS: Primary renal artery operations were undertaken 132 times. Procedures included resection beyond the stenosis and implantation into the aorta in 49, renal artery in 7, or superior mesenteric artery in 3; aortorenal and iliorenal bypasses with vein or iliac artery grafts in 40; focal arterioplasty in 10; resection with reanastomosis in 4; operative dilation in 4; splenorenal bypass in 2; and primary nephrectomy in 13 when arterial reconstructions proved impossible. Bilateral renal operations were done in 34 children, and 17 underwent celiac or superior mesenteric arterial reconstructions, including 15 at the time of the renal operation. Thirty patients underwent abdominal aortic reconstructions with patch aortoplasty (n = 19) or thoracoabdominal bypass (n = 11). Twenty-five of the aortic procedures were performed coincidently with the renal operations. Thirty secondary renal artery procedures were done in 19 patients, including nine nephrectomies. Hypertension was cured in 68 children (70%), improved in 26 (27%), and was unchanged in three (3%). Follow-up averaged 4.2 years. No patients required dialysis, and there were no operative deaths. CONCLUSION: Contemporary surgical treatment of pediatric renovascular hypertension emphasizes direct aortic implantation of the normal renal artery beyond its stenosis and single-staged concomitant splanchnic and aortic reconstructions when necessary. Benefits accompany carefully executed operative procedures in 97% of these children.

Adolescent↗

PubMed2006

Acute limb ischemia associated with type B aortic dissection: clinical relevance and therapy.

BACKGROUND: The goal of the current study is to characterize the presentation, therapy, and outcomes of acute limb ischemia (ALI) associated with type B aortic dissection (AoD). METHODS: The prospective/retrospective International Registry for Acute Aortic Dissection (IRAD) database and a single institutional database were queried for all patients with type B AoD from 1996 to 2002. Univariate and multivariate statistics were used to delineate factors associated with morbidity and mortality outcomes. RESULTS: According to the IRAD data (n = 458), the mean age of patients was 64 years, and 70% were men. The overall mortality was 12%; of these, 6% had ALI. Pulse (3-fold) and neurologic deficits (5-fold) were more common in those with ALI (P < .001). Endovascular, but not surgical therapy, was more commonly performed in patients with ALI compared with those without ALI (31% vs 10%, P = .004). No difference in age, race, gender, or origin of dissection was observed. ALI was associated with acute renal failure (odds ratio [OR] = 2.7; 95% confidence interval [CI] 1.1-7.1; P = .048) and acute mesenteric ischemia/infarction (OR = 6.9; 95% CI 2.5-20; P < .001). Adjusting for patient characteristics, ALI was associated with death (3.5; 95% CI 1.1-10; P = .02). The single institution analysis revealed similar patient demographics and mortality in 93 AoD patients, of whom 28 had ALI. Aortic fenestration or aorto-iliac stenting was the primary therapy in 93%; surgical bypass was used in 7%. Limb salvage was 93% in those with ALI at a mean of 18 months follow-up. The number of organ systems with malperfusion was 2-fold higher at aortography than suspected preprocedure (P = .002). By stepwise regression modeling, mortality was greater in those not taking a beta-blocker (OR = 19; 95% CI 3.1-111; P = .001). CONCLUSIONS: ALI secondary to AoD is predictive of death and visceral ischemia. Endovascular therapy confers excellent limb salvage and allows diagnosis of unsuspected visceral ischemia.

Acute Disease↗

PubMed2006

Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model.

CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses. Deep vein thrombosis (DVT) resolution represents a specific inflammatory response whereby the thrombus must be dissolved for restoration of blood flow. Using a stasis model of DVT in the mouse, we investigated the role of CCR2 on DVT resolution. Genetic deletion of CCR2 (CCR2-/-) was associated with larger thrombi at early and later time points, increased thrombus collagen, fewer thrombus monocytes (F4/80), and significantly impaired neovascularization. IL-2 and IFN-gamma were significantly reduced in early CCR2-/- thrombi, whereas MCP-1 was significantly increased, and Th2 lymphokines were unaffected. Supplementation of CCR2-/- mice with IFN-gamma normalized early thrombus resolution without increasing monocyte influx. Neither Ab depletion of IFN-gamma nor genetic deletion of IFN-gamma impaired early DVT resolution. Early fibrinolysis was not impaired in CCR2-/- mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed. However, only MMP-9 activity was restored with administration of IFN-gamma. We conclude that an early CCR2-dependent Th1 lymphokine response predominates in normal DVT resolution, mediates this in part by MMP-9 activation, but is not solely dependent on IFN-gamma.

Animals↗

PubMed2006

Role and results of surgery in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD).

BACKGROUND: The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era. METHODS AND RESULTS: A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean+/-SD age, 60.6+/-15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49). CONCLUSIONS: The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.

Acute Disease↗

PubMed2006

Early increased MT1-MMP expression and late MMP-2 and MMP-9 activity during Angiotensin II induced aneurysm formation.

BACKGROUND: Angiotensin II (Ang II) is associated with a variety of cardiovascular diseases including aneurysm formation. The aim of this study was to evaluate the temporal changes in MT1-matrix metalloproteinase (MMP) and MMP-2 and -9 expression and activity during the course of Ang II induced experimental aneurysm formation. METHODS: Apolipoprotein E knockout mice (ApoE null) were infused with either 1000 ng/kg/min of Ang II (n = 20) or saline (n = 20) and then sacrificed at 7, 14, 21, and 28 days of infusion (n = 5/group/strain). Aortic diameters were measured by digital microscopy. Systolic blood pressure (SBP) was measured in the rodent tail. Suprarenal abdominal aortas had MT1-MMP mRNA levels and MMP-2 and MMP-9 mRNA levels and activity quantitated using reverse transcriptase-polymerase chain reaction (rt-PCR) and gelatin zymography, respectively. Statistical analyses included nonpaired t-test, Fisher's exact test, and analysis of variance (ANOVA). RESULTS: Aneurysms occurred in 40, 40, 20, and 80% of ApoE null-Ang II mice at 7, 14, 21, and 28 days, respectively. An early and significant rise in MT1-MMP mRNA occurred in ApoE null mice infused with Ang II mice, while there was no significant change in MMP-2 or MMP-9 mRNA levels. Total MMP-2 and MMP-9 activity increased over time in ApoE null mice infused with Ang II, peaking at 28 days (ANOVA, P < 0.01). SBP was significantly elevated by 7 days in ApoE null mice infused with Ang II compared to ApoE null mice infused with saline (123 +/- 16 versus 102 +/- 6 mm Hg, P < 0.05). CONCLUSIONS: Angiotensin II induces an early increase in aortic MT1-MMP expression with a subsequent increase in MMP-2 and MMP-9 activity. The process by which these changes cause aneurysm formation warrants further investigation.

Analysis of Variance↗

PubMed2006

Abdominal aortic aneurysm.

Most abdominal aortic aneurysms (AAAs) are asymptomatic, not detectable on physical examination, and silent until discovered during radiologic testing for other reasons. Tobacco use, hypertension, a family history of AAA, and male sex are clinical risk factors for the development of an aneurysm. Ultrasound, the preferred method of screening, is cost-effective in high-risk patients. Repair is indicated when the aneurysm becomes greater than 5.5 cm in diameter or grows more than 0.6 to 0.8 cm per year. Asymptomatic patients with an AAA should be medically optimized before repair, including institution of beta blockade. Symptomatic aneurysms present with back, abdominal, buttock, groin, testicular, or leg pain and require urgent surgical attention. Rupture of an AAA involves complete loss of aortic wall integrity and is a surgical emergency requiring immediate repair. The mortality rate approaches 90 percent if rupture occurs outside the hospital. Although open surgical repair has been performed safely, an endovascular approach is used in select patients if the aortic and iliac anatomy are amenable. Two large randomized controlled trials did not find any improvement in mortality rate or morbidity with this approach compared with conventional open surgical repair.

Aortic Aneurysm, Abdominal↗

PubMed2006

The nitric oxide donor DETA-NONOate decreases matrix metalloproteinase-9 expression and activity in rat aortic smooth muscle and abdominal aortic explants.

Our objective was to examine the role of an exogenous nitric oxide (NO) donor, DETA-NONOate (DETA), on matrix metalloproteinase (MMP)-9, MMP-2, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 expression and activity in interleukin (IL)-1beta-induced rat aortic smooth muscle cells (RA-SMCs) and rat aortic explants (RAEs). RA-SMCs were incubated with IL-1beta (2 ng/ml), an inflammatory cytokine known to induce MMP-9 expression, and increasing concentrations of DETA (0, 1.0, 10, 100 microM; n = 3/group) for 48 hr. RAEs were incubated with IL-1beta (2 ng/mL) and increasing concentrations of DETA (0, 5.0, 50, 100, and 500 microM; n = 3/group) for 48 hr. Media were collected and assayed for NO(x) by the Griess reaction and MMP-9 activity by zymography. Messenger RNA (mRNA) was extracted from cells and analyzed for MMP-9, MMP-2, and TIMP-1 expression levels by quantitative real-time reverse-transcriptase polymerase chain reaction. All statistical analyses were performed by analysis of variance. In RA-SMCs and RAEs, DETA administration resulted in a dose-dependent increase in media NOx concentration (RA-SCM p < 0.01, RAE p < 0.01) and a concurrent decrease in both MMP-9 expression (RASMC p = 0.01, RAE p = 0.01) and activity (RASMC p = 0.04, RAE p = 0.006). There were no significant differences seen in MMP-2 and TIMP-1 expression or activity in response to DETA exposure. DETA decreased IL-1beta-induced MMP-9 expression and activity in both RA-SMCs and RAEs in a dose-dependent fashion. In addition, DETA administration had no effect on MMP-2 or TIMP-1 expression or activity in vitro. These data suggest that NO donors may be beneficial in decreasing MMP-9 levels and might serve to inhibit MMP-9-dependent vessel wall remodeling seen during abdominal aortic aneurysm formation.

Animals↗

PubMed2006

Long-term results from a 12-year experience with endovascular therapy for thoracic aortic disease.

BACKGROUND: Endovascular approaches promise to revolutionize therapy for thoracic aortic disease. This study describes a long-term analysis of endovascular thoracic aortic repair. METHODS: Seventy-three patients (mean age, 67.4 years) underwent endovascular thoracic aortic repair from 1993 to 2005. Indications for intervention included aneurysm (38%), dissection (23%), or penetrating ulcer or pseudoaneurysm (34%). Rupture was present in 16 patients (22%). Seventy-one percent were considered high risk for open surgery for reasons of age or comorbid conditions. Treated segments included ascending aorta (n = 1), distal arch (n = 24), and proximal (n = 50) or distal (n = 55) descending aorta. The total descending thoracic aorta was covered in 31 patients. Procedural success was achieved in 96%. Devices were delivered by femoral (79%), retroperitoneal iliac (18%), or carotid (2.7%) exposure. Devices used included Excluder (n = 30), Talent (n = 23), Zenith (n = 3), AneuRx (n = 5), and custom-fabricated (n = 14). Follow-up was 100% complete. RESULTS: Thirty-day mortality was 5.5%. Significant morbidity included stroke (8.2%) and need for dialysis (4.1%). Although 3 patients had transient spinal cord ischemia (4.1%), none had permanent sequelae. Intervention for fusiform aneurysm was independently associated with a composite end point of 30-day mortality, need for dialysis, and stroke (p = 0.015). Eight patients (11%) had new or persistent endoleaks, and aortic reintervention was performed in 7 patients (9.6%). Mean survival for the entire cohort was 46.8 +/- 5.1 months. Intervention for penetrating ulcer or pseudoaneurysm (p = 0.045) was independently associated with long-term all-cause mortality. CONCLUSIONS: An endovascular approach produces acceptable results for a broad range of thoracic aortic disease. However, the potential for endoleak or need for reintervention mandates continued close follow-up to achieve satisfactory long-term results.

Aged↗

PubMed2006

A biologic basis for asymmetric growth in descending thoracic aortic aneurysms: a role for matrix metalloproteinase 9 and 2.

OBJECTIVE: This study was undertaken to define matrix metalloproteinase (MMP) expression in the anterior and posterior wall of descending thoracic aortic aneurysms (TAAs) and correlate it with specific computed tomography (CT) image sites within the descending thoracic aorta. METHODS: Serial CT images of patients with TAAs were compared with age- and gender-matched normal descending thoracic aortas at levels T4-T12. The mean circumference of the TAAs was 153 mm (n = 12) and 148 mm (n = 11) at T8 and T10, respectively, compared with 75 mm (n = 12) and 75 mm (n = 10) in controls (P < .001). Aortic tissue was collected from a separate set of eight patients undergoing descending TAA resection (processed < or =12 hours of excision) and six cadavers (processed < or =24 hours of death). Tissue collected between the intercostals arteries was defined as posterior wall, and directly opposite was the anterior wall. MMP-9 and MMP-2 messenger RNA (mRNA) extracted from aortic tissue was analyzed by quantitative real time polymerase chain reaction (PCR) and normalized to beta-actin. Immunohistochemistry was performed for MMP-9 and MMP-2. CT aortic measurements and MMP expression were compared by t tests and analysis of variance, respectively. RESULTS: The ratio of arc distance between the intercostals on the posterior wall to total aortic circumference was 0.14 in healthy controls compared with 0.08 in TAAs at vertebral level T8 (P = .001). At T10, the ratio was 0.15 in healthy controls compared with 0.11 in TAAs (P = .001). MMP-9 expression in TAAs was 4.3-fold higher in the anterior wall compared with the posterior wall (P = .03). Conversely, MMP-2 expression in TAAs was 3.2-fold higher in the posterior wall compared with the anterior wall (P = .008). MMP expression was not detected in control cadaver aortas. CONCLUSION: Anterior walls of expanding TAAs grow at a greater rate than the posterior wall, as determined from the lower ratio of intercostal arc distance to total circumference in TAAs. Differential MMP expression appears to be a biologic marker for asymmetric growth in the TAA wall. CLINICAL RELEVANCE: The pathogenesis of thoracic aortic aneurysms (TAAs) is poorly understood. Multiple lines of evidence suggest that matrix metalloproteinases (MMPs), a family of enzymes, are important in aneurysm development. Earlier experiments documented a regional variation of MMP-9 in stimulated rodent aortas, with production greater in the abdominal aorta compared with the thoracic aorta. The present study extends that observation and documents asymmetric aneurysm development in the TAA wall, with increased anterior wall growth in correlation to increased MMP-9 production. An improved understanding of the mechanisms by which MMP production is regulated is critical.

Aortic Aneurysm, Thoracic↗

PubMed2006

Experimental pulmonary embolism: effects of the thrombus and attenuation of pulmonary artery injury by low-molecular-weight heparin.

BACKGROUND: Pulmonary embolism (PE) is a life-threatening condition that is associated with the long-term sequelae of chronic pulmonary hypertension. Prior experimental work has suggested that post-PE inflammation is accompanied by pulmonary artery intimal hyperplasia. This study evaluated the effect of the thrombus and tested the hypothesis that thrombolytic, antiplatelet, and anticoagulant agents would decrease pulmonary injury. METHODS: Male Sprague-Dawley rats (n = 267) underwent laparotomy and temporary clip occlusion of the infrarenal inferior vena cava for the formation of endogenous thrombus or placement of an inert silicone "thrombus." Two days later, repeat laparotomy was performed, the clip removed, and the thrombus or silicone plug was embolized to the lungs. The endogenous thrombus group received normal saline, low-molecular-weight heparin (LMWH), tissue plasminogen activator (tPA), or a gIIB/IIIA antagonist (abciximab). Lung tissue was harvested at various times over 21 days and assayed for total collagen, monocyte chemoattractant protein-1 (MCP-1), interleukin-13 (IL-13), and transforming growth factor-beta (TGF-beta). Fixed sections were stained with trichrome for intimal hyperplasia determination and ED-1 monocytes and alpha-actin-positive staining. RESULTS: The overall survival for rats undergoing PE was 90%, was not affected by treatment, and 84% of all PE localized to the right pulmonary artery. The PE significantly reduced Pa(O2) in all groups. Compared with controls, the silicone emboli group had an increased level of IL-13 on day 1, an increased level of MCP-1 on day 4, and an increase in the levels of all inflammatory mediators on day 14 (P < .05). Accompanying these differences were greater pulmonary artery intimal hyperplasia at days 4 and 21 in the silicone group compared with controls (P < .05). LMWH treatment in the thrombus of PE rats significantly decreased IL-13 levels at all time points, whereas treatment with abciximab or tPA significantly increased IL-13 levels compared with controls. TGF-beta levels were significantly increased by LMWH at day 4 and 14, and abciximab was associated with lower TGF-beta at day 14. Only LMWH was associated with less pulmonary artery intimal hyperplasia at day 14 compared with controls and the other treatment groups. CONCLUSIONS: Persistent pulmonary artery distention by an inert material is sufficient to invoke significant inflammation and intimal hyperplasia independent of the thrombus itself. Compared with nontreated PE, LMWH is the only therapy associated with a significant reduction in late intimal hyperplasia and, with the exception of TGF-beta, lower profibrotic growth-factor production.

Angiography↗

PubMed2006

Aortic branch artery pseudoaneurysms accompanying aortic dissection. Part I. Pseudoaneurysm anatomy.

PURPOSE: Small areas of blood flow are sometimes seen within an otherwise thrombosed false lumen on computed tomography (CT) scans of intramural hematomas of the aorta. These are blood-filled spaces that, although they have no apparent communication with the true lumen, appear isodense with the aorta on contrast-enhanced CT scans. The purpose of this report is to describe angiographic and autopsy studies that establish the nature of this entity and describe the principal CT features distinguishing it from a penetrating ulcer. MATERIALS AND METHODS: Conventional angiographic and CT aorta findings in two cases with small collections of contrast material within an otherwise thrombosed false lumen of an aortic dissection are discussed. Also examined is another case with pathologic and histologic findings in addition to those of small collections of contrast material within an otherwise thrombosed false lumen of an aortic dissection, which illustrate the pathoanatomy of these lesions. RESULTS: Angiographic and necropsy evidence shows that some of these lesions represent branch artery pseudoaneurysms and, as such, are secondary to an intramural hematoma, not the primary cause of it. CONCLUSIONS: Difficulty in demonstrating communication between these collections of contrast material and the adjacent true lumen of the aorta on helical CT examinations and the characteristic location of these lesions along the nonpleural portion of the aortic circumference distinguish them from penetrating ulcers and should suggest the diagnosis of branch artery pseudoaneurysm. Demonstration of a branch artery originating from the contrast collection confirms the diagnosis. These branch artery pseudoaneurysms should be distinguished from penetrating atherosclerotic ulcers.

Aged, 80 and over↗

PubMed2006

Aortic branch artery pseudoaneurysms accompanying aortic dissection. Part II. Distinction from penetrating atherosclerotic ulcers.

PURPOSE: Small collections of contrast material are frequently seen within the otherwise thrombosed false lumen of an aortic dissection (AD). These collections can be divided into those without apparent communication with the aortic lumen (ie, pseudoaneurysms) and those with obvious communications (ie, ulcers). The present study was performed to test the hypotheses that pseudoaneurysms and ulcers differ in their distribution around the aorta and that the distribution of pseudoaneurysms is similar to that of small aortic branch arteries. MATERIALS AND METHODS: Computed tomography (CT) scans in 187 patients with AD and thrombosed false lumens showed 335 intramural contrast medium collections, including 128 pseudoaneurysms and 207 ulcers. CT scans in 40 control individuals without AD were reviewed to localize small aortic branch arteries. The angular distributions around the circumference of the aorta of pseudoaneurysms and ulcers and the branch artery origins were tabulated and compared. The frequency of detection of small branch arteries arising from the contrast material collections was noted. RESULTS: The angular distribution of pseudoaneurysms did not differ significantly from that of branch artery origins but did differ from that of ulcers. Pseudoaneurysms were found along the posterior, medial, and anterior walls of the aorta in the chest, sparing the lateral wall abutting the pleura. Ulcers tended to spare the arc containing branch artery origins. The composite distribution of ulcers and pseudoaneurysms appears uniform around the circumference of the aorta except at the T10-T12 levels. CONCLUSIONS: Branch artery pseudoaneurysms spare the pleural surface of the aorta and have nearly the same distribution around the circumference of the aorta as the origins of small aortic branch arteries. In contrast, ulcers tend to spare branch artery origins. The characteristic appearance and distribution of pseudoaneurysms on CT can help differentiate them from ulcers.

Adult↗

PubMed2006

Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization.

Early deep venous thrombosis (DVT) resolution is associated with neutrophil (PMN) influx. This study examined the role of PMNs in thrombus neovascularization and vein wall injury after DVT. A rat model of DVT by inferior vena cava (IVC) ligation was performed with control serum or rabbit anti-rat PMN serum administered perioperatively with sacrifice at 2 and 7 days. At 2 days, neutropenic rats had 1.6-fold larger thrombi (P = .04) and 1.4-fold higher femoral venous pressures by water manometry (P = .008) but no difference in thrombus neovascularization was observed. By 7 days, DVT sizes were similar, but vein wall injury persisted in the neutropenic rats with a 2.0-fold increase in vein wall stiffness by microtensiometry (P < .05), as well as a 1.2-fold increased thickness (P = .04). Collagen and profibrotic growth factors were significantly increased in neutropenic IVC at 7 days (all P < .05). Vein wall and intrathrombus uPA byWestern immunoblotting, and intrathrombus MMP-9 gelatinase activity were significantly less in neutropenic rats than controls (P < .001). Conversely, MMP-2 was significantly elevated in neutropenic IVC at 2 days after DVT. However, neutropenia induced 24 hours after DVT formation resulted in no significant increase in vein wall stiffness or collagen levels at 7 days, despite 1.4-fold larger thrombi (P < .05). These data suggest a critical early role for PMN in post DVT vein wall remodeling.

Animals↗

PubMed2006

Diffusion of Alexa Fluor 488-conjugated dendrimers in rat aortic tissue.

In this study, the distribution of labeled dendrimers in native and aneurysmal rat aortic tissue was examined. Adult male rats underwent infrarenal aorta perfusion with generation 5 (G5) acetylated Alexa Fluor 488-conjugated dendrimers for varying lengths of time. In a second set of experiments, rats underwent aortic elastase perfusion followed by aortic dendrimer perfusion 7 days later. Aortic diameters were measured prior to and postelastase perfusion, and again on the day of harvest. Aortas were harvested 0, 12, or 24 h postperfusion, fixed, and mounted. Native aortas were harvested and viewed as negative controls. Aortic cross-sections were viewed and imaged using confocal microscopy. Dendrimers were quantified (counts/high-powered field). Results were evaluated by repeated measures ANOVA and Student's t-test. We found that in native aortas, dendrimers penetrated the aortic wall in all groups. For all perfusion times, fewer dendrimers were present as time between dendrimer perfusion and aortic harvest increased. Longer perfusion times resulted in increased diffusion of dendrimers throughout the aortic wall. By 24 h, the majority of the dendrimers were through the wall. Dendrimers in aneurysmal aortas, on day 0 postdendrimer perfusion, diffused farther into the aortic wall than controls. In conclusion, this study documents labeled dendrimers delivered intra-arterially to native rat aortas in vivo, and the temporal diffusion of these molecules within the aortic wall. Increasing perfusion time and length of time prior to harvest resulted in continued dendrimer diffusion into the aortic wall. These preliminary data provide a novel mechanism whereby local inhibitory therapy may be delivered locally to aortic tissue.

Aneurysm↗

PubMed2006

Attenuation of experimental aortic aneurysm formation in P-selectin knockout mice.

The aim of this study was to determine the role of P-selectin, an adhesion molecule found on the surface of activated platelets and endothelial cells during experimental aortic aneurysm formation. Infrarenal abdominal aortas of C57 black wild-type (WT) mice and P-selectin knockout (PKO) mice were measured in situ and then perfused with porcine pancreatic elastase (0.332 U/mL). Whole blood was drawn from the tail artery on day 2 pre-perfusion to determine total and differential white blood cell (WBC) counts. On day 14 postperfusion, aortic diameters (AD) of WT mice (N = 19) and PKO mice (N = 9) were measured. An aortic aneurysm was defined as a 100% or greater increase in AD from pre-perfusion measurement. Immunohistochemistry, including H&E, trichrome and von Gieson staining, was performed on harvested aortic tissue. Statistical analysis was performed by t-test and Fisher's exact test. There were no significant differences in peripheral leukocyte counts at baseline between the two groups. WT mice had significantly larger AD compared to PKO mice at day 14 postperfusion (116 % vs. 38 %, P < 0.001). Aortic aneurysm penetrance was 52% in WT mice, while 0% (P = 0.01) of PKO mice formed aneurysms. On histologic examination, WT mouse aortas were associated with a significant inflammatory response and degradation of elastin and collagen fibers, while PKO mouse aortas lacked signs of inflammation or vessel wall injury. P-selectin deficiency attenuates aneurysm formation in the elastase aortic perfusion model. This was associated with a blunting of the inflammatory response and preserved vessel wall intergrity following elastase perfusion in the P-selectin knockout mice. Further investigation to elucidate the independent contributions of endothelial cell and platelet P-selectin in experimental aortic aneurysm formation is required.

Animals↗

PubMed2006

Female gender attenuates cytokine and chemokine expression and leukocyte recruitment in experimental rodent abdominal aortic aneurysms.

Female gender appears to be protective in the development of abdominal aortic aneurysms (AAAs). This study sought to identify gender differences in cytokine and chemokine expression in an experimental rodent AAA model. Male and female rodent aortas were perfused with either saline (control) or elastase to induce AAA formation. Aortic diameter was determined and aortic tissue was harvested on postperfusion days 4 and 7. Cytokine and chemokine gene expression was examined using focused gene arrays. Immunohistochemistry was used to quantify aortic leukocyte infiltration. Data were analyzed by Student's t-tests and ANOVA. Elastase-perfused female rodents developed significantly smaller aneurysms compared to males by day 7 (93 +/- 10% vs. 201 +/- 25%, P = 0.003). Elastase-perfused female aortas exhibited a fivefold decrease in expression of the BMP family and ligands of the TNF superfamily compared to males. In addition, the expression of members of the TGF beta and VEGF families were three to fourfold lower in female elastase-perfused aortas compared to males. Multiple members of the interleukin, CC chemokine receptor, and CC ligand families were detectable in only the male elastase-perfused aortas. Female elastase-perfused aortas demonstrated a corollary twofold lower neutrophil count (females: 17.5 +/- 1.1 PMN/HPF; males: 41 +/- 5.2 neutrophils/HPF, P = 0.01) and a 1.5-fold lower macrophage count (females: 12 +/- 1.1 macrophages/HPF; males: 17.5 +/- 1.1 macrophages/HPF, P = 0.003) compared to male elastase-perfused aortas. This study documents decreased expression of multiple cytokines and chemokines and diminished leukocyte trafficking in female rat aortas compared to male aortas following elastase perfusion. These genes may contribute to the gender disparity seen in AAA formation.

Animals↗